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WO2006038119A1 - Synthese stereoselective d'alcoxy-prolines n-protegees - Google Patents

Synthese stereoselective d'alcoxy-prolines n-protegees Download PDF

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Publication number
WO2006038119A1
WO2006038119A1 PCT/IB2005/003205 IB2005003205W WO2006038119A1 WO 2006038119 A1 WO2006038119 A1 WO 2006038119A1 IB 2005003205 W IB2005003205 W IB 2005003205W WO 2006038119 A1 WO2006038119 A1 WO 2006038119A1
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formula
compound
salt
pyrrolidine
salts
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PCT/IB2005/003205
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English (en)
Inventor
Derek Clinton Vrieze
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Warner-Lambert Company Llc
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Publication of WO2006038119A1 publication Critical patent/WO2006038119A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to materials and methods for preparing optically- active N-protected alkoxy prolines, including (2i?,4i?)-4-methoxy-pyrroli dine- 1,2- dicarboxylic acid 1-tert-butyl ester.
  • the N-protected alkoxy prolines are useful for preparing various serine protease factor Xa inhibitors, which are thought to be useful for treating diseases associated with abnormal thrombosis.
  • the '787 application describes a number of methods for preparing the cyclic amino acid and proline derivatives. Many of these methods employ, as chemical intermediates, optically active N-protected alkoxy prolines, including (2i?,4i?)-4-methoxy-pyrrolidine-l,2-dicarboxylic acid l-tert-butyl ester. As described in the '787 application, the N-protected alkoxy prolines are prepared from an appropriate optically active cyclic amino acid, such as (2i?,4/?)-4-hydroxy- pyrrolidine-2-carboxylic acid (cis-4-hydroxy-D-proline), using a rather involved, six- step synthesis.
  • optically active cyclic amino acid such as (2i?,4/?)-4-hydroxy- pyrrolidine-2-carboxylic acid (cis-4-hydroxy-D-proline)
  • the present invention provides a comparatively short and efficient method for preparing N-protected alkoxy prolines from commercially available starting materials.
  • (2i?,4i?)-4-methoxy-pyrrolidine-l,2-dicarboxylic acid 1-tert- butyl ester may be prepared from cis-4-hydroxy-D-proline in two steps with a yield of 85% or better.
  • the N-protected alkoxy prolines are useful for preparing various serine protease factor Xa inhibitors, which are thought to be useful for treating diseases associated with abnormal thrombosis.
  • One aspect of the present invention provides a method of making a compound of Formula IA,
  • Another aspect of the present invention provides a method of making a compound of Formula IA or a salt thereof.
  • the method comprises reacting a compound of Formula 2A or a salt thereof with a compound of Formula 3, in the presence of a base, to give the compound of Formula IA or a salt thereof, where Formula IA, Formula 2 A, and Formula 3, including their substituents, R 1 , R 2 , and X, are as defined above in the preceding paragraph.
  • a further aspect of the present invention provides a method of making a compound of Formula 5,
  • the present invention includes all salts, whether pharmaceutically acceptable or not, solvates, hydrates, and polymorphic forms of the disclosed compounds.
  • Certain compounds may contain an alkenyl or cyclic group, so that cisltrans (or ZlE) stereoisomers are possible, or may contain a keto or oxime group, so that tautomerism may occur.
  • the present invention generally includes all ZIE isomers and tautomeric forms, whether they are pure or mixtures.
  • Substituted groups are those in which one or more hydrogen atoms have been replaced with one or more non-hydrogen atoms or groups, provided that valence requirements are met and that a chemically stable compound results from the substitution.
  • Alkyl refers to straight chain and branched saturated hydrocarbon groups, generally having a specified number of carbon atoms (i.e., C 1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms).
  • alkyl groups include, without limitation, methyl, ethyl, n-propyl, /-propyl, ⁇ -butyl, s-butyl, z-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, 2- methylbut-2-yl, 2,2,2-trimethyleth-l-yl, rc-hexyl, and the like.
