HK1159095A - Synthesis and novel salt forms of (r)-5-(e)-2-(pyrrolidin-3-ylvinyl)pyrimidine - Google Patents

Description

Synthesis and novel salt forms of (R) -5- ((E) -2- (pyrrolidin-3-ylvinyl) pyrimidine

Technical Field

The present invention relates to the stereospecific synthesis of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine, its salt forms and novel polymorphic forms of these salts. The invention also includes pharmaceutical compositions of these salt forms and methods of treating various conditions and disorders, including pain, inflammation, and conditions and diseases associated with dysfunction of the central and autonomic nervous systems.

Background

The compound (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine is a neuronal nicotinic acid receptor (NNR) agonist that is selective for the α 4 β 2 nicotinic acid subtype over other nicotinic acid subtypes, such as the α 7 subtype, ganglion and muscle subtypes. (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine provides therapeutic or prophylactic benefit for Central Nervous System (CNS) disorders and pain.

(R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine has the following structural formula:

commercial development of drug candidates such as (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine involves a number of steps, including development of cost effective synthetic methods suitable for large scale production processes. Commercial development also includes research on salt forms of drug substances that exhibit suitable purity, chemical stability, pharmaceutical properties, and characteristics that facilitate convenient handling and processing. Furthermore, the composition comprising the drug substance should have a sufficient shelf life. I.e., they should not exhibit changes in physicochemical characteristics such as, but not limited to, chemical composition, water content, density, hygroscopicity, and solubility when stored over an appreciable period of time. In addition, reproducible and constant plasma concentration profiles of the drug are also important factors when administered to a patient.

Solid salt forms are generally preferred for oral formulations due to their tendency to exhibit these properties in a preferential manner; and for basic drugs such as (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine, acid addition salts are generally the preferred salt forms. However, the different salt forms are significantly variable in their ability to influence these properties, and such properties cannot be predicted with reasonable accuracy. For example, some salts are solid at ambient temperature, while other salts are liquid, viscous oils or gums at ambient temperature. Furthermore, some salt forms are stable to heat and light under extreme conditions, while other salts are prone to decomposition under very mild conditions. Therefore, the development of acid addition salt forms of basic drugs for use in pharmaceutical compositions is a highly unpredictable process.

The synthesis of 5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine and its hemi-lactobionate, its separation into optical isomers by chiral chromatography and the galactarate salt of the isomer are disclosed in published WO 04/078752 and U.S. patent No. US7,098,331, each of which is incorporated by reference. However, stereospecific synthesis of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine suitable for large scale production is desirable. Furthermore, because the free base form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine is a viscous oil with limited water solubility and stability, there is a need for salt forms that exhibit improved properties including purity, stability, solubility and bioavailability. Preferred features of these novel salt forms include those which increase the convenience or efficiency with which the active ingredients and their formulations can be prepared and made into commercial products. Finally, there is a need for stable polymorphic forms of these salts that increase the convenience or efficiency with which the active ingredients and their formulations can be prepared into commercial products.

Summary of The Invention

One aspect of the present invention is an acid addition salt of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine. In some embodiments, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, 1-hydroxy-2-naphthoic acid, ketoglutaric acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-malic acid, hippuric acid, L-lactic acid, benzoic acid, succinic acid, adipic acid, acetic acid, nicotinic acid, propionic acid, orotic acid, 4-hydroxybenzoic acid, di-p-toluoyl-D-tartaric acid, di-p-anisoyl-D-tartaric acid, di-benzoyl-D-tartaric acid, 10-camphorsulfonic acid, camphoric acid, or phencyphos.

One aspect of the present invention is the maleate salt of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine. Another aspect of the present invention is the orotate salt of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine. Another aspect of the present invention is the citrate salt of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine.

One aspect of the present invention is (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate. Another aspect of the present invention is a crystalline polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate.

One aspect of the present invention is the stereospecific synthesis of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine. Other aspects and embodiments of the invention will be described herein. The scope of the present invention includes combinations of aspects, embodiments and preferred embodiments.

Brief Description of Drawings

Figure 1 is an XRPD pattern of an amorphous form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate.

Figure 2 is an XRPD pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form I.

Figure 3 is an XRPD pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate crystalline form II.

Figure 4 is an XRPD pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form III.

Figure 5 is an XRPD pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form IV.

Figure 6 is an XRPD pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-orotate form I.

Figure 7 is an XRPD pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate form I.

Figure 8 is an XRPD pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate form II.

Detailed Description

Definition of

The following definitions are meant to clarify, but not limit, the defined terms. Specific terms used herein should not be considered ambiguous if such terms are not specifically defined. But rather terms are used within their acceptable meaning.

The phrase "compound of the present invention" as used herein means (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or an acid addition salt thereof. The acid is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, 1-hydroxy-2-naphthoic acid, ketoglutaric acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-malic acid, hippuric acid, L-lactic acid, benzoic acid, succinic acid, adipic acid, acetic acid, nicotinic acid, propionic acid, orotic acid, 4-hydroxybenzoic acid, di-p-toluoyl-D-tartaric acid, di-p-anisoyl-D-tartaric acid, di-benzoyl-D-tartaric acid, 10-camphorsulfonic acid, camphoric acid or 2-hydroxy-5, 5-dimethyl-4-phenyl-1, 3, 2-dioxaphosphorinan-2-one (phencyphos). The phrase includes hydrate or solvate forms.

Furthermore, the term "compound" as used herein may be used to refer to the free base form or salt form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine, as will be apparent from context. One skilled in the art can distinguish this difference.

The term "pharmaceutically acceptable" as used herein means carriers, diluents, excipients or salt forms that are compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.

The term "pharmaceutical composition" as used herein means a compound of the invention, optionally mixed with one or more pharmaceutically acceptable carriers, diluents, excipients or adjuvants. The pharmaceutical compositions preferably exhibit a degree of stability to environmental conditions such that they are suitable for manufacturing and commercialization purposes.

The terms "effective amount", "therapeutic amount" or "effective dose" as used herein mean an amount of active ingredient sufficient to elicit the desired pharmacological or therapeutic effect, thereby resulting in effective prevention or treatment of the disorder. Prevention of a disorder may be manifested by delaying or preventing the progression of the disorder and delaying or preventing the onset of symptoms associated with the disorder. Treatment of the disorder may be manifested by reduction or elimination of symptoms, inhibition or reversal of the progression of the disorder, and any other benefit to the patient.

The effective dosage may vary depending on factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered. Typically, in order to be administered at an effective dose, it is desirable to administer the compound in an amount of less than 5mg/kg of patient body weight. The compounds are generally administered in amounts of from less than about 1mg/kg of patient body weight to less than about 100 μ g/kg of patient body weight, and sometimes from about 10 μ g/kg to less than 100 μ g/kg of patient body weight. The effective dosages above typically represent amounts administered as a single dose or in one or more doses over a 24 hour period. For human patients, an effective dose of the compound may require administration of the compound in an amount of at least about 1mg/24 hr/patient, but not more than about 1000mg/24 hr/patient and usually not more than about 500mg/24 hr/patient.

The phrase "substantially crystalline" as used herein includes greater than 20%, preferably greater than 30%, and more preferably greater than 40% (e.g., greater than any of 50, 60, 70, 80, or 90%) crystallization.

The term "stability" as used herein includes chemical stability and solid state stability, wherein the term "chemical stability" includes the possibility to store the salt of the invention in isolated form or in a formulated form under normal storage conditions, said formulated form being provided in admixture with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant, e.g. an oral dosage form, e.g. a tablet, capsule, etc., wherein the degree of chemical degradation or decomposition is insignificant, and the phrase "solid state stability" includes the possibility to store the salt of the invention in isolated solid form or in solid formulation under normal storage conditions, said solid formulated form being provided in admixture with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant, e.g. an oral dosage form, e.g. a tablet, capsule, etc., wherein the degree of solid state conversion is insignificant, e.g. crystallization, recrystallization, solid state phase transition, Hydration, dehydration, solvation or desolvation.

Examples of "normal storage conditions" include one or more of the following: temperature-80 ℃ to 50 ℃, preferably 0 ℃ to 40 ℃ and most preferably ambient temperature such as 15 ℃ to 30 ℃, pressure 0.1 to 2 bar, preferably atmospheric pressure, relative humidity 5 to 95%, preferably 10 to 60% and exposure to UV/visible light of 460lux or less for an extended period of time, such as greater than or equal to 6 months. Under such conditions, the salts of the invention may, if appropriate, be determined to be less than 5%, more preferably less than 2% and especially less than 1% of chemical degradation or decomposition or solid state conversion. It will be understood by those skilled in the art that the upper and lower limits of temperature, pressure and relative humidity set forth above represent extremes of normal storage conditions and that some combination of these extremes are not experienced during normal storage (e.g., 50 ℃ temperature and 0.1 bar pressure).

Compound (I)

One embodiment of the present invention includes (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine (formula I) or a pharmaceutically acceptable salt thereof.

Formula I

In one embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof, is substantially pure. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is substantially free of (S) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is present in an amount of about 75% by weight or more compared to (S) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine, preferably greater than 85% by weight, more preferably greater than 95% by weight, more preferably greater than 98% by weight and most preferably 99% by weight or more.

One embodiment of the present invention includes a process for the preparation of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof, said (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine comprising less than 25%, preferably less than 15%, more preferably less than 5%, even more preferably less than 2% and most preferably less than 1% by weight of (S) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine. Another embodiment of the present invention encompasses a process for the preparation of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof, said (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine comprising less than 25%, preferably less than 15%, more preferably less than 5%, even more preferably less than 2% and most preferably less than 1% of the weight of (S) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine without the use of a chiral chromatographic separation step.

One embodiment of the present invention includes a process for the preparation of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof, the (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine comprising less than 25%, preferably less than 15%, preferably less than 5%, even more preferably less than 2% and most preferably less than 1% by weight of (S) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine. Another embodiment of the present invention encompasses a process for the preparation of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof, said (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine comprising less than 25%, preferably less than 15%, more preferably less than 5%, even more preferably less than 2% and most preferably less than 1% of the weight of (S) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine without the use of a chiral chromatographic separation step. Thus, in one embodiment of the present invention, a process for the preparation of substantially pure (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine is provided which does not rely on chromatographic separation. One embodiment of the present invention includes a process for the commercial scale preparation of the compounds of the present invention, i.e., wherein the process is a fully validated cGMP commercial scale production of the Active Pharmaceutical Ingredient (API), reference is made to 21CFR portions 210 and 211, which are incorporated by reference.

One embodiment of the present invention includes the use of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.

One embodiment of the present invention encompasses methods for the treatment or prevention of various disorders and dysfunctions comprising administering to a mammal in need of such treatment a therapeutically effective amount of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof. More specifically, the disorder or dysfunction may be selected from CNS disorders, inflammation, inflammatory responses associated with bacterial and/or viral infections, pain, metabolic syndrome, autoimmune diseases or other disorders described in further detail herein. Another embodiment of the invention includes compounds having utility as diagnostic agents and in the receptor binding studies described herein.

One embodiment of the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. One embodiment of the invention includes the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of central nervous system disorders and dysfunctions. Another embodiment of the present invention includes (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine referred to in any of the examples or a pharmaceutically acceptable salt thereof. Another embodiment of the present invention is (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance. Another embodiment of the present invention includes (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof for use in modulating NNR in a patient in need thereof. Another embodiment of the invention includes (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an NNR-mediated condition or disorder. Another embodiment of the invention includes the use of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating NNR in a subject in need thereof. Another embodiment of the invention encompasses the use of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of an NNR-mediated condition or disorder. Another embodiment of the invention encompasses methods of modulating NNR in a subject in need thereof by administering (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof.

Unless otherwise stated, structures described herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, having the structure of the invention but with hydrogen atoms replaced by deuterium or tritium or with carbon atoms¹³C or¹⁴C instead of, or with nitrogen atoms¹⁵N instead of, or with oxygen atoms¹⁷O or¹⁸O substituted compounds are within the scope of the invention. Such isotopically labeled compounds are useful as research or diagnostic tools.

As used herein, the invention includes specific representative compounds, which are identified herein as being specific. The compounds of the invention can be prepared by a variety of methods, including standard synthetic methods that are well known. Exemplary general synthetic methods are set forth below, followed by the preparation of specific compounds of the invention in the preparation examples.

In all the examples described below, protective groups for sensitive or reactive groups are used, if necessary, according to the general principles of synthetic chemistry. Protecting Groups were manipulated according to standard methods of organic synthesis (T.W.Green and P.G.M.Wut s, Protecting Groups in organic Synthesis, 3 rd edition, John Wiley & Sons, New York (1999)). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art. The choice of method and reaction conditions and the order of their execution should be consistent with the preparation of the compounds of the invention.

The invention also provides a method for synthesizing the compound used as the intermediate.

General synthetic methods

One aspect of the present invention includes the stereospecific synthesis of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine (11) as outlined in scheme 1. Commercial tert-butyl (R) -3-hydroxypyrrolidine-1-carboxylate (compound 1) was treated with methanesulfonyl chloride to give tert-butyl (R) -3- (methylsulfonyloxy) pyrrolidine-1-carboxylate (compound 2), which was then reacted with diethyl malonate and a suitable base (e.g., potassium tert-butoxide or sodium ethoxide) to give diethyl (R) -2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) malonate (compound 3) having a stereochemistry around the chiral carbon in the opposite direction.

