HK1107821B - Method for the production of dihydropteridinones - Google Patents

Description

Process for preparing dihydropteridinones

Field of the invention

The invention relates to a method for producing dihydropteridinones of general formula (I)

Wherein the group L, R¹、R²、R³、R⁴And R⁵Having the definitions given in the claims and the description.

Prior Art

Pteridinone derivatives are known from the prior art as active substances having antiproliferative activity. WO03/020722 describes the use of dihydropteridinone derivatives in the treatment of neoplastic diseases and a process for their preparation.

The object of the present invention is to provide an improved process for the preparation of dihydropteridinones according to the invention.

Detailed Description

The present invention solves the above problem by the synthetic method described below, which is a convergent method compared to the method described in WO 03/020722.

The invention therefore relates to a process for preparing dihydropteridinones of the general formula (I),

wherein

R¹、R²Which may be the same or different, represent hydrogen or optionally substituted C₁-C₆-alkyl, or

R¹And R²Together represent a 2-to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms,

R³represents hydrogen or is selected from optionally substituted C₁-C₁₂Alkyl radical, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl and C₆-C₁₄A radical of an aryl group, or

Selected from optionally substituted and/or bridged C₃-C₁₂-cycloalkyl, C₃-C₁₂-cycloalkenyl radical, C₇-C₁₂Polycycloalkyl, C₇-C₁₂Polycyclic alkenyl, C₅-C₁₂Spirocycloalkyl, C containing 1 to 2 heteroatoms₃-C₁₂Heterocycloalkyl, and C containing 1 to 2 hetero atoms₃-C₁₂-a heterocycloalkenyl group, or

R¹And R³Or R²And R³Together representSaturated or unsaturated C₃-C₄An alkyl bridge, which may optionally contain 1 heteroatom,

R⁴represents a group selected from hydrogen, CN, hydroxy, -NR⁶R⁷And halogen, or

Selected from optionally substituted C₁-C₆Alkyl radical, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₅-alkoxy, C₂-C₅-alkenyloxy, C₂-C₅-alkynyloxy, C₁-C₆Alkylthio radical, C₁-C₆-alkylsulfinyl (sulfoxo) and C₁-C₆-a group of alkylsulfonyl groups,

l represents a linker selected from optionally substituted C₂-C₁₀Alkyl radical, C₂-C₁₀-alkenyl, C₆-C₁₄-aryl, -C₂-C₄-alkyl-C₆-C₁₄-aryl, -C₆-C₁₄-aryl-C₁-C₄Alkyl, optionally bridged C₃-C₁₂Cycloalkyl and heteroaryl optionally containing 1 or 2 nitrogen atoms,

n represents a number of 0 or 1,

m represents a number of 1 or 2,

R⁵represents a compound selected from the group consisting of optionally substituted morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropanyl, R⁸Diketomethylpiperazinyl, 4-oxothiomorpholinyl, 4-dioxothiomorpholinyl, thiomorpholinyl, -NR⁸R⁹And the group of azepinyl,

R⁶、R⁷may be the same or different and represents hydrogen or C₁-C₄-alkyl, and

R⁸、R⁹is represented by R⁵Substituted by unsubstituted nitrogenRadicals, which may be identical or different, are hydrogen or are selected from C₁-C₆-alkyl, -C₁-C₄-alkyl-C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₆-C₁₄-aryl, -C₁-C₄-alkyl-C₆-C₁₄Aryl, pyranyl, pyridinyl, pyrimidinyl, C₁-C₄Alkoxycarbonyl, C₆-C₁₄-arylcarbonyl group, C₁-C₄-alkylcarbonyl group, C₆-C₁₄Aryl methoxycarbonyl, C₆-C₁₄-arylsulfonyl, C₁-C₄-alkylsulfonyl and C₆-C₁₄-aryl-C₁-C₄-a group of alkylsulfonyl groups,

wherein the compound of formula (II)

Wherein

R¹To R³Is as defined and A is a leaving group,

with compounds of the formula (III)

Wherein

R⁴、R⁵L and m, n may be as defined.

Another subject of the invention is a process as described above for the preparation of dihydropteridinones of the general formula (I), in which R⁵Represents a morpholinyl or piperazine group which may be mono-or disubstituted by alkyl or cycloalkyl, preferably cyclopropylmethyl or dimethyl.