  • alkenyl refers to straight chain and branched hydrocarbon groups having one or more unsaturated carbon-carbon bonds, and generally having a specified number of carbon atoms.
  • alkenyl groups include, without limitation, ethenyl, 1-propen-l-yl, l-propen-2-yl, 2-pro ⁇ en-l-yl, 1-buten-l-yl, 1- buten-2-yl, 3-buten-l-yl, 3-buten-2-yl, 2-buten-l-yl, 2-buten-2-yl, 2-methyl- 1-propen- l-yl, 2-methyl-2-propen-l-yl, 1,3-butadien-l-yl, l,3-butadien-2-yl, and the like.
  • alkanoyl refers to alkyl-C(O)-, where alkyl is defined above, and generally includes a specified number of carbon atoms, including the carbonyl carbon.
  • alkanoyl groups include, without limitation, formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, and the like.
  • Alkoxy and alkoxycarbonyl refer, respectively, to alkyl-O- and alkyl- O-C(O)-, where alkyl is defined above.
  • alkoxy groups include, without limitation, methoxy, ethoxy, n-propoxy, z-propoxy, n-butoxy, s-butoxy, t-butoxy, n- pentoxy, s-pentoxy, and the like.
  • alkoxycarbonyl groups include, without limitation, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i- propoxycarbonyl, n-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, n- pentoxycarbonyl, s-pentoxycarbonyl, and the like
  • Halo “Halo,” “halogen” and “halogeno” may be used interchangeably, and refer to fluoro, chloro, bromo, and iodo.
  • Cycloalkyl refers to saturated monocyclic and bicyclic hydrocarbon rings, generally having a specified number of carbon atoms that comprise the ring (i.e., C 3-7 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms as ring members).
  • the cycloalkyl may be attached to a parent group or to a substrate at any ring atom, unless such attachment would violate valence requirements.
  • the cycloalkyl groups may include one or more non-hydrogen substituents unless such substitution would violate valence requirements.
  • Useful substituents include, without limitation, alkyl, alkoxy, alkoxycarbonyl, alkanoyl, and halo, as defined above, and hydroxy, mercapto, nitro, and amino.
  • Examples of monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Examples of bicyclic cycloalkyl groups include, without limitation, bicyclo[1.1.0]butyl, bicyclo[l.l.l]pentyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.0]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.1.1]octyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, bicyclo[3.3.1]n
  • Cycloalkanoyl refers to cycloalkyl-C(O)-, where cycloalkyl is defined above, and generally includes a specified number of carbon atoms, excluding the carbonyl carbon.
  • Examples of cycloalkanoyl groups include, without limitation, cyclopropanoyl, cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, cycloheptanoyl, and the like.
  • Aryl and “arylene” refer to monovalent and divalent aromatic groups, respectively.
  • aryl groups include, without limitation, phenyl, naphthyl, biphenyl, pyrenyl, anthracenyl, fluorenyl, and the like, which may be unsubstituted or substituted with 1 to 4 substituents.
  • substituents include, without limitation, alkyl, alkoxy, alkoxycarbonyl, alkanoyl, cycloalkanoyl, and halo, as defined above, as well as nitro.
  • Arylalkyl refers to aryl-alkyl, where aryl and alkyl are defined above. Examples include, without limitation, benzyl, fluorenylmethyl, and the like.
  • Leaving group refers to any group that leaves a molecule during a fragmentation process, including substitution reactions, elimination reactions, and addition-elimination reactions. Leaving groups may be nucleofugal, in which the group leaves with a pair of electrons that formerly served as the bond between the leaving group and the molecule, or may be electrofugal, in which the group leaves without the pair of electrons. The ability of a nucleofugal leaving group to leave depends on its base strength, with the strongest bases being the poorest leaving groups.
  • Common nucleofugal leaving groups include nitrogen (e.g., from diazonium salts), sulfonates (including tosylates, brosylates, nosylates, and mesylates), triflates, nonaflates, tresylates, halide ions, carboxylate anions, phenolate ions, and alkoxides. Some stronger bases, such as NH 2 and OH " can be made better leaving groups by treatment with an acid. Common electrofugal leaving groups include the proton, CO 2 , and metals.