Suitable solvents for these reactions may be selected from the group consisting of toluene, xylene, 1-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, ethanol, tert-butanol, tetrahydrofuran, 1, 2-dimethoxyethane, dioxane, and mixtures thereof. In one embodiment, the solvent used for mesylate formation is toluene and the solvent used for malonate replacement is 1-methyl-2-pyrrolidone. In another embodiment, the solvent used for malonate replacement is ethanol. Suitable bases for these reactions may be selected from triethylamine, diethylisopropylamine, diisopropylethylamine, potassium tert-butoxide, sodium metal, sodium hydride, sodium ethoxide, potassium hydride and lithium hydride. In one embodiment, the base used for mesylate formation is triethylamine and the base used for malonate replacement is potassium tert-butoxide. In another embodiment, the base used for malonate replacement is sodium ethoxide.

The diester 3 was hydrolyzed with an aqueous potassium hydroxide solution to give (R) -2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) malonic acid (compound 4), which was decarboxylated to give (R) -2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) acetic acid (compound 5). Suitable solvents for these reactions may be selected from the group consisting of water, ethanol, tetrahydrofuran, dimethylformamide, dimethylacetamide, 1, 2-dimethoxyethane, dioxane, 1-methyl-2-pyrrolidone, toluene, dimethylsulfoxide, and mixtures thereof. In one embodiment, the solvent used for ester hydrolysis is aqueous tetrahydrofuran and the solvent used for decarboxylation is 1-methyl-2-pyrrolidone. In another embodiment, the solvent used for ester hydrolysis is ethanol and the solvent used for decarboxylation is a mixture of dimethyl sulfoxide and toluene. Suitable bases for the hydrolysis reaction may be selected from potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, barium hydroxide and cesium carbonate. In one embodiment, the base is potassium hydroxide. The compound 5 is reduced to obtain (R) -3- (2-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (compound 6), which is reacted with methanesulfonyl chloride and then sodium iodide to obtain (R) -3- (2- (methylsulfonyloxy) ethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (compound 7) and (R) -3- (2-iodoethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (compound 8), respectively. Suitable solvents for the reduction reaction may be selected from tetrahydrofuran, diethyl ether, dioxane, 1, 2-dimethoxyethane and mixtures thereof. In one embodiment, the solvent is tetrahydrofuran. Suitable reducing agents may be selected from borane, diborane, borane-tetrahydrofuran complex, borane dimethyl ether complex and borane-methyl sulfide complex. Suitable solvents for mesylate formation may be selected from toluene, xylene, diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane, dioxane, and mixtures thereof. In one embodiment, the solvent used for mesylate formation is toluene. Suitable bases for the mesylate formation may be selected from triethylamine, diethylisopropylamine and diisopropylethylamine. In one embodiment, the base used for mesylate formation is triethylamine. Suitable solvents for iodide replacement may be selected from 1-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, ethanol, tert-butanol, tetrahydrofuran, 1, 2-dimethoxyethane, dioxane, dimethylsulfoxide, and mixtures thereof. In one embodiment, the solvent used for iodide replacement is 1, 2-dimethoxyethane.

Finally, compound 8 is treated with potassium tert-butoxide to give compound 9. Suitable solvents for this reaction may be selected from 1, 2-dimethoxyethane, 1-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, ethanol, tetrahydrofuran, dioxane, and mixtures thereof. In one embodiment, the solvent is 1, 2-dimethoxyethane. Suitable bases for this reaction may be selected from potassium tert-butoxide, sodium ethoxide and diazabicycloundecane. In another embodiment, the base is potassium tert-butoxide.

Palladium-catalyzed coupling of compound 9 with 5-bromopyrimidine gives (R) -1- (tert-butoxycarbonyl) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine (10), which is deprotected in the final step to give (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine (11). Suitable solvents for the palladium-catalyzed coupling reaction may be selected from 1-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide and acetonitrile. In one embodiment, the solvent is dimethylacetamide. Suitable bases for the palladium-catalyzed coupling reaction may be selected from triethylamine, diethylisopropylamine, diisopropylethylamine, and sodium acetate. In one embodiment, the base is sodium acetate. Suitable phosphine ligands for the palladium catalysed coupling reaction may be selected from tri-n-butylphosphine, tri-t-butylphosphine, tricyclohexylphosphine, triphenylphosphine, tri-o-tolylphosphine and 1, 1' -bis (diphenylphosphino) ferrocene. In one embodiment, the phosphine ligand is 1, 1' -bis (diphenylphosphino) ferrocene. Suitable palladium catalysts for the palladium catalyzed coupling reaction may be selected from palladium acetate, palladium chloride and tris (dibenzylacetone) dipalladium. In one embodiment the palladium catalyst is palladium acetate. The solvent used for the deprotection reaction may be selected from water, dichloromethane, chloroform and dichloroethane. In one embodiment, the solvent is water. Suitable acids for the deprotection reaction may be selected from trifluoroacetic acid, hydrochloric acid and sulfuric acid. In one embodiment, the acid is hydrochloric acid.

One of ordinary skill in the art of organic synthesis will appreciate that there are a variety of ways to produce the compounds of the present invention, which may be labeled with radioisotopes suitable for different diagnostic applications. For example,¹¹the C-labeled 5-bromopyrimidine is coupled with compound 9, or the protecting group is then removed as described, yielding a compound suitable for positron emission tomography.

Synthesis scheme 1

Salt forms

One aspect of the present invention relates to novel salt forms of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine. The free base form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine is a viscous oil with limited water solubility. However, the free base can react with inorganic and organic acids to form some acid addition salts that have advantageous physical properties for preparing pharmaceutical compositions, such as crystallinity, water solubility, and stability to chemical degradation. Typically, these salt forms are pharmaceutically acceptable salts.

One aspect of the present invention includes acid addition salts of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine. The acid is selected from the group consisting of hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, 1-hydroxy-2-naphthoic acid, ketoglutaric acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-malic acid, hippuric acid, L-lactic acid, benzoic acid, succinic acid, adipic acid, acetic acid, nicotinic acid, propionic acid, orotic acid, 4-hydroxybenzoic acid, di-p-toluoyl-D-tartaric acid, di-p-anisoyl-D-tartaric acid, di-benzoyl-D-tartaric acid, 10-camphorsulfonic acid, camphoric acid, and enyphosphas. The invention also includes hydrates and solvates of these salt forms.

The stoichiometric amount of the present invention comprising salt may vary. For example, the molar ratio of acid to (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine is typically 1: 2 or 1: 1, but other ratios such as 3: 1, 1: 3, 2: 3, 3: 2, and 2: 1 are also possible. Depending on the manner in which the salts described herein are formed, the salts may have a crystal structure that blocks the solvent present during salt formation. Thus, the salts may exist as hydrates and other solvates in varying stoichiometric amounts relative to (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine.

In one embodiment of the invention, the salt has a stoichiometric ratio of acid to (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine of 1: 2. In another embodiment, the salt has a 1: 1 stoichiometric ratio of acid to (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine.

Another embodiment of the present invention includes (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate or a hydrate or solvate thereof. Another embodiment of the present invention includes (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-orotate or a hydrate or solvate thereof. Another embodiment of the present invention includes (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate or a hydrate or solvate thereof.

Another aspect of the invention comprises a process for the preparation of said salts. The precise conditions under which the salt is formed can be determined empirically. The salts may be obtained by crystallization under controlled conditions.

The preparation of the salt form may vary. The preparation of the (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine salt form typically comprises:

(i) mixing a solution of the free base or suitably pure (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base in a suitable solvent with the acid in any pure form or as a solution of any acid in a suitable solvent, typically 0.5 to 1 equivalent of the acid;

(ii) (a) if necessary, cooling the resulting salt solution to produce a precipitate; or

(ii) (b) adding a suitable anti-solvent to produce a precipitate; or

(ii) (c) evaporating the first solvent, adding fresh solvent, and repeating step (ii) (a) or step (ii) (b); and

(iii) filtration to collect the salt and optional recrystallization.

The stoichiometry, solvent mixture, solute concentration and temperature used may vary. Representative solvents that may be used to prepare or recrystallize the salt forms include, but are not limited to, ethanol, methanol, isopropanol, isopropyl acetate, acetone, ethyl acetate, toluene, water, methyl ethyl ketone, methyl isobutyl ketone, t-butyl methyl ether, tetrahydrofuran, dichloromethane, n-heptane, and acetonitrile.

One embodiment of the present invention comprises the salts of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine in substantially crystalline form with hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, 1-hydroxy-2-naphthoic acid, ketoglutaric acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-malic acid, hippuric acid, L-lactic acid, benzoic acid, succinic acid, adipic acid, acetic acid, nicotinic acid, propionic acid, orotic acid, 4-hydroxybenzoic acid, di-p-toluoyl-D-tartaric acid, di-p-anisoyl-D-tartaric acid, di-benzoyl-D-tartaric acid, 10-camphorsulfonic acid, camphoric acid and phencyphos.

The degree of crystallinity (%) can be determined by one skilled in the art by using x-ray powder diffraction (XRPD). Other techniques such as solid state NMR, FT-IR, raman spectroscopy, Differential Scanning Calorimetry (DSC) and microcalorimetry may also be used. For the compounds of the present invention, it has been determined that salts of crystalline forms with greater than 80% crystallinity can be produced.

Several of these crystalline salts have been shown to be sufficient to establish their desired stability in the manufacture of pharmaceutical formulations. This stability can be demonstrated in different ways. The tendency to gain and release atmospheric humidity can be evaluated by dynamic water vapor sorption (DVS). The stability of the respective weight, appearance studies to elevated temperature and humidity can be re-examined by storing the solid salt at 40 ℃/75% RH for up to 8 days and then under microscope and XRPD.

Polymorphic substance

The compounds of the invention may crystallize in more than one form, which is characterized by what is known as polymorphism and such polymorphism ("polymorph") is within the scope of the invention. Polymorphisms generally occur as a response to temperature, pressure, or both. Polymorphism is also caused by changes in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as XRPD patterns (diffractograms), solubility in different solvents, and melting point.

The present invention includes various polymorphic forms of the salt form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine including hydrates and solvates of the salt. This polymorph is characterized by its x-ray powder diffraction (XRPD) pattern (diffractogram).

One embodiment of the present invention includes a crystalline form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate. Another embodiment of the present invention includes amorphous forms of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate. Another embodiment of the present invention includes an amorphous form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citric acid having an XRPD pattern substantially corresponding to the pattern shown in figure 1.

One embodiment of the present invention includes a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form I characterized by an XRPD pattern comprising at least one of the following peaks:

2θ
	5.27
10.03
	13.77
21.73

another embodiment of the present invention includes a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form I having an XRPD pattern substantially corresponding to the pattern shown in figure 2.

One embodiment of the present invention includes a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form II characterized by a powder x-ray diffraction pattern comprising at least one of the following peaks:

another embodiment of the present invention includes a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form II having an XRPD pattern substantially corresponding to the pattern shown in figure 3.

One embodiment of the present invention includes a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form III characterized by an XRPD pattern comprising at least one of the following peaks:

2θ
	9.43
12.24
	16.24
18.38
	19.18
19.48
	21.52
22.89
	23.08
24.28
	30.77
31.27
	32.36
33.09
	34.86
37.26
	37.63
39.47

another embodiment of the present invention encompasses a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form III having an XRPD pattern substantially corresponding to the pattern shown in figure 4.

One embodiment of the present invention includes a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form IV characterized by an XRPD pattern comprising at least one of the following peaks:

2θ
	5.05
10.81
	14.06
15.20
	17.43
23.57
	24.21
25.52
	26.95

another embodiment of the present invention encompasses a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form IV having an XRPD pattern substantially corresponding to the pattern shown in figure 5.

One embodiment of the present invention includes a crystalline form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-orotate.

One embodiment of the present invention includes a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-orotate form I characterized by an XRPD pattern comprising at least one of the following peaks:

another embodiment of the present invention encompasses a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-orotate form I having an XRPD pattern substantially corresponding to the pattern shown in figure 6.

One embodiment of the present invention includes a crystalline form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate.

One embodiment of the present invention includes a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate form I characterized by an XRPD pattern comprising at least one of the following peaks:

2θ
	12.81
16.09
	18.00
19.07
	24.49
26.40
	26.04
27.88

another embodiment of the present invention includes a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate form I having an XRPD pattern substantially corresponding to the pattern shown in figure 7.

One embodiment of the present invention includes a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate form II characterized by an XRPD pattern comprising at least one of the following peaks:

2θ
	4.31
16.56
	18.29
18.78
	19.64
20.27
	21.02
21.46
	21.90
22.43
	22.86
25.40
	25.73
26.15
	26.56
27.40
	28.59
29.57

another embodiment of the present invention includes a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate form II having an XRPD pattern substantially corresponding to the pattern shown in figure 8.

As noted, the salt forms of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine may exist in solvated forms, e.g., hydrated forms and unsolvated forms. The present invention includes all such forms.

The present invention also includes isotopically-labeled compounds, in which one or more atoms are replaced by an atom having an atomic mass or number of atoms different from the atomic mass or number of atoms usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O and¹⁷and O. Such isotopically labeled compounds are useful as research or diagnostic tools.

Pharmaceutical composition

Although the compounds of the present invention can be administered in the form of a bulk active chemical, it is preferred to administer the compounds in the form of a pharmaceutical composition or formulation. Accordingly, one aspect of the present invention includes a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable carriers, diluents, or excipients. Another aspect of the invention provides a process for the preparation of a pharmaceutical composition comprising admixing a compound of the invention and one or more pharmaceutically acceptable carriers, diluents or excipients.

The mode of administration of the compounds of the invention may vary. Preferably, the compounds of the present invention are administered orally. Preferred pharmaceutical compositions for oral administration include tablets, capsules, sachets, syrups, solutions and suspensions. The pharmaceutical compositions of the present invention may be provided in modified release dosage forms such as timed release tablets and capsules.

The pharmaceutical compositions may also be administered by injection, i.e., intravenous, intramuscular, subcutaneous, intraperitoneal, intraarterial, intrathecal and intracerebroventricular injection. Intravenous administration is the preferred method of injection. Suitable carriers for injections are well known to those skilled in the art and include 5% dextrose solution, saline and phosphate buffered saline.