Another subject of the invention is a process as described above for the preparation of a dihydropteridinone of the general formula (I), wherein the dihydropteridinone is selected from the group consisting of the dihydropteridinones of the following general formula (I)

Abbreviations X used in the tables₁、X₂、X₃、X₄And X₅Each representing a substituent attached to the corresponding position R in the formula set forth in the table¹、R²、R³、R⁴And L_n-R⁵ _m。

In a preferred method, the reaction is carried out in the presence of an acid catalyst, such as: in the presence of inorganic or organic acids.

Also preferred is a process in which the acid catalyst used is an organic sulfonic acid, preferably methanesulfonic acid, ethanesulfonic acid, ethane-1, 2-disulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.

In a particularly preferred process, the amount of acid catalyst added is between 0.001 and 2 equivalents.

If a compound of formula (I) is represented by R⁵ _m-L_nContaining one or more basic groups in the radical, it is necessary, in addition to a catalytic amount of acid, to add a further equivalent of acid or a relatively greater equivalent of acid to effect protonation and thus blocking of one or more basic groups. In this case, in a particularly preferred process, the amount of acid catalyst added is more than one equivalent.

Also particularly preferred is a process wherein the reaction is carried out in a solvent selected from the group consisting of: amides, such as: dimethylformamide, dimethylacetamide or N-methylpyrrolidone, ureas, for example: 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (DMPU or dimethylpropylurea), sulfoxides, for example: dimethyl sulphoxides or sulphones, for example: sulfolane, primary alcohols, for example: methanol, ethanol, 1-propanol, 1-butanol or 1-pentanol, secondary alcohols, for example: 2-propanol or 2-butanol, isomeric secondary alcohols of pentane or hexane, tertiary alcohols of butane, pentane or hexane, acetonitrile and 2-propylnitrile. Particularly preferred are secondary alcohols, such as: 2-propanol, 2-butanol or 2-methyl-4-pentanol.

Particularly preferred is a process wherein the reaction temperature is from 18 to 180 ℃, preferably from 100 ℃ to 150 ℃.

The reaction can also be carried out in a low boiling solvent under pressure or using microwaves as an energy source.

The workup of the reaction can be carried out by customary methods, for example: by extraction purification steps or precipitation and crystallization procedures.

The compounds according to the invention may exist in the form of individual optical isomers, mixtures of individual enantiomers, diastereomers or racemates, in the form of tautomers, also as free bases or with pharmacologically acceptable acids, for example: hydrohalic acids, for example: hydrochloric or bromic acid, or organic acids, such as: oxalic acid, fumaric acid, diglycolic acid methanesulfonic acid.

Alkyl groups as well as alkyl groups which are part of other groups represent branched or straight chain alkyl groups having from 1 to 12 carbon atoms, preferably from 1 to 6, most preferably from 1 to 4 carbon atoms, for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl. Unless otherwise indicated, the above terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl include all possible isomeric forms. For example: the term propyl includes both the n-propyl and isopropyl isomers, and the term butyl includes: n-butyl, isobutyl, sec-butyl and tert-butyl, the term pentyl comprising: iso-pentyl and neopentyl.

In the above alkyl groups, one or more hydrogen atoms may be optionally substituted with other groups. For example, such alkyl groups may be substituted with fluorine. All hydrogen atoms of the alkyl group may also be optionally substituted.

Unless otherwise indicated, the term alkyl bridge is intended to represent a branched or straight chain alkyl group having from 1 to 5 carbon atoms, for example: methylene, ethylene, propylene, isopropylene, n-butylene, isobutyl, sec-butyl, tert-butyl and the like. Methylene, ethylene, propylene and butylene bridges are particularly preferred. In the so-called alkyl bridge 1 to 2C atoms may optionally be substituted by one or more heteroatoms selected from oxygen, nitrogen or sulfur.

As alkenyl group (including being part of another group) represents a branched or straight chain alkylene group having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, most preferably 2 to 3 carbon atoms, and which has at least one double bond. Examples thereof include: ethenyl, propenyl, butenyl, pentenyl, and the like. Unless otherwise indicated, the above terms propenyl, butenyl and the like also include all possible isomeric forms. For example: the term butenyl includes 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, and 1-ethyl-1-ethenyl.

Unless otherwise specified, in the above alkenyl groups, one or more hydrogen atoms may be optionally substituted with other groups. For example, an alkyl group may be substituted with a halogen atom, fluorine. All hydrogen atoms of the alkenyl group may also be optionally substituted.

As alkynyl group (including being part of another group) stands for a branched or straight-chain alkynyl group having 2 to 10 carbon atoms and which has at least one triple bond, for example: ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like, and ethynyl or propynyl is preferred.