  • Enantiomeric excess or "ee” is a measure, for a given sample, of the excess of one enantiomer over a racemic sample of a chiral compound and is expressed as a percentage. Enantiomeric excess is defined as 100 x (er - 1) / (er + 1), where "er” is the ratio of the more abundant enantiomer to the less abundant enantiomer.
  • "Diastereomeric excess” or “de” is a measure, for a given sample, of the excess of one diastereomer over a sample having equal amounts of diastereomers and is expressed as a percentage. Diastereomeric excess is defined as 100 x (dr - 1) / (dr + 1), where "dr” is the ratio of a more abundant diastereomer to a less abundant diastereomer.
  • Stepselective refer to a given process (e.g., hydrogenation) that yields more of one stereoisomer, enantiomer, or diastereoisomer than of another, respectively.
  • High level of stereoselectivity refers to a given process that yields products having an excess of one stereoisomer, enantiomer, or diastereoisomer, which comprises at least about 90% of the products.
  • a high level of enantioselectivity or diastereoselectivity would correspond to an ee or de of at least about 80%.
  • Stepoisomerically enriched refers, respectively, to a sample of a compound that has more of one stereoisomer, enantiomer or diastereomer than another.
  • the degree of enrichment may be measured by % of total product, or for a pair of enantiomers or diastereomers, by ee or de.
  • substantially pure stereoisomer refers, respectively, to a sample containing a stereoisomer, enantiomer, or diastereomer, which comprises at least about 95% of the sample.
  • a substantially pure enantiomer or diastereomer would correspond to samples having an ee or de of about 90% or greater.
  • a "pure stereoisomer,” “pure enantiomer,” “pure diastereomer,” and variants thereof, refer, respectively, to a sample containing a stereoisomer, enantiomer, or diastereomer, which comprises at least about 99.5% of the sample.
  • a pure enantiomer or pure diastereomer would correspond to samples having an ee or de of about 99% or greater.
  • Optesite enantiomer refers to a molecule that is a non-superimposable mirror image of a reference molecule, which may be obtained by inverting all of the stereogenic centers of the reference molecule. For example, if the reference molecule has S absolute stereochemical configuration, then the opposite enantiomer has R absolute stereochemical configuration. Likewise, if the reference molecule has S,S absolute stereochemical configuration, then the opposite enantiomer has R,R stereochemical configuration, and so on.
  • “Pharmaceutically acceptable salts” refers to acid or base addition salts of claimed and disclosed compounds, which are within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • the chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification may be carried out at about RT, but particular reactions may require the use of higher or lower temperatures, depending on reaction kinetics, yields, and the like. Many of the chemical transformations may also employ one or more compatible solvents, which depending on the nature of the reactants, may be polar protic solvents, polar aprotic solvents, non-polar solvents, or some combination. Although the choice of solvent or solvents may influence the reaction rate and yield, such solvents are generally considered to be inert (unreactive). Any reference in the disclosure to a stoichiometric range, a temperature range, a pH range, etc., includes the indicated endpoints.
  • N-protected alkoxy prolines are represented by Formula IA or Formula IB (above and Scheme I), and by opposite enantiomers of the compounds of Formula IA and Formula IB.
  • R 1 is an N-protecting group and R 2 is C 1-6 alkyl.
  • R 1 may be any group used to protect an amine, including, but not limited to C 1-6 alkyl, C 2-6 alkenyl, and aryl C 1-6 alkyl.
  • R 1 include -C(O)R 3 , -CH 2 OR 3 , -CO 2 R 3 , -C(O)S n R 3 , -S(O) n R 3 , -NHR 3 , -NR 3 R 4 , -NHC(O)R 3 , -OC(O)NHR 3 , -OC(O)NHC(O)R 3 , -OC(O)NR 3 R 4 , -C(O)R 3 Y, -COR 3 Y, -CO 2 R 3 Y, -C(O)S n R 3 Y, -S(O) n R 3 Y, -NHR 3 Y, -NHC(O)R 3 Y, -OC(O)NHR 3 Y, or -OC(O)NHC(O)R 3 Y, in which Y is -Si(R 4 ) 3 , -S(O) n R 4 , -
  • Typical R 1 substituents include, but are not limited to, benzyl, Cbz, Boc, Fmoc, and trityl
  • typical R 2 substituents include, but are not limited to methyl, ethyl, n-propyl, and z-propyl.