Other modes of administration of the formulation may also be used, for example rectal administration. Formulations for rectal administration, such as suppositories, are well known to those skilled in the art. The compounds may also be administered by: inhalation, for example in the form of an aerosol; topically, e.g., in the form of a lotion; transdermal, e.g., using a transdermal patch (e.g., by using techniques commercially available from Novartis and Alza Corporation); by powder injection or by buccal, sublingual or intranasal absorption.

The pharmaceutical compositions may be formulated in unit dosage form or in multiple or sub-dosage form.

Administration of the pharmaceutical compositions described herein may be intermittent or at a gradual, continuous, constant or controlled rate. The pharmaceutical composition can be administered to a warm-blooded animal, such as a mammal, e.g., a mouse, rat, cat, rabbit, dog, pig, cow, or monkey; but advantageously administered to humans. In addition, the number of days and times of daily administration of the pharmaceutical composition may vary.

The compounds of the present invention may be used in the treatment of various disorders and conditions, and as such, may be used in combination with various other suitable therapeutic agents for the treatment or prevention of those disorders or conditions. Accordingly, one embodiment of the invention encompasses the administration of a compound of the invention in combination with other therapeutic compounds. For example, the compounds of the present invention may be used in combination with the following therapeutic agents: other NNR ligands (e.g., varenicline), antioxidants (e.g., free radical scavengers), antimicrobials (e.g., penicillin antibiotics), antivirals (e.g., nucleoside analogs such as zidovudine and acyclovir), anticoagulants (e.g., warfarin), anti-inflammatory drugs (e.g., NSAIDs), antipyretics, analgesics, anesthetics (e.g., for surgery), acetylcholinesterase inhibitors (e.g., donepezil and galantamine), antipsychotics (e.g., haloperidol, clozapine, olanzapine and quetiapine), immunosuppressive agents (e.g., cyclosporin and methotrexate), neuroprotective agents, steroids (e.g., steroid hormones), corticosteroids (e.g., dexamethasone, prednisone and hydrocortisone), vitamins, minerals, nutraceuticals, antidepressants (e.g., imipramine, fluoxetine, paroxetine, escitalopram), Sertraline, venlafaxine and duloxetine), anxiolytics (e.g. alprazolam and buspirone), anticonvulsants (e.g. phenytoin and gabapentin), vasodilators (e.g. prazosin and sildenafil), mood stabilizers (e.g. valproate and aripiprazole), anti-cancer drugs (e.g. antiproliferatives), antihypertensives (e.g. atenolol, clonidine, amlodipine, verapamil and olmesartan), laxatives, diuretics (e.g. furosemide), antispasmodics (e.g. bismeryline), anti-dyskinesias and anti-ulcers (e.g. esomeprazole). Such combinations of pharmaceutically active agents may be administered together or separately, and when administered separately, may be administered simultaneously or sequentially in any order. The amount of compound or agent and the relative timing of administration are selected to achieve the desired therapeutic effect. Co-administration of the compounds of the invention with other therapeutic agents may be carried out by simultaneous administration in combination: (1) a single pharmaceutical composition comprising both compounds; or (2) separate pharmaceutical compositions each comprising one of the compounds. Alternatively, the combination may be administered separately in a sequential manner, wherein one therapeutic agent is administered first, while the second therapeutic agent is administered. Such sequential administration may be at similar times or at longer intervals.

Another aspect of the invention includes combination therapy comprising administering to a subject a therapeutically or prophylactically effective amount of a compound of the invention and one or more other therapies, including chemotherapy, radiation therapy, gene therapy, or immunotherapy.

Method of treatment

(R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine, its pharmaceutically acceptable salts, or pharmaceutical compositions containing them may be used to prevent or treat various conditions or disorders to which other types of nicotinic acid compounds have been proposed or shown to be useful as therapeutic agents, such as CNS disorders, inflammation, inflammatory responses associated with bacterial and/or viral infections, pain, metabolic syndrome, autoimmune diseases, or other disorders described in further detail herein. The compounds may also be used as diagnostic reagents (in vitro and in vivo) in receptor binding studies. Such therapeutic agents and other teachings are described, for example, in the references cited above herein, including Williams et al, Drug News Perspec.7 (4): 205(1994), Arneric et al, CNS Drug rev.1 (1): 1-26(1995), Arneric et al, exp. opin. invest. drugs 5 (1): 79-100(1996), Bencherif et al, J.Pharmacol.Exp.Ther.279: 1413(1996), Lippieillo et al, J.Pharmacol.Exp.Ther.279: 1422(1996), Damaj et al, j. pharmacol. exp. ther.291: 390 (1999); chiari et al, Anestheology 91: 1447(1999), Lavand' homme and Eisenbach, Anesthesiology 91: 1455(1999), Holladay et al, j.med.chem.40 (28): 4169-94(1997), Bannon et al, Science 279: 77(1998), PCT WO 94/08992, PCT WO 96/31475, PCT WO96/40682 and U.S. Pat. No. 5,5,583,140 to Bencherif et al, U.S. Pat. No. 5,597,919 to Dull et al, U.S. Pat. No. 5,604,231 to Smith et al and U.S. Pat. No. 5,852,041 to Cosford et al.

CNS disorders

(R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine, its pharmaceutically acceptable salts, or pharmaceutical compositions containing them are useful for treating or preventing various CNS disorders including neurodegenerative disorders, neuropsychiatric diseases, neurological disorders, and addiction. The compounds and pharmaceutical compositions thereof may be used for: treatment or prevention of cognitive deficits and dysfunctions, which may or may not be age-related; attention disorders and dementias, including those caused by a pathogenic or metabolic disorder; providing neuroprotection; treatment of convulsions and multiple cerebral infarction; treatment of mood disorders, obsessive-compulsive and addictive behaviors; providing analgesia; control of inflammation mediated by, for example, cytokines and nuclear factor κ B; treating inflammatory disorders; providing pain relief; and as anti-infective agents for the treatment of bacterial, fungal and viral infections. Among the disorders, diseases, and conditions for which the compounds and pharmaceutical compositions of the present invention may be useful in the treatment or prevention of are: age-associated memory impairment (AAMI), Mild Cognitive Impairment (MCI), age-associated cognitive decline (ARCD), pre-senile dementia, early onset Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, Alzheimer's disease, dementia-free Cognitive Impairment (CIND), Lewy body dementia, HIV-dementia, AIDS dementia complex, vascular dementia, Down's syndrome, head injury, Traumatic Brain Injury (TBI), dementia pugilistica, spongiform encephalopathy and prion disease, stroke, ischemia, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive dysfunction in schizophrenia, cognitive deficits in parkinson's disease including Parkinson's disease, post-encephalitic Parkinson's disease, Gaum Parkinson's disease, Gauss Parkinson's disease, Alzheimer's disease, dementia with dementia, dementia with Lewy body dementia, HIV-dementia, AIDS, frontotemporal dementia of parkinsonism type (FTDP), pick's disease, Niemann-pick's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, progressive supranuclear palsy, progressive supranuclear paresis, restless leg syndrome, Kugejie's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis (ALS), Motor Neuron Disease (MND), Multiple System Atrophy (MSA), corticobasal degeneration, Guillain-Barre syndrome (GBS) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), epilepsy, autosomal dominant nocturnal paroxysmal frontal epilepsy, mania, anxiety, depression, premenstrual dysphoria, panic disorder, bulimia, anorexia, narcolepsy, hypersomnia daytime, bipolar disorder, generalized anxiety disorder, obsessive-compulsive disorder, anger-induced outbreaks, oppositional defiance disorder, Huntington's disorder, multiple, Tourette's syndrome, autism, drug and alcohol addiction, tobacco addiction, and eating disorders.

Cognitive impairment or dysfunction may be associated with psychosis or disorders such as schizophrenia and other psychoses including, but not limited to, psychotic disorders, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, affective disorders, and psychosis resulting from general medical conditions, dementia and other cognitive disorders including, but not limited to, mild cognitive impairment, pre-senile dementia, Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, age-related memory impairment, Lewy body dementia, vascular dementia, AIDS dementia complex, dyslexia, Parkinson's disease including Parkinson's disease, cognitive impairment and Parkinson's disease dementia, cognitive impairment from multiple sclerosis, cognitive impairment due to traumatic brain injury, dementia due to other medical conditions, anxiety disorders, panic disorders including, but not limited to, agoraphobia, Phobic disorders with agoraphobia, history of agoraphobia without phobic conditions, specific phobias, social phobias, obsessive-compulsive disorders, post-traumatic stress disorder, acute stress disorder, general anxiety disorder, and general anxiety disorder resulting from general medical conditions, mood disorders including, but not limited to, major depressive disorder, dysthymic disorder, bipolar depression, bipolar mania, bipolar I disorder, depression or mixed episodes associated with mania and depression, bipolar II disorder, cyclothymic disorder, and mood disorder resulting from general medical conditions, sleep disorders including, but not limited to, sleep disorders, primary insomnia, primary narcolepsy, deep sleep disorders, nightmare disorders, sleep retardation, learning disorders, motor skills disorders, communication disorders, synthetic mental development disorders, Attention deficit and schizobehavioral disorders, attention deficit hyperactivity disorder, eating and eating disorders in infants, children, or adults, tic movement disorders, exclusion disorders, substance-related disorders including, but not limited to, substance dependence, substance abuse, substance intoxication, substance withdrawal, alcohol-related disorders, amphetamine or amphetamine-like related disorders, caffeine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen-related disorders, inhalant-related disorders, nicotine-related disorders, opioid-related disorders, phencyclidine or phencyclidine-like related disorders, and sedative-, hypnotic-, or anxiolytic-related disorders, personality disorders including, but not limited to, obsessive-compulsive personality disorders, and impulse control disorders.

The above conditions and disorders are further discussed in detail in, for example: american psychiatric Association: diagnostic and Statistical Manual of mental Disorders, 4 th edition, revision, Washington, D.C., American psychiatric Association, 2000.

Inflammation(s)

The nervous system, primarily through the vagus nerve, is known to modulate the magnitude of the innate immune response by inhibiting macrophage Tumor Necrosis Factor (TNF) release. This physiological mechanism is called The "cholinergic anti-inflammatory pathway" (see, e.g., Tracey, "The infllamation reflex," Nature 420: 853-9 (2002)). Excessive inflammation and tumor necrosis factor synthesis lead to morbidity and even death from a variety of diseases. These diseases include, but are not limited to, endotoxemia, rheumatoid arthritis, osteoarthritis, psoriasis, asthma, atherosclerosis, idiopathic pulmonary fibrosis, and inflammatory bowel disease.

Inflammatory conditions that may be treated or prevented by administration of the compounds described herein include, but are not limited to, chronic and acute inflammation, psoriasis, endotoxemia, gout, acute pseudogout, acute gouty arthritis, rheumatoid arthritis, osteoarthritis, allograft rejection, chronic graft rejection, asthma, atherosclerosis, mononuclear phagocyte-dependent lung injury, idiopathic pulmonary fibrosis, atopic dermatitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute chest syndrome in sickle cell disease, inflammatory bowel disease, irritable bowel syndrome, crohn's disease, ulcerative colitis, acute cholangitis, aphteous stomatitis, cryptitis, glomerulonephritis, lupus nephritis, thrombosis, and graft-versus-host reaction.

Inflammatory response associated with bacterial and/or viral infection

Many bacterial and/or viral infections are associated with side effects caused by toxin formation and the body's natural response to the bacteria or viruses and/or toxins. As mentioned above, the body's response to infection typically involves the production of large amounts of TNF and/or other cytokines. Overexpression of these cytokines can lead to significant damage, such as septic shock (when the bacteria are sepsis), endotoxic shock, urosepsis, viral pneumonia, and toxic shock syndrome.

Cytokine expression is mediated by NNRs and can be inhibited by administration of agonists or partial agonists of these receptors. Described herein are those compounds that are agonists or partial agonists of these receptors and thus can be used to minimize inflammatory responses associated with bacterial infections as well as viral and fungal infections. Examples of such bacterial infections include anthrax, botulism and sepsis. Some of these compounds may also have antimicrobial properties.

These compounds can also be used as adjunctive therapies in combination with existing therapies to treat bacterial, viral and fungal infections, such as antibiotics, antivirals and antifungals. Antitoxins can also be used to bind toxins produced by infectious agents and can bind toxins to pass through the body without producing an inflammatory response. Examples of antitoxins are disclosed, for example, in U.S. patent No. US6,310,043 to Bundle et al. Other active agents that are effective against bacteria and other toxins may be effective and their therapeutic effects may be supplemented by co-administration of the compounds described herein.

Pain (due to cold or dampness)

The compounds of the present invention and pharmaceutical compositions thereof are particularly useful in the treatment and prevention of pain, including acute, persistent and chronic pain. Pain types and pain conditions that may be treated or prevented using the compounds and pharmaceutical compositions thereof include nociceptive pain, neuropathic pain, female specific pain, inflammatory pain, fibromyalgia, post-operative pain, pain resulting from medical conditions (e.g., AIDS or other disorders), arthritic pain, temporomandibular joint disorders, burn pain, traumatic pain, back pain, sciatica, foot pain, headache, abdominal pain, muscle and connective tissue pain, joint pain, penetrating pain, cancer pain, body driving pain, visceral pain, chronic fatigue syndrome, psychiatric pain, and pain disorders.

Neuropathic pain syndromes are the result of abnormal changes occurring within the pain signaling system of the peripheral and central nervous systems. Their different etiologies and symptomatologies have traditionally made them difficult to treat with any consistency. Examples of neuropathic pain syndromes include those attributed to: trigeminal or herpetic neuralgia, peripheral neuropathy (diabetic neuropathy, chemotherapy-induced neuropathy), post-herpetic neuralgia, nerve entrapment (carpal tunnel syndrome), radiculopathy, complex regional pain syndrome, burning pain of the skin, low back pain, idiopathic pain (pain without external stimulation), and afferent nerve block syndrome such as brachial plexus avulsion and spinal cord injury. Hyperalgesia (intense pain associated with mild stimuli), allodynia (pain associated with innocuous stimuli), parethesias (numbing or stinging sensations in the absence of external stimuli), and dysesthesia (spontaneous or evoked adverse paresthesia) are also typically characterized as types of neuropathic pain. The compounds of the present invention and their pharmaceutical compositions are particularly useful in the treatment and prevention of these neuropathic pain types and related disorders.

Other disorders

In addition to treating CNS disorders, inflammation and pain, the compounds of the invention may also be useful in the prevention or treatment of certain other conditions, diseases and disorders in which NNRs play a role. Examples include: autoimmune diseases, such as lupus; disorders associated with cytokine release; cachexia secondary to infection (e.g., as occurs in AIDS, AIDS-related complex and neoplasia), obesity, pemphitis, urinary incontinence, retinal disease, infectious disease, muscle weakness, eaton-lambert syndrome, hypertension, osteoporosis, vasoconstriction, vasodilation, arrhythmia, type I diabetes, type II diabetes, bulimia, anorexia, diarrhea, constipation, and ulcers, as well as those indications set forth in published PCT application WO 98/25619. The compounds of the invention may also be administered to treat convulsions, such as those which are symptoms of epilepsy, and to treat conditions such as syphilis and kugerbil's disease.

Diagnostic applications

The compounds may be used in the form of diagnostic compositions, such as probes, particularly where they are modified to include suitable labels. Probes can be used, for example, to determine the relative quantity and/or function of specific receptors, particularly the α 4 β 2 receptor subtype. For this purpose, it is most preferred to use a radioisotope moiety such as¹¹C、¹⁸F、⁷⁶Br、¹²³I or¹²⁵I labels the compounds of the invention.

The administered compound can be detected using well known detection methods appropriate to the label used. Examples of detection methods include Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT). The radiolabelling being used for PET (e.g. as in¹¹C、¹⁸F or⁷⁶Br) and SPECT (e.g.¹²³I) Imaging of half life¹¹About 20.4 minutes of C,¹⁸F about 109 minutes,¹²³I is about 13 hours and⁷⁶br was about 16 hours. Highly specific activity is required to develop a selected receptor subtype at unsaturated concentrations. The dose administered is typically below the toxic range and provides high contrast images. The contemplated compounds can be administered at non-toxic levelsThe medicine is prepared. Dosimetry is performed in a manner well known to those of ordinary skill in the art of radiological imaging. See, for example, U.S. patent No. US5,969,144 to London et al.

The compounds may be administered using known techniques. See, for example, U.S. patent No. US5,969,144 to London et al. The compounds may be administered in the form of pharmaceutical compositions incorporating other ingredients, such as those types of ingredients used in formulating diagnostic compositions. Most preferably, the compounds used in accordance with the practice of the present invention are used in high purity form. See U.S. patent US5,853,696 to Elmalch et al.

After administration of a compound to a subject (e.g., a human subject), the presence of the compound in the subject can be imaged and quantified by appropriate techniques to indicate the presence, amount, and functionality of a selected NNR subtype. In addition to humans, the compounds can be administered to animals such as mice, rats, dogs, and monkeys. SPECT and PET imaging can be performed using any suitable techniques and instrumentation. See Villemagne et al: arneric et al (Eds.) neural nicotinic acid Receptors: pharmacology and Therapeutic Opportunities, 235-250(1998) and Elmalch et al, US patent US5,853,696.

The radiolabeled compounds bind to selected NNR subtypes (e.g., α 4 β 2) with high affinity and preferably exhibit negligible non-specific binding to other nicotinic cholinergic receptor subtypes (e.g., those associated with muscle and ganglia). As such, the compounds may be used as non-invasive imaging of nicotinic acid cholinergic receptor subtypes within the body of a subject, particularly the brain, for diagnosis associated with various CNS diseases and disorders.

In one aspect, the diagnostic composition may be used in a method of diagnosing a disease in a subject, e.g., a human patient. The methods involve administering to the patient a detectably labeled compound as described herein and detecting binding of the compound to a selected NNR subtype (e.g., the α 4 β 2 receptor subtype). Those skilled in the art using diagnostic tools such as PET and SPECT can use the radiolabeled compounds described herein to diagnose a variety of conditions and disorders, including conditions and disorders associated with dysfunction of the central and autonomic nervous systems. Such disorders include various CNS diseases and disorders, including alzheimer's disease, parkinson's disease, and schizophrenia. These and other representative diseases and disorders that may be evaluated include those set forth in U.S. patent No. US5,952,339 to Bencherif et al.

In another aspect, the diagnostic compositions may be used in methods of monitoring a subject, such as a human patient, for a selective nicotinic acid receptor subtype. The method involves administering to the patient a detectably labeled compound as described herein and detecting binding of the compound to a selected nicotinic acid receptor subtype, i.e., the α 4 β 2 receptor subtype.

Receptor binding

The compounds of the invention can be used as reference ligands in binding assays for compounds that bind to NNR subtypes, in particular the α 4 β 2 receptor subtype. For this purpose, preference is given to using radioisotope moieties such as³H or¹⁴C labels the compounds of the invention. Examples of such binding assays are described in detail below.

Examples

The following examples are provided to illustrate the invention and should not be construed as limiting the invention. In these examples, all parts and percentages are by weight unless otherwise noted.

Example 1: methods and protocols for the characterization of salt forms of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine

X-ray powder diffraction (XRPD)

Acquisition of X-ray powder with Bruker AXS C2GADDS diffractometer using CuK alpha radiation (40kV, 40mA), automated XYZ stage, laser imaging microscope for automated sample positioning and HiStar 2-dimensional flat panel detectorA diffraction pattern. X-ray optics consisting of a single coupled 0.3mm pinhole collimatorA multilayer mirror. The beam divergence (i.e. the effective size of the X-ray beam on the sample) is about 4 mm. The theta-theta continuous scan mode is used with a sample-detector spacing of 20cm to give an effective 2 theta range of 3.2 deg. -29.7 deg.. Typically, the sample is exposed to the X-ray beam for 120 seconds. Samples run at ambient conditions were prepared as flat plate samples using the powder received as unmilled. Approximately 1-2mg of the sample was lightly pressed onto the slide to obtain a flat surface. Samples run under non-ambient conditions were mounted on a silicon wafer containing a heat conducting compound. The sample was then heated to the appropriate temperature at about 10 ℃/min, then held isothermal for about 5min, after which data acquisition was initiated. Peak positions are reported as ° 2 θ with an accuracy of ± 0.1 °.

Single crystal XRD (SXD)

Data were collected using a Bruker AXS1K SMART CCD diffractometer equipped with an Oxford Cryosys Cryotostream cooling unit. The structure was resolved using either the SHELXS or SHELXD program and partially refined for the Bruker AXS SHELXTL component using the SHELXL program. Unless otherwise stated, the hydrogen atoms attached to the carbon are positioned geometrically, allowing refinement with riding isotropic substitution parameters. The hydrogen atoms attached to the heteroatoms are positioned in the differential fourier synthesis allowing free refinement with isotropic substitution parameters.

Nuclear Magnetic Resonance (NMR) spectroscopy

NMR spectra were collected using a Varian Unity 300MHz instrument or a Bruker 400MHz instrument with an auto sampler installed and controlled by a DRX400 console. Automated experiments were acquired using standard Bruker load experiments using ICONNMR v4.0.4 (component 1) run with Topspin v 1.3 (patch level 8). In the case of non-conventional spectroscopy, data is acquired by using separate topsppins.

Melting Point

A Fisher-Johns bench top thermal melting point apparatus set at an environment corresponding to a heating rate of about 5 ℃/min was used.

Differential Scanning Calorimetry (DSC)

DSC data were collected using a TA Instruments Q1000 or Mettler DSC823e equipped with a 50-bit auto sampler. The energy and temperature calibration of the instrument was calibrated using the verified indium. Typically, 0.5-1.5mg of sample in a pinhole aluminum dish are heated from 25 ℃ to 175-200 ℃ each at 10 ℃/min. A nitrogen purge was maintained at 30mL/min on the sample.

Thermogravimetric analysis (TGA)

TGA data was collected using a TA Instruments Q500TGA with a 16 bit auto sampler installed or a Mettler TGA/SDTA 851e with a 34 bit auto sampler installed. TA instruments q 500: the temperature of the instrument was calibrated using a verified Alumel. Typically, 5-10mg samples were each pre-tared on a platinum crucible and an aluminum DSC pan, heated from ambient temperature to 350 ℃ at 10 ℃/min. A nitrogen purge was maintained at 60mL/min on the sample. MettlerTG/SDTA 851 e: the temperature of the instrument was calibrated using the verified indium. Typically, 5-10mg samples are each pre-tared on aluminum crucibles, heated at 10 ℃/min from ambient temperature to 350 ℃. A nitrogen purge was maintained at 50mL/min on the sample.

Polarized Light Microscopy (PLM)

The samples were studied using a Leica LM/DM polarized light microscope with a digital video camera for image capture. A small amount of each sample was placed on a glass slide, fixed in oil for immersion, covered with a cover slip, and the particles were each separated as much as possible. The sample was observed with appropriate magnification and local polarized light coupled with a lambda false color filter.

Microscopic examination of fever period (HSM)

Heated stage microscopy was performed using a Leica LM/DM polarized light microscope incorporating a Mettler-Toledo MTFP82HT heating-stage and a digital video camera for image capture. A small amount of each sample was placed on a slide to separate the particles as far as possible each. The sample is observed with suitable magnification and local polarized light coupled with a lambda false color filter while heating from ambient temperature, typically at 10 deg.c/min.

Dynamic water vapor adsorption (DVS)

Sorption isotherms were determined using a SMS DVS intragenic moisture sorption analyzer controlled by SMS Analysis component software. The sample temperature was maintained at 25 ℃ by instrument control. Humidity was controlled by mixing dry and wet nitrogen streams at a total flow rate of 200 mL/min. Relative humidity was measured by a calibrated Rotronic probe (dynamic range 1.0-100% RH) located close to the sample. The change in weight of the sample (mass loss) as a function of% RH was constantly monitored by means of a microbalance (accuracy ± 0.005 mg).

Typically, 5-20mg of sample is placed on a tared, screened stainless steel basket at ambient conditions. Load and no load at 40% RH and 25 ℃ (typically ambient conditions). Moisture sorption isotherms were completed as outlined below (2 scans resulted in 1 complete cycle). Standard isotherms were completed at 25 ℃ in 10% RH intervals over a range of 0-90% RH.

DVS general method parameters

Parameter(s)	Value of
		Adsorption-scanning 1	40-90
Desorption/adsorption-Scan 2	90-drying, drying-40
		Interval (% RH)	10
Number of scans	2
		Flow rate (mL/min)	200
Temperature (. degree.C.)	25
		Stability (. degree. C./min)	0.2
Adsorption time (hours)	6 hours pause time

The samples were recovered after completion of the isotherm and analyzed by XRPD.

Water determination by Karl Fischer (KF)

The water content of each sample was determined using a Mettler Toledo DL39 Coulometer, using a Hydranal Coulomat AG reagent and an argon purge. The weighed solid sample was introduced into a container attached to a sub-sealed (subcase) platinum TGA tray to avoid water ingress. About 10mg of sample was used for each titration, and the assay was performed in duplicate.

Thermodynamic water solubility by HPLC

Aqueous solubility is determined by suspending a sufficient amount of the compound in water to give a maximum final concentration of the parent compound in free form of ≥ 10 mg/mL. The suspension was equilibrated at 25 ℃ for 24h and then the pH was measured. The suspension was then filtered through a glass fiber C filter into 96-well culture plates. The filtrate was then diluted 101-fold. Quantitation was performed by HPLC, referencing a standard solution of about 0.1mg/mL in DMSO. Different volumes of standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak area determined by integrating the peaks determined at the same retention time as the main peak in the standard injection. XRPD was collected if sufficient solids were present in the filter plate.

HPLC method parameters for the thermodynamic water-soluble method

The analysis was performed using an Agilent HP1100 series system equipped with a diode array detector and using the ChemStation software vB.02.01-SR 1.

Chemical purity by HPLC

Purity analysis was performed using an Agilent HP1100 series system equipped with a diode array detector and using ChemStation software vb.02.01-SR 1.

HPLC method parameters for chemical purity determination

Ion chromatography

Data were collected using Metrohm 761 Advanced Compact IC (for cations) and Metrohm861 Advanced Compact IC (for anions), using IC Net software v 2.3. Samples were prepared as 1000ppm stock solutions in DMSO. Samples were diluted to 100ppm with DMSO and then tested. Quantification is performed by comparison with standard solutions of known concentrations of the ions being analyzed.

Ion chromatography of anions

Cation ion chromatography

pKa determination and prediction

Data were collected using a Sirius GlpKa instrument with a D-PAS attachment. The determination was carried out by UV in aqueous solution at 25 ℃ and by potentiometry in methanol-water mixture. The titration medium is adjusted for Ionic Strength (ISA) by 0.15M KCl (aq). The values measured in the methanol-water mixture to 0% co-solvent were corrected by Yasuda-Shedlovsky extrapolation. Data were refined using the referement Pro software v 1.0. pKa values were predicted using ACD pKa prediction software v 9.

Log P determination

Three ratios of octanol were used with a Sirius GlpKa instrument: potentiometric titration of the ion-intensity-adjusted (ISA) water to collect data to generate Log P, Log P_ionAnd Log D values. Data were refined using the referement Pro software v 1.0. The Log P values were predicted using ACD v9 and Syracuse kowwinv1.67 software.