  • Compounds of Formula IA and Formula IB may thus include, without limitation, (R,R)- and (4S,22?)-l-benzyl-4-methoxy-pyrrolidine-2- carboxylic acid; (R,R)- and (45,2i?)-4-methoxy-pyrrolidine-l,2-dicarboxylic acid 1- benzyl ester; (R,R)- and (45,2i?)-4-methoxy-pyrrolidine-l,2-dicarboxylic acid 1-tert- butyl ester; (R,R) ⁇ and (4S,2i?)-4-methoxy-pyrrolidine-l,2-dicarboxylic acid 1-(9H- fluoren-9-ylmethyl) ester; and (R,R)- and (45,2/?)-4-methoxy-l-trityl-pyrrolidine-2- carboxylic acid.
  • N-protected alkoxy prolines include the opposite enantiomers of Formula IA and Formula IB, such as (S,S)- and (2S,4i?)-l-benzyl-4- methoxy-pyrrolidine-2-carboxylic acid; (S,S)- and (2S,4i?)-4-methoxy-pyrrolidine- 1,2-dicarboxylic acid 1 -benzyl ester; (S, S)- and (25,4i?)-4-methoxy-pyrrolidine-l,2- dicarboxylic acid 1-tert-butyl ester; (S, S)- and (2S,4_R)-4-methoxy-pyrroUdine-l,2- dicarboxylic acid l-(9H-fluoren-9-ylmethyl) ester; and (S, S)- and (2,S,42?)-4-methoxy- l-trityl-pyrrolidine-2-carboxylic acid.
  • Scheme I shows a method for preparing optically active N-protected alkoxy prolines of Formula IA or Formula IB.
  • the method includes installing a protecting group, R 1 , on (i?,i?)-4-hydroxy-pyrrolidine-2- carboxylic acid (Formula 4A) or on (2i?,45)-4-hydroxy-pyrrolidine-2-carboxylic acid (Formula 4B) to give an N-protected, (i?,i?)-4-hydroxy-pyrrolidine-2-carboxylic acid (Formula 2A) or an N-protected, (2i?,45)-4-hydroxy-pyrrolidine-2-carboxylic acid (Formula 2B), which is subsequently reacted with an alkylating agent (Formula 3) to give the desired optically active N-protected alkoxy proline (Formula IA or formula IB).
  • a protecting group, R 1 on (i?,i?)-4-hydroxy-pyrrolidine-2- carboxylic acid (Formula
  • the opposite enantiomers of the compounds of Formula IA and Formula IB may be prepared by installing R 1 on (>S,5)-4-hydroxy-pyrrolidine-2- carboxylic acid or on (42?,25)-4-hydroxy-pyrrolidine-2-carboxylic acid, respectively, and then reacting the resulting N-protected intermediate with an alkylating agent (Formula 3).
  • an alkylating agent Forma 3
  • the above chemical transformations may be carried out using salts of the compounds represented by formula IA, IB, 2A, 2B, 4A, 4B, as well as their opposite enantiomers.
  • R 1 is installed using standard techniques such as acylation, alkylation, sulfonylation, and the like.
  • Table II lists conditions for installing and removing representative protecting groups. For a more complete list of methods for installing and removing N-protecting groups, see T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry, and P. Kocienski, Protective Groups, as noted above. See also, M. Bodanszky & A. Bodanszky, The Practice of Peptide Synthesis (2d ed. 1994), and references cited therein. Table II. Conditions for Protecting and De-protecting Amines
  • the method also includes reacting an N-protected, (R,R)- 4-hydroxy-pyrrolidine-2-carboxylic acid (Formula 2A) or an N-protected, (2i?,45)-4- hydroxy-pyrrolidine-2-carboxylic acid (Formula 2B), or opposite enantiomers thereof, with an alkylating agent (formula 3) in a solvent and in the presence of a base.