EXAMPLE 2 Synthesis of (R) -3- (methylsulfonyloxy) pyrrolidine-1-carboxylic acid tert-butyl ester (2)

The method A comprises the following steps:to a solution of (R) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (200g, 1.07mol) and triethylamine (167g, 1.63mol) in toluene (700mL) was added methanesulfonyl chloride (156g, 1.36mol) dropwise at-20 to-30 ℃ while maintaining the temperature at-10 to-20 ℃. The solution was warmed to ambient temperature and stirred. The reaction solution was sampled every hour and analyzed by HPLC to establish completion of the reaction. Upon completion of the reaction, the suspension was filtered to remove triethylamine hydrochloride. The filtrate was washed with 600mL of dilute aqueous sodium bicarbonate. The organic layer was dried and concentrated under reduced pressure to give 2 as a viscous oil (260g, 92%), which was used without further purification.¹H NMR(CDCl₃，400MHz)δ5.27(m，1H)，3.44-3.76(m，4H)，3.05(s，3H)，2.26(m，1H)，2.15(m，1H)，1.47(s，9H).

The method B comprises the following steps:to the reactor were added (R) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2.00kg, 10.7mol), toluene (8.70kg) and triethylamine (1.75kg, 17.3 mol). The reactor was purged with nitrogen for 15 min. The mixture was stirred and cooled to 3 ℃. Methanesulfonyl chloride (1.72kg, mol) (exothermic reaction) was added slowly (over a 2h period) with continuous ice bath cooling (temperature 14 ℃ after addition was complete). The viscous mixture, now with precipitated triethylamine hydrochloride, was stirred for 12h, at which time it was warmed to 20 ℃. GC and TLC analysis (ninhydrin staining) showed no material remaining. The mixture was filtered to remove triethylamine hydrochloride salt and the filtrate was returned to the reactor. The filtrate was then washed with 5% aqueous sodium bicarbonate (2 × 3)kg) for each wash with 15min stirring and 15min settling time. The resulting organic layer was dried over anhydrous sodium sulfate and filtered. Volatile materials were removed from the filtrate under reduced pressure, first at 50 ℃ for 4h, then at ambient temperature for 10 h. The residue weighed 3.00kg (106% yield) and was shown by chromatography and NMR analysis to be the same as the previously prepared sample, except that it contained toluene.

EXAMPLE 3 Synthesis of (R) -2- (1- (tert-Butoxycarbonyl) pyrrolidin-3-yl) malonic acid diethyl ester (3)

Preparation A:to a solution of potassium tert-butoxide (187g, 1.62mol) in 1-methyl-2-pyrrolidone (1.19L) was added diethyl malonate (268g.1.67mol) while maintaining the temperature below 35 ℃. The solution is heated to 40 ℃ and stirred for 20-30 min. Tert-butyl (R) -3- (methylsulfonyloxy) pyrrolidine-1-carboxylate (112g, 420mmol) was added and the solution was heated to 65 ℃ and stirred for 6 h. The reaction solution was sampled every 2h and analyzed by HPLC to establish completion of the reaction. When the reaction was complete (10-12h), the mixture was cooled to about 25 ℃. To this solution was added deionized water (250mL) and the pH was adjusted to 3-4 by the addition of 2N hydrochloric acid (650 mL). The resulting suspension was filtered and water (1.2L) and chloroform (1.4L) were added. The solution was mixed well, the chloroform layer was collected and evaporated under reduced pressure to give a yellow oil. The oil was dissolved in hexane (2.00L) and washed with deionized water (2X 1.00L). The organic layer was concentrated under reduced pressure at 50-55 ℃ to give a pale yellow oil (252g),¹h NMR analysis showed 49.1% of 3(123.8g) with 48.5% diethyl malonate (122g) and 2% 1-methyl-2-pyrrolidone (5 g). The material was used in the next step without further purification.¹H NMR(CDCl₃，400MHz)δ4.20(q，4H)，3.63(m，1H)，3.48(m，1H)，3.30(m，1H)，3.27(d，J＝10Hz，1H)，3.03(m，1H)，2.80(m，1H)，2.08(m，1H)，1.61(m，1H)，1.45(s，9H)，1.27(t，6H).

Preparation B:a reactor maintained under a nitrogen atmosphere was charged with anhydrous ethanol (5.50kg) and 21% by weight of sodium ethoxide in ethanol (7.00kg, 21.6 mol). The mixture was stirred and warmed to 30 ℃. Adding the mixture within 20minDiethyl malonate (3.50kg, 21.9mol) was added. The reaction mixture was then warmed at 40 ℃ for 1.5 h. A solution of tert-butyl (R) -3- (methylsulfonyloxy) pyrrolidine-1-carboxylate (3.00kg of product from example 2, method B, 10.7mol) in absolute ethanol (5.50kg) was added and the resulting mixture was heated at reflux (78 ℃ C.) for 2 h. GC and TLC analysis (ninhydrin staining) showed no starting material remaining. The stirred mixture was then cooled to 25 ℃, diluted with water (2.25kg) and slowly treated with a solution of concentrated hydrochloric acid (1.27kg, 12.9mol) in water (5.44 kg). The mixture was washed twice with methyl tert-butyl ether (MTBE) (14.1kg and 11.4kg) using 15min stirring for 15min settling time. The combined MTBE washings were dried over anhydrous sodium sulfate (1kg), filtered, and concentrated in vacuo at 50 ℃ for 6 h. The residue (red oil) weighed 4.45kg and was analyzed by GC to be 49% of the desired product (62% overall yield from (R) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester).

EXAMPLE 4 Synthesis of (R) -2- (1- (tert-Butoxycarbonyl) pyrrolidin-3-yl) malonic acid (4)

Method A: to a solution containing 123.8g (380mmol) of 3 and 121.8g (760mmol) of the product of method A of example 3 (232g) diethyl malonate in tetrahydrofuran (1.2L) was added 21% potassium hydroxide solution (450g of 0.50L deionized water) while maintaining the temperature below 25 ℃. The reaction mixture was heated to 45 ℃ and stirred for 1 h. The reaction solution was sampled every 1 hour and analyzed by HPLC to confirm completion of the reaction. Upon completion of the reaction (2-3h), the mixture was cooled to about 25 ℃. The water layer was collected and cooled to 5 ℃. The pH was adjusted to 2 by the addition of 4N hydrochloric acid (750mL) and the resulting suspension was maintained at 5-10 ℃ for 30 min. The mixture was filtered and the filter cake was washed with hexane (1L). The aqueous filtrate was extracted with chloroform (1L), and the chloroform layer was left to stand. The solid collected in the filtration step was redissolved in chloroform (1L) by heating to 40 ℃. The solution was filtered to remove undissolved inorganic solids. The chloroform layers were combined and concentrated under reduced pressure at 50-55 deg.C to give an off-white solid (15 g). The solids were combined and dissolved in ethyl acetate (350mL) to give a suspension which was warmed to 55-60 ℃ for 2 h. The suspension was filtered while warm, with ethyl acetate (2X 150mL) and hexane (2X 250mL)The resulting filter cake was washed to give 83.0g (80.1%) of 4 as a white solid, which was used in the next step without further purification.¹H NMR(d₄-CH₃OH，400MHz)δ3.60(m，1H)，3.46(m，1H)，3.29-3.32(m，2H)，2.72(m，1H)，2.09(m，1H)，1.70(m，1H)，1.45(s，9H).

The method B comprises the following steps:a solution comprising 2.13kg (6.47mol)3 in tetrahydrofuran (13.9kg) of example 3 method B (4.35kg) was added to a stirred cooled solution of potassium hydroxide (1.60kg, 40.0mol) in deionised water (2.00kg) under a nitrogen atmosphere whilst maintaining the temperature below 35 ℃. The reaction mixture was heated and maintained at 40-45 ℃ for 24h, until at which time GC and TLC analysis indicated that the reaction was complete. The mixture was cooled to 25 ℃, washed with MTBE (34kg), stirred for 15min, and settled for 15 min. The water layer was collected and cooled to 1 ℃. A mixture of concentrated hydrochloric acid (2.61kg, 26.5mol) in deionised water (2.18kg) was then added slowly, the temperature of the mixture being maintained < 15 ℃ during and 15min after the addition. The pH of the solution was adjusted to 3.7 by further addition of hydrochloric acid. The white solid was collected by filtration, washed with water (16kg) and dried under vacuum at ambient temperature for 6 d. The dry solid weighed 1.04 kg. The filtrate was cooled to < 10 ℃ and maintained at this temperature while lowering the pH by further addition of hydrochloric acid (using 1.6L 6N; 9.6 mol; final pH 2). The white solid was collected by filtration, washed with water (8L) and dried in vacuo at 40 ℃ for 3 d. The dry solid weighed 0.25 kg. The combined solids (1.29kg, 73% yield) were chromatographically found to be identical to the previously prepared samples.

EXAMPLE 5 Synthesis of (R) -2- (1- (tert-Butoxycarbonyl) pyrrolidin-3-yl) acetic acid (5)

The method A comprises the following steps:a solution of (R) -2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) malonic acid (83g) in 1-methyl-2-pyrrolidone (0.42L) was stirred at 110 ℃ and 112 ℃ under a nitrogen atmosphere for 2 h. The reaction solution was sampled every 1 hour and analyzed by HPLC to confirm completion of the reaction. Upon completion of the reaction, the mixture was cooled to 20-25 ℃. The solution was mixed with deionized water (1.00L) and MTBE (1.00L) was added. The phases were separated and the organic layer was collected. M for aqueous phaseTBE (1.00L) followed by chloroform (1.00L). The combined organic layers were concentrated under reduced pressure at 50-55 deg.C to give an oil. The oil was dissolved in MTBE (2.00L) and washed twice with 0.6N hydrochloric acid (2 × 1.00L). Collecting organic layer, and concentrating under reduced pressure at 50-55 deg.C to obtain semisolid. The semi-solid was suspended in 1: 4 ethyl acetate/hexane (100mL), heated to 50 deg.C for 30min, cooled to-10 deg.C, and filtered. The filtrate was concentrated under reduced pressure to give an oil, which was dissolved in MTBE (250mL) and washed twice with 0.6N hydrochloric acid (2X 100 mL). Concentrating the organic layer at 50-55 deg.C under reduced pressure to obtain semi-solid, suspending in 1: 4 ethyl acetate/hexane (50mL), heating to 50 deg.C, holding for 30min, cooling to-10 deg.C, and filtering. The solid was collected, suspended in hexane (200mL) and collected by filtration to give 54.0g (77.6%) of 5.¹H NMR(CDCl₃，400MHz)δ11.00(br s，1H)，3.63(m，1H)，3.45(M，1H)，3.30(M，1H)，2.97(m，1H)，2.58(m，1H)，2.44(m，2H)，2.09(m，1H)，1.59(M，1H)，1.46(s，9H).

The method B comprises the following steps:a solution of (R) -2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) malonic acid (1.04kg, 3.81mol) in 1-methyl-2-pyrrolidone (6.49kg) was stirred at 110 ℃ under nitrogen for 5h until GC and TLC analysis indicated completion of the reaction. The mixture was cooled to 25 deg.C (4h) and combined with water (12.8kg) and MTBE (9.44 kg). The mixture was stirred vigorously for 20min and the phases were separated (10 h). The organic phase was collected and the aqueous phase was combined with MTBE (9.44kg) and stirred for 15min to allow it to settle (45 min). The organic phase was collected and the aqueous phase was combined with MTBE (9.44kg) and stirred for 15min to allow it to settle (15 min). The three organic phases were combined, washed three times with 1N hydrochloric acid (8.44kg portions) and once with water (6.39kg) using 15min stirring for 15min each wash for a settling time of 15 min. The resulting solution was dried over anhydrous sodium sulfate (2.0kg), filtered, and the filtrate was concentrated under reduced pressure at 31 deg.C (2h, to give a solid, which was heated at 39 deg.C for 4h under vacuum and at 25 deg.C for 16h under vacuum to give 704g (81%) of 5 (purity 99.7% by GC).

Method C(modified synthesis of 5, using 2 as starting material): a stirred solution of sodium ethoxide in ethanol (21% by weight, 343g, 1)A mixture of 05mol), ethanol (anhydrous, 300mL) and diethyl malonate (168g, 1.05mo) was heated to 40 ℃ for 1.5 h. To the mixture was added a solution of (R) -tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate (138g, 0.592mol) in ethanol (100mL) and the reaction mixture was heated to 78 ℃ for 8 h. The cooled reaction mixture was diluted with water (2.0L) and acidified to pH 3 with 6M HCl (100 mL). The aqueous ethanol mixture was extracted with toluene (1.0L) and the organic phase was concentrated in vacuo to give 230g of a red oil. The red oil was added to 22.5 weight percent aqueous potassium hydroxide (748g, 3.01mol) at 85 ℃. After the addition was complete, the reaction temperature was slowly raised to 102 ℃ while distilling the ethanol produced. When the reaction temperature reached 102 ℃ and the distillation stopped, heating was continued for another 90 min. The reaction mixture was cooled to ambient temperature and washed with toluene (2X 400 mL). To the aqueous layer was added 600mL of 6M hydrochloric acid while maintaining the internal temperature below 20 ℃. Starting at a pH of about 4-5 results in the formation of a precipitate. The suspension was filtered and the filter cake was washed with 300mL of water. The solid was dried in vacuo to give 77g of (R) -2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) malonic acid as an off-white solid (yield 54% relative to (R) -tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate).¹H NMR(DMSO-d₆，400MHz)：δ3.47(m，1H)；3.32(m，1H)；3.24(m，1H)；3.16(m，1H)；3.92(m，1H)；2.86(m，1H)；1.95(m，1H)；1.59(m，1H)；1.39(s，9H).