  • R 2 is as defined above in connection with Formula IA and Formula IB
  • X is a leaving group.
  • Useful leaving groups include, without limitation, halo substituents, Cl, Br, and I, and sulfonate substituents, such as toluene-p-sulfonate, methylsulfonate, p-bromo-benzene-sulfonate, triflate, and the like.
  • Typical alkylating agents thus include, without limitation, alkyl halides, such as MeCl, MeBr, MeI, EtCl, EtBr, EtI, H-PrCl, 7Z-PrBr, n-Prl, i-PrCl, /-PrBr, /-PrI, and the like, and alkylsulfonate esters, such as, MeOTs, MeOMs, MeOBs, MeOTf, EtOTs, EtOMs, EtOBs, EtOTf, n- PrOTs, n-PrOMs, n-PrOBs, n-PrOTf, /-PrTs, /-PrMs, /-PrBs, /-PrTf, and the like.
  • the alkylating agents may be obtained from commercial sources or may be prepared using methods that are well known in the art.
  • Useful bases include those that are capable of deprotonating the hydroxy moiety of the N-protected hydroxy proline (formula 2A, 2B, etc.), but do not react appreciably with the alkylating agent (formula 3) — i.e., non-nucleophilic bases whose conjugate acids have pKa's greater than about 16. These include, without limitation, LiH, NaH, LDA, LHMDS, KHMDS, LTMP, /-PrONa, ⁇ -BuOK, and the like, which may be obtained from commercial sources or may be prepared using methods that are well known in the art.
  • the alkylation may be carried out in an inert organic solvent.
  • solvent generally depends on the polarity of the reactants, the nature of the R 2 substituent, and other factors known in the art.
  • aprotic solvent may provide improved yields over a more polar aprotic solvent, whereas the opposite may hold for cases when R 2 is a tertiary alkyl group.
  • Useful solvents include THF, Et 2 O, DMSO, DMF, ACN, toluene, 1,4-dioxane, MeCl 2 , 1,2-dichloroethane, and the like, and are generally used in amounts needed to completely dissolve the reagents.
  • the alkylation reaction may employ stoichiometric amounts of the reactants (i.e., molar ratio of the N-protected hydroxy proline to the alkylating agent of 1:1), but to improve conversion, minimize side-products, and so on, the alkylation step may employ an excess of one of the reactants (e.g., molar ratio of 1:1.1 to 1.1:1, 1:1.5 to 1.5:1, 2:1 to 1:2, 3:1 to 1:3, etc.).
  • the reactants i.e., molar ratio of the N-protected hydroxy proline to the alkylating agent of 1:1
  • the alkylation step may employ an excess of one of the reactants (e.g., molar ratio of 1:1.1 to 1.1:1, 1:1.5 to 1.5:1, 2:1 to 1:2, 3:1 to 1:3, etc.).
  • the alkylation reaction may employ stoichiometric amounts of base (i.e., molar ratio of base to N-protected hydroxy proline of 2: 1), but it may also employ an excess of base (e.g., molar ratio of 2.1:1, 2.5:1, 3:1, etc.).
  • base i.e., molar ratio of base to N-protected hydroxy proline of 2: 1
  • an excess of base e.g., molar ratio of 2.1:1, 2.5:1, 3:1, etc.
  • the alkylation may be run at temperatures of about O 0 C to reflux. Typically, the alkylation step is carried out at RT, but the reaction may benefit from higher or lower temperatures. For example, during the addition of reactants, the reaction mixture may be cooled to a temperature of about 0°C to about 5 0 C and then allowed to react at RT or above.
  • Pharmaceutically acceptable acid addition salts include nontoxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like.
  • Pharmaceutically acceptable base salts include nontoxic salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as amines.