A suspension of (R) -2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) malonic acid (15g, 55mmol) in toluene (150mL) and dimethylsulfoxide (2mL) was heated to reflux for a 2h period. The mixture was brought to ambient temperature and diluted with MTBE (150 mL). The organic solution was washed with 10% aqueous citric acid (2X 200mL) and the solvent removed in vacuo to give 11.6g of (R) -2- (1- (tert-butoxycarbonyl) -pyrrolidin-3-yl) acetic acid as an off-white solid (92% yield).¹H NMR(DMSO-d₆，400MHz)：δ12.1(s，1H)；3.36-3.48(m，1H)；3.20-3.34(m，1H)；3.05-3.19(m，1H；2.72-2.84(m，1H)；2.30-2.42(m，1H)，2.22-2.30(m，2H)；1.85-2.00(m，1H)；1.38-1.54(m，，1H)，1.35(2，9H).

EXAMPLE 6 Synthesis of (R) -3- (2-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (6)

The method A comprises the following steps:a solution of (R) -2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) acetic acid (49.0g, 214mmol) in Tetrahydrofuran (THF) (200mL) was cooled to-10 ℃. 250mL (250mmol) of a 1M solution of borane in THF was slowly added to the flask while maintaining the temperature below 0 ℃. The solution was warmed to ambient temperature and stirred for 1 h. The solution was sampled every 1 hour and analyzed by HPLC to establish completion of the reaction. Upon completion of the reaction, the solution was cooled to 0 ℃ and a 10% sodium hydroxide solution (80mL) was added dropwise over a 30 minute period to control gas evolution. The solution was extracted with 500mL of a 1: 1 hexane/ethyl acetate solution. The organic layer was washed with saturated sodium chloride solution and dried over 10g of silica gel. The silica gel was removed by filtration and washed with 100mL of a 1: 1 hexane/ethyl acetate solution. The organic layers were combined and concentrated in vacuo to afford 6(42g, 91.3%) as a light orange oil which solidified upon standing.¹H NMR(CDCl₃，400MHz)δ3.67(m，2H)，3.38-3.62(m，2H)，3.25(m，1H)，2.90(m，1H)，2.25(m，1H)，1.98-2.05(m，1H)，1.61-1.69(m，2H)，1.48-1.59(m，2H)，1.46(s，9H).

The method B comprises the following steps:borane-THF complex (3.90kg or L of a 1M solution in THF, mol) was slowly added to a stirred solution of (R) -2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) acetic acid (683g, 3.03mol) in THF (2.5kg) maintained under a nitrogen atmosphere and at a temperature of 23-28 ℃ using a water bath. The addition was carried out for 1.75 h. Stirring was continued for 1h at 25 ℃ after which GC analysis indicated the reaction was complete. The reaction mixture was cooled to < 10 ℃ and maintained below 25 ℃, at which time 10% aqueous sodium hydroxide (1.22kg) was slowly added. The addition took 40 min. The mixture was stirred at 25 ℃ for 1h and then combined with 1: 1(v/v) heptane/ethyl acetate (7L). The mixture was stirred for 15min and allowed to separate into phases (1 h). The organic phase was extracted and the aqueous phase was combined with a second portion of 7L 1: 1 heptane/ethyl acetate. It was stirred for 15min and allowed to separate into phases (20 min). The organic phases were again extracted and the combined organic phases were washed with saturated aqueous sodium chloride (4.16kg), mixed for 15min and settled for 1 h. Mixing organic phase with silica gel(140g) Mixing, and stirring for 1 h. Anhydrous sodium sulfate (700g) was added and the mixture was stirred for 1.5 h. The mixture was filtered and the filter cake was washed with 1: 1 heptane/ethyl acetate (2L). The filtrate was concentrated in vacuo at < 40 ℃ for 6 h. The resulting oil weighed 670g (103% yield) and contained traces of heptane, but was otherwise found to be identical to previously prepared sample 6 by NMR analysis.

Example 7: (R) -3- (2- (methylsulfonyloxy) ethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (7)

The method A comprises the following steps:to a solution of (R) -3- (2-hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (41.0g, 190mmol)) was added triethylamine (40mL) in toluene (380mL) and cooled to-10 ℃. Methanesulfonyl chloride (20.0mL, 256mmol) was added slowly to maintain the temperature at about-5 to 0 ℃. The solution was warmed to ambient temperature and stirred for 1 h. The solution was sampled every 1 hour and analyzed by HPLC to establish completion of the reaction. Upon completion of the reaction, the solution was filtered and the filtrate was washed with 5% sodium bicarbonate solution (250 mL). The organic layer was collected and washed with saturated aqueous sodium chloride (250 mL). The organic layer was collected, dried over silica gel (10g) and concentrated in vacuo to give 7(53.0g, 92.8%) as a pale yellow viscous oil.¹H NMR(CDCl₃，400MHz)δ4.26(t，J＝6.8Hz，2H)，3.41-3.63(m，2H)，3.27(m，1H)，3.02(s，3H)，2.92(m，1H)，2.28(m，1H)，2.05(m，1H)，1.83(m，2H)，1.50-1.63(m，1H)，1.46(s，9H).

The method B comprises the following steps:a solution of triethylamine (460g, 4.55mol) and tert-butyl (R) -3- (2-hydroxymethyl) pyrrolidine-1-carboxylate (all samples from example 7, method B, 3.03mol) in toluene (5.20kg) was stirred under a nitrogen atmosphere and cooled to 5 ℃. Methanesulfonyl chloride (470g, 4.10mol) was added slowly over 1.25h, cooled using an ice bath to maintain the temperature below 15 ℃. The mixture was gradually warmed (over 1.5 h) to 35 ℃ and the temperature was maintained for 1.25h at which time GC analysis indicated that the reaction was complete. The mixture was cooled to 25 ℃, the solid was filtered off and the filter cake was washed with toluene (1.28 kg). The filtrate was stirred with 10% aqueous sodium bicarbonate (4.0kg) for 15min, and the phases were separated for 30 min. The organic phase is then mixed with saturated sodium chlorideThe aqueous solution (3.9kg) was stirred together for 30min and the phases were allowed to separate for 20 min. The organic phase was combined with silica gel (160g) and stirred for 1 h. Anhydrous sodium sulfate (540g) was added and the mixture was stirred for a further 40 min. The mixture was then filtered and the filter cake was washed with toluene (460 g). The filtrate was concentrated in vacuo at 50 ℃ for 5h and the resulting oil was held at 23 ℃ in vacuo for a further 8 h. 798g 7 were obtained and 93% pure by GC analysis.

Example 8: synthesis of tert-butyl (R) -3-vinylpyrrolidine-1-carboxylate (9)

The method A comprises the following steps:a solution of (R) -tert-butyl 3- ((methylsulfonyloxy) ethyl) pyrrolidine-1-carboxylate (49.0g, 167mmol), sodium iodide (30.0g, 200mmol) and 1, 2-dimethoxyethane (450mL) was stirred at 50-60 ℃ for 4 h. The solution was sampled every 1 hour and analyzed by HPLC to establish completion of the reaction. Upon completion of the reaction, the solution was cooled to-10 ℃ and solid potassium tert-butoxide (32.0g, 288mmol) was added while maintaining the temperature below 0 ℃. The reaction mixture was warmed to ambient temperature and stirred for 1 h. The solution was sampled every 1 hour and analyzed by HPLC to establish completion of the reaction. Upon completion of the reaction, the mixture was filtered through a pad of celite (25g dry basis). The filter cake was washed with 1, 2-dimethoxyethane (100 mL). The combined filtrates were concentrated in vacuo to give an orange oil containing suspended solids. The oil was dissolved in hexane (400mL), stirred for 30min, and filtered to remove solids. The organic layer was dried over silica gel (10g) and concentrated in vacuo to give 9(26.4g, 82.9%) as an anhydrous oil.¹H NMR(CDCl₃，400MHz)δ5.77(m，1H)，5.10(dd，J＝1.2Hz，J＝16Hz，1H)，5.03(dd，J＝1.2Hz，J＝8.8Hz，1H)，3.41-3.59(m，2H)，3.29(m，1H)，3.05(m，1H)，2.78(m，1H)，2.01(m，1H)，1.62-1.73(m，1H)，1.46(m，9H).

The method B comprises the following steps:a solution of (R) -tert-butyl 3- (2- (methylsulfonyloxy) ethyl) pyrrolidine-1-carboxylate (792g, product of method B, example 7,. about.2.5 mol), sodium iodide (484g, 3.27mol), and 1, 2-dimethoxyethane (7.2L) was stirred at 55 deg.C for 4.5h under a nitrogen atmosphere at which time GC analysis indicated that the reaction was complete. Dissolving the mixture in waterThe solution was cooled to < 10 ℃ and solid potassium tert-butoxide (484g, 4.32mol) was added portionwise (1.25h for an additional time) while maintaining the temperature below 15 ℃. The reaction mixture was stirred at 5 ℃ for 1h, slowly warmed (6h) to 20 ℃ and stirred at 20 ℃ for 1 h. The mixture was filtered through a pad of celite (400g dry basis). The filter cake was washed with 1, 2-dimethoxyethane (1.6 kg). The combined filtrates were concentrated in vacuo and the semi-solid residue was stirred with (6.0L) heptane for 2 h. The solid was removed by filtration (the filter cake was washed with 440mL heptane) and the filtrate was concentrated in vacuo at 20 ℃ to give 455g 9 (90.7% pure). A sample of this material (350g) was fractionally distilled at 20-23 torr to give 296g of purified 9(bp 130 ℃.) (found > 99% pure by GC analysis).

Example 9: synthesis of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine (11)

Nitrogen was bubbled through a solution of 3-vinylpyrrolidine-1-carboxylic acid (R) -tert-butyl ester (25g, 127mmol), 5-bromopyrimidine (30.3g, 190mmol), 1' -bis (diphenylphosphino) ferrocene (2.11g, 3.8mmol) and sodium acetate (18.8gr, 229mmol) in N, N-dimethylacetamide (250mL) for 1h, palladium acetate (850mg, 3.8mmol) was added. The reaction mixture was heated to 150 ℃ at a rate of 40 ℃/h and stirred for 16 h. The mixture was cooled to 10 ℃ and quenched with water (750mL) while maintaining the internal temperature below 20 ℃. MTBE (300mL) was added followed by diatomaceous earth (40g, dry weight basis). The suspension was stirred at ambient temperature for 1h and filtered through a bed of celite. The residue was washed with MTBE (2X 100mL) and the filtrate was transferred to a 2-L vessel equipped with an overhead stirrer and activated carbon (40g) was added. The suspension was stirred at ambient temperature for 2h and filtered through celite. The residue was washed with MTBE (2X 100mL) and the filtrate was concentrated in vacuo to give 28.6g of an orange oil. This oil was dissolved in MTBE (100mL) and Si-Thiol was added(2.0g, 1.46mmol thiol/g, Silicone Inc.). The suspension was stirred at ambient temperature under nitrogen for 3h, filtered through a fine filter and kept in a glass container.

The filtrate was added to a 6M HCl solution (70mL) over a 30min period while maintaining the internal temperature at 20 ℃ to 23 ℃. The mixture was stirred vigorously for 1h and the organic layer was removed. The remaining aqueous layer was basified with 45 wt% KOH (50mL) and the resulting suspension was extracted once with chloroform (300 mL). Evaporation of the solvent in vacuo (bath temperature at 45 ℃) gave 16.0g (71.8%) of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base as a red oil, which was immediately dissolved in isopropanol (50mL) for salt formation.

Example 10: synthesis of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate

To a solution of citric acid (17.6g, 91.6mmol) in isopropanol (250mL) and water (25mL) was added dropwise a solution of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (16.0g, 91.2mmol) in isopropanol (50mL) at 55 ℃. The resulting solution was inoculated with (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form II (200mg) and stirred for 15 min. The suspension was heated to 65 ℃ and stirred for 1h, after which the suspension was cooled to 20 ℃ at-10 ℃/h and allowed to stand at 20 ℃ for 12 h. The suspension was filtered through a coarse glass filter and the collected solid was washed with isopropanol (64mL) and methyl tert-butyl ether (64 mL). The resulting free-flowing brown solid was dried under vacuum at 70 ℃ to give 17.4g (36%) (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate (mixture of forms II and III) as a brown solid.¹H NMR(D₂O，400MHz)δ8.85(s，1H)，8.70(s，1H)，6.50(d，J＝17Hz，1H)，6.35(dd，J＝7Hz，J＝17Hz，1H)，3.43-3.50(m，1H)，3.34-3.43(m，1H)，3.20-3.30(m，1H)，3,08-3.19(m，1H)，3.00-3.08(m，1H)，2.77(d；J＝16Hz，2H)，2.65(d，J＝16Hz，2H)，2.16-2.26(m，1H)，1.80-1.92(m，1H).

Example 11: screening of salt with acid addition salt of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine

(R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base is dissolved in either isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone, acetonitrile or isopropanol and the resulting solution is treated with 1eq. hcl delivered in one of the following forms: a 1M solution in diethyl ether, a 1M solution in water, a 5M solution in isopropanol or a 4M solution in dioxane. The mixture was incubated (4h cycle) at 50 ℃/ambient temperature for 24 h. If the experiment resulted in a stable solid, the material was analyzed by XRPD.

Example 12: screening of "mono" acid addition salts of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine

(R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (10mg, 0.057mmol) was dissolved in isopropyl acetate or acetonitrile. The solution was treated with 1eq. of the corresponding acid (see below), warmed to 50 ℃, and slowly cooled to ambient temperature overnight. The solvent was then evaporated in vacuo without heating and the residue was analyzed by XRPD. The solid was then stored in a humidity chamber at 40 ℃ and 75% RH for 1 week and analyzed by XRPD.

To the extent that the experiment did not produce a crystalline solid, the sample was aged in tetrahydrofuran and isopropanol, and if a solid was obtained, the solid was analyzed by XRPD and stored in a humidity chamber for 1 week to assess stability.

The following acids were screened using the method described above for the formation of "mono" acid addition salts: hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, 1-hydroxy-2-naphthoic acid, ketoglutaric acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-malic acid, hippuric acid, L-lactic acid, benzoic acid, succinic acid, adipic acid, acetic acid, nicotinic acid, propionic acid, orotic acid, 4-hydroxybenzoic acid, and di-p-toluoyl-D-tartaric acid.

Example 13: screening of "half" acid addition salts of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine

(R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (10mg, 0.057mmol) was dissolved in isopropyl acetate or acetonitrile. The solution was then treated with 0.5eq. of the corresponding acid (see below), warmed to 50 ℃, and slowly cooled to ambient temperature overnight. The solvent was then evaporated in vacuo without heating and the residue was analyzed by XRPD. The solid was then stored in a humidity chamber at 40 ℃ and 75% RH for 1 week and analyzed by XRPD.

To the extent that this experiment did not produce a crystalline solid, these samples were aged in tetrahydrofuran and isopropanol, and if a solid was obtained, the solid was analyzed by XRPD and stored in a humidity chamber for 1 week to assess stability.

Experimental the above procedure for the formation of "half" acid addition salts the following acids were screened: sulfuric acid, maleic acid, phosphoric acid, ketoglutaric acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-malic acid, succinic acid, adipic acid, and di-p-toluoyl-D-tartaric acid.

Example 14: general amplification method for selected salts of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine

A number of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine salts were selected to be amplified to-200 mg for further characterization. These salt forms include: citrate (mono-and hemi), orotate (mono), 4-hydroxybenzoate (mono), di-p-toluoyl-D-tartrate (mono-and hemi), maleate (mono-and hemi), and fumarate (mono-and hemi).

(R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (189mg, 1.077mmol in acetonitrile. the solution was then treated with 1.1eq. corresponding acid to prepare a salt and 0.5eq. corresponding acid to prepare a half salt the mixture was warmed to 50 ℃ and slowly cooled to ambient temperature overnight.

The resulting solid was filtered, drained and then passed through XRPD and¹H-NMR analysis. TGA experiments were performed to determine water or other solvent content, and DSC experiments were performed to establish the stability of the isolated forms and the potential for new forms of each salt. DVS experiments were used to evaluate the hygroscopicity of the salts. HPLC purity and thermodynamic solubility were also determined for each salt.

Example 15: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate crystalline form I

(R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate crystalline form I was obtained from isopropyl acetate by evaporation and maturation in tetrahydrofuran according to the monosalt screening method. Alternatively, form I mono-citrate is obtained from acetonitrile by evaporation and maturation in isopropanol according to the mono-salt screening method. An XRPD diffraction pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form I is shown in figure 2.

Example 16: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate crystalline form II

A suspension of a mixture of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate forms II and III in methanol was heated to 50 ℃ and stirred for 1 h. The suspension was then cooled to 20 ℃ at-30 ℃/h and then immediately heated back to 50 ℃ at +30 ℃/h. The heating was discontinued when 50 ℃ was reached, the suspension was cooled and stirred at ambient temperature for 16 h. The suspension was filtered and any material remaining in the flask was rinsed off with additional methanol. The residue was dried under vacuum at 70 ℃ for 16h to give (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate crystalline form II. An XRPD diffraction pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate crystalline form II is shown in figure 3.

Example 17: amorphous (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate

Amorphous (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate is prepared by freeze-drying an aqueous solution of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form II. The XRPD diffraction pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate is shown in figure 1.

Example 18: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate crystalline form III

(R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form III is prepared by allowing amorphous (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate to stand at ambient temperature for 2 hours. An XRPD diffraction pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form III is shown in figure 4.

Example 19: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate crystalline form IV

(R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate form IV is obtained by curing form II in acetone/methyl isobutyl ketone. The XRPD diffraction pattern of form IV of mono-citrate is shown in figure 5.

Example 20: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono- (R) - (-) -orotate

Orotic acid (0.965g, 6.18mmol) was added as a solid in a round bottom flask to a stirred hot solution of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (1.084g, 6.18mmol) in 2-propanol (10 mL). The resulting solid mixture was heated at reflux for 5min, cooled to ambient temperature, and stirred overnight. The light brown powder was filtered, washed with 2-propanol (10, 8mL), dried (pump off) in a vacuum oven at 50 ℃ for 20h to give 1.872g (77.9%) as an off-white to white crude solid, mp 230-,¹H NMR(D₂o): δ 8.80(s, 1H), 8.60(s, 2H), 6.40(d, 1H), 6.25(dd, 1H), 5.93(s, 1H, orotic acid ═ CH, showing one salt stoichiometry), 3.38(dd, 1H), 3.29(m, 1H), 3.17(m, 1H), 3.04(m, 1H), 2.97(dd, 1H), 2.13(m, 1H), 1.78(m, 1H), elemental analysis suggests the presence of excess orotic acid and 1: 1.1 alkali orotate stoichiometry. Elemental analysis: calculated value C₁₀H₁₃N₃·C₅H₄N₂O₄: (C, 54.38%; H, 5.17%, N, 21.14%); measurement value: (C, 53.49%, 53.44%; H, 5.04%, 5.10%; N, 20.79%, 20.84%).

Example 21: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-orotate form I

(R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (189mg, 1.077mmol, freshly prepared) was dissolved in acetonitrile (5 mi). Then with 1.1eq. of orotic acid solution (1) at ambient temperatureEthanol solution of M) to the solution. The mixture was warmed to 50 ℃ and slowly cooled to ambient temperature overnight. The resulting solid was filtered, dried under vacuum, then passed through XRPD and¹H-NMR analysis. An XRPD diffraction pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-orotate form I is shown in figure 6.

Example 22: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate crystalline form I

(R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (189mg, 1.077mmol, freshly prepared) was dissolved in acetonitrile (5 ml). The solution was then treated with 1.1eq. The mixture was warmed to 50 ℃ and slowly cooled to ambient temperature overnight. The resulting solid was filtered, dried under vacuum, then passed through XRPD and¹H-NMR analysis. An XRPD diffraction pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate form I is shown in figure 7.

Example 23: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate crystalline form II

(R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate (form I) was slurried in ethanol and incubated at 50 ℃/r.t. for 4 h-48 h of the cycle. XRPD analysis of the solid showed form II. An XRPD diffraction pattern of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate form II is shown in figure 8.

Example 24: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-oxalate

Oxalic acid (0.516g, 5.73mmol) was added as a solid to a stirred warm solution of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine (1.00g, 5.70mmol) in ethanol (10 mL). The salt precipitated as the solution was further warmed. To facilitate stirring, the mixture was diluted with ethanol (6mL) and the mass broken up with a spatula. The mixture was cooled to ambient temperature and left to stand overnight. The light brown powder was filtered, washed with ethanol and dried in a vacuum oven at 50 ℃ for 6h to give 1.40g (92).3%) cream-like white loose powder, mp149-151 deg.C.¹H NMR(DMSO-d₆)：δ9.03(s，1H)，8.86(s，2H)，6.56(m，2H)，3.40(dd，1H)，3.31(m，1H)，3.18(m，1H)，3.08(m，1H)，2.96(dd，1H)，2.15(m，1H)，1.80(m，1H)，¹³C NMR(DMSO-d₆): δ 164.90(C ═ O oxalic acid), 156.97, 154.17, 133.66, 130.31, 124.20, 48.70, 44.33, 40.98, 30.42, elemental analysis: calculated value C₁₀H₁₃N₃·C₂H₂O₄(C, 54.33%; H, 5.70%, N, 15.84%); found (C, 54.39%, 54.29%; H, 5.68%, 5.66%; N, 15.68%, 15.66%).

Example 25: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine hemi-di-p-toluoyl-D-tartrate

Solid di-p-toluoyl-D-tartrate is obtained according to the "hemi" salt screening method from isopropyl acetate or acetonitrile by evaporation or by using isopropyl acetate by evaporation followed by maturation with tetrahydrofuran or by evaporation of acetonitrile followed by maturation with isopropanol.

The following procedure was used to prepare the bulk of the salt. (+) -O, O' -di-p-toluoyl-D-tartaric acid (1.103g, 2.85mmol) was added as a solid to a stirred warm solution of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (1.007g, 5.74mmol) in ethanol (10 mL). A few insoluble solids precipitated which were difficult to dissolve when the mixture was heated to reflux. The light amber solution (containing a little solid fines) was stirred for 4-5h and then allowed to stand overnight at ambient temperature. The salt slowly precipitated as a pale yellow-white powder. After stirring for 15 days, the solid was filtered, washed with ethanol (5mL), and dried in a vacuum oven at 50 ℃ for 21h to give 1.50g (71.5%) of an off-white to light yellow powder, mp 178-.¹H NMR(DMSO-d₆) The stoichiometric amount of base to acid salt was confirmed to be 1: 0.5.¹H NMR(DMSO-d₆): Δ 10.30 (broad s,. about.1H), 9.02(s, 1H), 8.80(s, 2H), 7.87(d, 2H, -C)₆H₄-, shows the half-salt stoichiometry), 7.27(d, 2H, -C₆H₄-, shows the half-salt stoichiometry), 6.40(dd, 1H), 6.34(d, 1H), 5.58(s, 1H, C of the acid moietyH(CO₂H) -O-, showing half-salt stoichiometry), 3.21(dd, 1H), 3.14(m, 1H), 3.00(m, 1H), 2.86(m, 1H), 2.75(dd, 1H), 2.30(s, 3H, — CH of the acid moiety₃Showing the half-salt stoichiometry), 1.93(m, 1H), 1.61(m, 1H).

Example 26: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine hemi-di-p-benzoyl-D-tartrate

(+) -O, O' -di-benzoyl-D-tartaric acid (1.025g, 2.72mmol) was added as a solid to a stirred warm solution of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (1.003g, 5.72mmol) in ethanol (10 mL). The mixture was heated on a heating block to near reflux, yielding a light amber solution. The resulting solution was cooled to ambient temperature and left to stand overnight. Since no solid was present, the solution was slowly evaporated in a fume hood to give a tan gummy solid. Isopropyl acetate (10mL) was added, scraped off with a spatula, stirred and a light brown solid precipitated. The mixture was stirred overnight. The solid was filtered, washed with isopropyl acetate (2X 5mL), dried in a vacuum oven at 50 ℃ for 24h to give 1.93g (95.2%) as an off-white powder, mp 155-.¹H NMR(DMSO-d₆) The stoichiometric amount of base to acid salt was confirmed to be 1: 0.5.¹H NMR(DMSO-d₆): Δ 10.25 (broad s,. about.1H), 9.02(s, 1H), 9.80(s, 2H), 7.98(d, 2H C)₆H₅-)，7.57(m，1H，C₆H₅-)，7.48(m，2H，C₆H₅-)，6.38(m，2H)，5.61(s，1H，-CH(CO₂H) -O-acid moiety, showing half-salt stoichiometry), 3.22(dd, 1H), 3.14(dt, 1H), 3.00(dt, 1H), 2.88(m, 1H), 2.77(dd, 1H), 1.92(m, 1H), 1.61(m, 1H).

Example 27: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine hemi-di-p-anisoyl-D-tartrate

Mixing (+) -di-p-anisoyl-D-tartaric acidThe acid (1.199g) was added as a solid to a stirred warm solution of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (0.999g) in ethanol (10 mL). The resulting solution had a little solid present, stirred, and heated to attempt to dissolve all of the solid. The solution thickened to a thick mass. After standing at ambient temperature for 4-5h, additional ethanol (10mL) was added. The mixture containing the light brown to cream solid was stirred overnight. The solid was filtered, washed with ethanol (10mL) and dried in a vacuum oven at 50 ℃ for 21h to give 1.91g (87.3%) of a white powder, mp 173-.¹H NMR(DMSO-d₆) The stoichiometric amount of base to acid salt was confirmed to be 1: 0.5.¹H NMR(DMSO-d₆): Δ 10.20 (broad s,. about.1H), 9.02(s, 1H), 8.80(s, 2H), 7.93(d, 2H, -C)₆H₄-, shows the half-salt stoichiometry), 7.00(d, 2H, -C₆H₄Semi-salt stoichiometry), 6.40(dd, 1H), 6.34(d, 1H), 5.56(s, 1H, C of the acid moietyH(CO₂H) -O-, shows the semi-salt stoichiometry), 3.76(s, 3H, -OCH of the acid moiety₃Showing half-salt stoichiometry), 3.22(dd, 1H), 3.14(m, 1H), 3.01(m, 1H), 2.85(m, 1H), 2.75(m, 1H), 1.92(m, 1H), 1.61(m, 1H).

Example 28: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-di-p-toluoyl-D-tartrate

Solid di-p-toluoyl-D-tartrate is obtained by evaporation from isopropyl acetate or acetonitrile according to the "mono" salt screening method.

The following procedure was used to prepare the bulk of the salt. (+) -O, O' -di-p-toluoyl-D-tartaric acid (2.205g, 5.71mmol) was added as a solid to a stirred warm solution of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (1.000g, 5.70mmol) in ethanol (21 mL). The precipitated salt is an intermediate. After moderate heating of the mixture on a near reflux hot plate, the resulting mixture was cooled to ambient temperature. The resulting solid was filtered, washed with ethanol (3X5mL) and dried in a vacuum oven at 50 ℃ for 13h to give 3.081g (96.1%) of a light brown powder, mp 181-.¹H NMR(DMSO-d₆) The 1: 1 salt stoichiometry was confirmed.¹H NMR(DMSO-d₆): Δ 9.60 (broad s,. about.1H), 9.03(s, 1H), 8.82(s, 2H), 7.83(d, 4H, -C)₆H₄-, shows one salt stoichiometry), 7.27(d, 4H, -C₆H₄-, shows one salt stoichiometry), 6.44(d, 2H), 5.62(s, 2H, C of the acid moietyH(CO₂H) -O-, one salt stoichiometry), 3.30(dd, 1H), 3.23(m, 1H), 3.09(m, 1H), 2.95(m, 1H), 2.85(dd, 1H), 2.33(6H, -CH of the acid moiety)₃One salt stoichiometry) 2.02(m, 1H), 1.69(m, 1H).