  • suitable metal cations include, without limitation, sodium cations (Na + ), potassium cations (K + ), magnesium cations (Mg 2+ ), calcium cations (Ca 2+ ), and the like.
  • suitable amines include, without limitation, iWV'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.
  • Certain physical properties (e.g., solubility, crystal structure, hygroscopicity, etc.) of a compound's free base, free acid, or zwitterion may differ from its acid or base addition salt. Generally, however, references to the free acid, free base or zwitterion of a compound would include its acid and base addition salts.
  • certain compounds of this disclosure may exist as an unsolvated form or as a solvated form, including hydrated forms.
  • Pharmaceutically acceptable solvates also include hydrates and solvates in which the crystallization solvent may be isotopically substituted, e.g. D 2 O, dVacetone, dg-DMSO, etc.
  • references to an unsolvated form of a compound also include the corresponding solvated or hydrated form of the compound.
  • the disclosed compounds also include all pharmaceutically acceptable isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.
  • isotopes suitable for inclusion in the disclosed compounds include, without limitation, isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, such as 13 C and 14 C; isotopes of nitrogen, such as 15 N; isotopes of oxygen, such as 17 O and 18 O; isotopes of phosphorus, such as 31 P and 32 P; isotopes of sulfur, such as S; isotopes of fluorine, such as F; and isotopes of chlorine, such as Cl.
  • Use of isotopic variations e.g., deuterium, 2 H
  • certain isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium, 3 H, or 14 C), which may be useful in drug and/or substrate tissue distribution studies.
  • a radioactive isotope e.g., tri
  • the mixture was filtered to give the titled compound as a white to yellow-white solid (20.16 g). After sitting for a day, the filtrate was filtered to give a second crop of the titled compound (1.42 g). The two crops were combined to give the titled compound as a white to yellow- white solid (21.58 g, 93% yield; chiral purity via chiral HPLC: 100%).
  • the titled compound was prepared in a manner similar to Example 1 and Example 2, except that (4i?,25)-4-hydroxy-pyrrolidine-2-carboxylic acid was used in place of (i?,/?)-4-hydroxy-pyrrolidme-2-carboxylic acid, and (4i?,25 r )-4-hydroxy- pyrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester was used in place of (R,R)-4- hydroxy-pyrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester.

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Abstract

L'invention concerne un procédé de préparation d'alcoxy-prolines N-protégées optiquement actives, comprenant un ester 1-tert-butyle d'acide (2R,4R)-4-méthoxy-pyrrolidine-1,2-dicarboxylique. Les alcoxy-prolines N-protégées de l'invention sont utiles pour préparer des inhibiteurs variés du facteur Xa de la sérine protéase qui sont utiles pour traiter des maladies associées à une thrombose anormale.
PCT/IB2005/003205 2004-10-08 2005-09-26 Synthese stereoselective d'alcoxy-prolines n-protegees WO2006038119A1 (fr)

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US9217015B2 (en) 2010-07-16 2015-12-22 S&T Global Inc. Cyclosporin derivatives for the treatment and prevention of a viral infection
US9573978B2 (en) 2010-08-12 2017-02-21 S&T Global, Inc. Cyclosporin derivatives for the treatment and prevention of a viral infection
US9890198B2 (en) 2010-12-03 2018-02-13 S&T Global Inc. Cyclosporin derivatives and uses thereof

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WO2011016576A1 (fr) 2009-08-04 2011-02-10 Takeda Pharmaceutical Company Limited Dérivés d'alanine comme inhibiteurs de protéines d'apoptose
US9217015B2 (en) 2010-07-16 2015-12-22 S&T Global Inc. Cyclosporin derivatives for the treatment and prevention of a viral infection
US9573978B2 (en) 2010-08-12 2017-02-21 S&T Global, Inc. Cyclosporin derivatives for the treatment and prevention of a viral infection
US9890198B2 (en) 2010-12-03 2018-02-13 S&T Global Inc. Cyclosporin derivatives and uses thereof
US10647747B2 (en) 2010-12-03 2020-05-12 S&T Global Inc. Cyclosporin derivatives and uses thereof

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