Example 29: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-di-p-benzoyl-D-tartrate

In a round bottom flask, (+) -O, O' -di-benzoyl-D-tartaric acid (2.05g, 5.72mmol) was added as a solid to a stirred warm solution of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (0.999g, 5.69 mmols) in ethanol (21mL) to produce a solution. After stirring and further heating, the salt precipitated in warm solution. The resulting mixture was cooled to ambient temperature over the course of 2 days. The resulting solid was filtered through a Buchner funnel, washed with ethanol (4X 5mL), dried (suction) in a vacuum oven at 50 ℃ for 13h to give 2.832g (93.0%) of a light brown to off-white powder, mp 165-.¹H NMR(DMSO-d₆) The 1: 1 salt stoichiometry was confirmed.¹H NMR(DMSO-d₆): Δ 9.65 (broad s,. about.1H), 9.03(s, 1H), 9.83(s, 2H), 7.94(d, 4H, C)₆H₅-)，7.60(m，2H，C₆H₅-)，7.50(m，4H，C₆H₅-), 6.45(m, 2H), 5.67(s, 2H, -C of the acid moietyH(CO₂H) -O-, one-salt stoichiometry), 3.31(dd, 1H), 3.22(m, 1H), 3.08(m, 1H), 2.96(m, 1H), 2.85(dd, 1H), 2.01(m, 1H), 1.69(m, 1H).

Example 30: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono- (1S) -10-camphorsulfonate

In a round bottom flask (1S) - (+) -10-camphorsulfonic acid (1.329g, 5.72mmol) was added as a solid to a stirred warm solution of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (1.00g) in 2-propanol (23mL, 5.70 mmol). Upon cooling to ambient temperature, no solid precipitated. The solution was allowed to stand overnight. A gel-like material comprising a white solid was observed. After stirring for 2 days, the mixture was diluted with 2-propanol (10.5mL) because it was difficult to stir the jelly-like white mass. After stirring overnight, the white powder was filtered through a Buchner funnel, washed with 2-propanol (5mL) (note: the solid showed some solubility in 2-propanol) and dried (suction) in a vacuum oven at 50 ℃ for 6h to give 1.47g (63.2%) of a white powder, mp 172-.¹H NMR(DMSO-d₆) The 1: 1 salt stoichiometry was confirmed. After standing for 7 days, a second batch of bright-brownish needles was observed in the crystallization liquid. The material was filtered, washed with 2-propanol (10mL), dried (evacuated) in a vacuum oven at 50 ℃ for 21h to give 0.245g of light brown needle crystals, mp 173-.¹H NMR(DMSO-d₆): Δ 9.03(s, 1H), 8.87(s, 2H), 6.57(m, 2H), 3.41(dd, 1H)3.33(m, 1H, partially H)₂O mask), 3.21(m, 1H), 3.10(m, 1H), 2.98(dd, 1H), 2.89(d, 1H, — CH of acid moiety₂-, shows one salt stoichiometry), 2.64(m, 1H), 2.41(d, 1H, -CH of the acid moiety₂-, one salt stoichiometry), 2.25(t, 0.5H), 2.20(t 0.5H), 2.15(m, 1H), 1.93(t, 1H), 1.82(m, 3H), 1.28(m, 2H, -CH of the acid moiety₂-, shows one-salt stoichiometry), 1.03(s, 3H, CH of the acid moiety₃One salt stoichiometry) 0.73(s, 3H, -CH₃Acid moiety, showing one-salt stoichiometry).

Example 31: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono- (1R, 2S) - (+) -camphorate

In a round bottom flask (1R, 2S) - (+) -camphoric acid (1.149g, 5.74mmol) was added as a solid to a stirred warm solution of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (1.00g, 5.70mmol) in ethanol (14 mL). In addition toWhen hot, all solids dissolved to give a yellow solution. No precipitate formed on standing overnight at ambient temperature. The solution was concentrated by rotary evaporation to give an amber-brown foam, which was dried (suction) under vacuum at 50 ℃ for 6h to give 2.098g of a viscous amber oil. Isopropyl acetate (10mL) was added and the solution was allowed to stand overnight at ambient temperature. Some evidence of nucleation of crystals was seen in the gummy red-amber oil. Isopropyl acetate (10mL) and 2-propanol (20 drops) were added and the mixture was heated slowly and stirred for over 48 h. The resulting cream-like solid with some orange lumps was broken up with a spatula and the mixture (colorless liquid) was stirred overnight. The off-white solid was filtered through a Buchner funnel, washed with cold isopropyl acetate (10mL), and dried (evacuated) in a vacuum oven at 50 ℃ for 21h to give 2.034g (94.9%) of an off-white to cream powder, mp 157-.¹H NMR(DMSO-d₆) The 1: 1 salt stoichiometry was confirmed.¹H NMR(DMSO-d₆): Δ 9.00(s, 1H), 8.85(s, 2H), 6.58(dd, 1H), 6.47(d, 1H), 3.17(dd, 1H), 3.08(m, 1H), 2.97(m, 1H), 2.92(dd, 1H)2.74(dd, 1H), 2.61(dd, 1H), 2.30 (sextuple, 1H), 2.00(m, 2H), 1.65(m, 2H), 1.32(m, 1H), 1.15(s, 3H, — CH of the acid moiety₃One salt stoichiometry is shown), 1.07(s, 3H, CH of acid moiety₃One salt stoichiometry), 0.75(s, 3H, -CH)₃Acid moiety, showing one-salt stoichiometry).

Example 32: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-di-p-anisoyl-D-tartrate

In a round bottom flask (+) -di-p-anisoyl-D-tartaric acid (2.388g, 5.71mmol) was added as a solid to a stirred warm solution of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (1.008g, 5.75mmol) in ethanol (22 mL). Precipitation of the salt occurred, and then all of the (+) -di-p-anisoyl-D-tartaric acid was added. The salt is insoluble on heating, but a change in solids occurs, i.e. conversion to a light-colored loose white powder. The mixture was cooled to ambient temperature and stirred for more than 48 h. The resulting solid was filtered through a Buchner funnel and washed with ethanol: (5 × 5mL) and dried (evacuated) in a vacuum oven at 50 ℃ for 13h to give 3.20g (94.4%) of an off-white to white chalk powder, mp 173-.¹H NMR(DMSO-d₆) The 1: 1 salt stoichiometry was confirmed.¹H NMR(DMSO-d₆): Δ 9.65 (broad s,. about.1H), 9.03(s, 1H), 8.82(s, 2H), 7.89(d, 4H, -C)₆H₄-, shows one salt stoichiometry), 7.01(d, 4H, -C₆H₄-, shows one salt stoichiometry), 6.44(m, 2H), 5.60(s, 2H, C of the acid moietyH(CO₂H) -O-, shows one-salt stoichiometry), 3.79(s, 6H, -OCH of acid moiety₃One salt stoichiometry) 3.30(dd, 1H), 3.22(m, 1H), 3.09(m, 1H), 2.95(m, 1H), 2.84(m, 1H), 2.01(m, 1H), 1.69(m, 1H).

Example 33: (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono- (R) - (-) -Phencyphos salt

In a round bottom flask (R) - (-) -Phencyphos (1.391g, 5.77mmol) was added as a solid to a stirred solution of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine free base (1.006g, 5.73mmol) in ethanol (10 mL). Most of the solid dissolved upon stirring at ambient temperature and all dissolved upon slow heating. The stirred amber solution was heated to reflux, cooled to ambient temperature and allowed to stand overnight. The resulting white needle crystals were filtered through a Buchner funnel, washed with cold ethanol (5mL), dried (evacuated) in a vacuum oven at 50 ℃ for 18h to give 0.811g (33.9%) of off-white crystals, mp 197-.¹H NMR(DMSO-d₆) The 1: 1 salt stoichiometry was confirmed.¹H NMR(DMSO-d₆): Δ 9.81 (broad s,. about.1H), 9.02(s, 1H), 8.85(s, 2H), 7.27(m, 5H, C)₆H₅-), 6.56(dd, 1H), 6.48(d, 1H), 5.00(d, 1H, -O-CH-of the acid moiety-shows one-salt stoichiometry), 4.00(d, 1H, -O-CH of the acid moiety₂-, shows one salt stoichiometry), 3.48(dd, 1H, acid moiety-O-CH)₂-, one salt stoichiometry), 3.36(dd, 1H), 3.30(m, 1H), 3.17(m, 1H), 3.07(m, 1H), 2.93(dd, 1H), 2.12(m, 1H)1.78(m, 1H), 0.79(s, 3H, — CH of the acid moiety)₃One salt stoichiometry is shown), 0.60(s, 3H, CH of the acid moiety)₃One salt stoichiometry is shown).

Although specific embodiments of the invention have been illustrated and described in detail herein, the invention is not so limited. The foregoing detailed description is provided as illustrative of the invention and is not to be construed as limiting in any way. Modifications will be apparent to those skilled in the art and all modifications that do not depart from the spirit of the invention are intended to be included within the scope of the appended claims.

Claims (35)

1. An acid addition salt of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, 1-hydroxy-2-naphthoic acid, ketoglutaric acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-malic acid, hippuric acid, L-lactic acid, benzoic acid, succinic acid, adipic acid, acetic acid, nicotinic acid, propionic acid, orotic acid, 4-hydroxybenzoic acid, di-p-toluoyl-D-tartaric acid, di-p-anisoyl-D-tartaric acid, di-benzoyl-D-tartaric acid, 10-camphorsulfonic acid, camphoric acid and phencyphos.
2. 2. An acid addition salt as claimed in claim 1, wherein the acid is citric acid, orotic acid or maleic acid salt.
3. 3. An acid addition salt as claimed in claim 1 or claim 2, wherein the salt is in substantially crystalline form.
4. A crystalline form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate.
5. An amorphous form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate.
6. An amorphous form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate having an XRPD pattern substantially equivalent to the pattern shown in figure 1.
7. A polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate characterized by a powder x-ray diffraction pattern comprising at least one of the following peaks:

   2θ 11.02 20.01 22.06 24.66 32.13 33.35 34.61 35.96 38.65 40.23
8. a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate having an XRPD pattern substantially equivalent to the pattern shown in figure 3.
9. A polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate characterized by a powder x-ray diffraction pattern comprising at least one of the following peaks:

   2θ 9.43 12.24 16.24 18.38 19.18 19.48 21.52 22.89 23.08 24.28 30.77 31.27 32.36 33.09 34.86 37.26 37.63 39.47
10. a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate having an XRPD pattern substantially equivalent to the pattern shown in figure 4.
11. A polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate characterized by a powder x-ray diffraction pattern comprising at least one of the following peaks:

    2θ 5.05 10.81 14.06 15.20 17.43 23.47 24.21 25.52 26.95
12. a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-citrate having an XRPD pattern substantially equivalent to the pattern shown in figure 5.
13. A crystalline form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-orotate.
14. A polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-orotate characterized by a powder x-ray diffraction pattern comprising at least one of the following peaks:
15. a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-orotate having an XRPD pattern substantially equivalent to the pattern shown in figure 6.
16. A crystalline form of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate.
17. A polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate characterized by a powder x-ray diffraction pattern comprising at least one of the following peaks:

    2θ 12.81 16.09 18.00 19.07 24.49 26.40 26.04 27.88
18. a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate having an XRPD pattern substantially equivalent to the pattern shown in figure 7.
19. A polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate characterized by a powder x-ray diffraction pattern comprising at least one of the following peaks:

    2θ

    4.31 16.56 18.29 18.78 19.64 20.27 21.02 21.46 21.90 22.43 22.86 25.40 25.73 26.15 26.56 27.40 28.59 29.57
20. a polymorph of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine mono-maleate having an XRPD pattern substantially equivalent to the pattern shown in figure 8.
21. 21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and one or more pharmaceutically acceptable carriers, diluents or excipients.
22. 22. A method of treatment or prophylaxis of pain, inflammation or CNS disorders comprising administering a compound according to any one of claims 1 to 20.
23. 23. The use of a compound according to any one of claims 1 to 20 for the manufacture of a medicament for the treatment or prevention of pain, inflammation or CNS disorders.
24. 24. A compound according to any one of claims 1 to 20 for use in the treatment or prevention of pain, inflammation or a CNS disorder.
25. 25. A process for the preparation of a compound according to claims 1-20 wherein (S) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine is present in an amount less than 25% by weight.
26. 26. The method of claim 25, wherein (S) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine is present in an amount less than 15% by weight.
27. 27. The method of claim 25, wherein (S) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine is present in an amount less than 5% by weight.
28. 28. The method of claim 25, wherein (S) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine is present in an amount less than 2% by weight.
29. 29. The method of claim 25, wherein (S) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine is present in an amount less than 1 weight percent.
30. 30. The method of claims 25-29, wherein no chiral chromatographic separation step is required.
31. 31. A process for the preparation of pharmaceutical grade (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof.
32. 32. A process for the preparation of (R) -5- ((E) -2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof on a scale suitable for commercial preparation.
33. 33. The method of claim 32, wherein the method is a fully validated cGMP commercial grade API preparation method.
34. 34. A product synthesized by any of claims 25-33.
35. 35. The method of claims 25-33 using one or more of (R) -diethyl 2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) malonate, (R) -2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) malonic acid, (R) -tert-butyl 3- (2-hydroxyethyl) pyrrolidine-1-carboxylate, and (R) -tert-butyl 3- (2-iodoethyl) pyrrolidine-1-carboxylate as a synthetic intermediate.