Unless otherwise specified, in the above alkynyl groups, one or more hydrogen atoms may be optionally substituted with other groups. For example, such alkynyl groups may be substituted with fluorine. All hydrogen atoms of the alkynyl group may also be optionally substituted.

The term aryl represents an aromatic ring system having 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, preferably phenyl, which, unless otherwise indicated, may carry one or more of the following substituents, for example: OH, NO₂、CH、OMe、-OCHF₂、-OCF₃、-NH₂Halogen, preferably fluorine or chlorine, C₁-C₁₀-alkyl, preferably C₁-C₅-alkyl, preferably C₁-C₃Alkyl, particularly preferably methyl or ethyl, -O-C₁-C₃-alkyl, preferably-O-methyl or-O-ethyl, -COOH, -COO-C₁-C₄-alkyl, preferably-O-methyl or-O-ethyl, or CONH₂，

Examples of heteroaryl groups in which up to two C atoms are replaced by one or two nitrogen atoms include: pyrrole, pyrazole, imidazole, triazole, pyridine, pyrimidine, where the individual heteroaryl rings mentioned above may optionally also be fused with a benzene ring, preferably benzimidazole, and such heterocycles may carry, for example, one or more of the following substituents, unless otherwise indicated: F. cl, Br, OH, OMe, methyl, ethyl, CN, CONH₂、NH₂Optionally substituted phenyl, optionally substituted heteroaryl, preferably optionally substituted pyridyl.

As cycloalkyl groups there are cycloalkyl groups having 3 to 12 carbon atoms, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, and each of the cycloalkyl groups mentioned may optionally also carry one or more substituents, for example: OH, NO₂、CN、OMe、-OCHF₂、-OCF₃、-NH₂Or halogen, preferably fluorine or chlorine, C₁-C₁₀-alkyl, preferably C₁-C₅-alkyl, preferably C₁-C₃Alkyl, particularly preferably methyl or ethyl, -O-C₁-C₃-alkyl, preferably-O-methyl or-O-ethyl, -COOH, -COO-C₁-C₄-alkyl, preferably-COO-methyl or-COO-ethyl or-CONH₂. Particularly preferred cycloalkyl group substituents are ═ O, OH, NH₂Methyl or F.

As cycloalkenyl radicals are cycloalkyl radicals having from 3 to 12 carbon atoms which have at least one double bond, for example: cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, preferably cyclopropenyl, cyclopentenyl or cyclohexenyl, and the cycloalkenyl groups mentioned above may optionally also carry one or more substituents.

"═ O" represents an oxygen atom bonded through a double bond.

Unless otherwise indicated, saturated or unsaturated heterocycles, which may contain the heteroatom nitrogen, oxygen or sulfur, are defined as heterocycloalkyl radicals having 3 to 12 members, preferably 5-, 6-or 7 members, and which may contain nitrogen, oxygen or sulfur, for example tetrahydrofuran, tetrahydrofuranone, gamma-butylpropyl, alpha-pyran, gamma-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan (diazepan), oxazine, tetrahydrooxazine, isothiazole, pyrazolidine, preferably morpholine, pyrrolidine, piperidine or piperazine, while the heterocyclic radical may optionally carry substituents, for example: c₁-C₄-alkyl, preferably methyl, ethyl or propyl.

As polycycloalkyl groups are optionally substituted di-, tri-, tetra-or pentacyclic cycloalkyl groups such as: pinane (pinane), 2.2.2-octane, 2.2.1-heptane or adamantane. As polycycloalkenyl radicals are optionally bridged and/or substituted 8-membered di-, tri-, tetra-or pentacyclic cycloalkenyl radicals, preferably bicycloalkenyl or tricycloalkenylA radical if it has at least one double bond such as: norbornene (norbomene). As spiro alkyl group is optionally substituted spirocyclic C₅-C₁₂-an alkyl group.

Halogen as a rule represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, particularly preferably chlorine.

As leaving group a represents a leaving group, for example: fluorine, chlorine, bromine, iodine, methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl or p-toluenesulfonyl, preferably chlorine.

The intermediate compounds (II) and (III) can be prepared by methods known in the literature, for example: similar to the synthetic method described in WO 03/020722.

The intermediate compound (III) can be prepared by a method of trans-diamino-substituted cyclohexanes by the method described below.

The compounds of formula (I) listed in Table 1 were obtained in a similar manner to that described above.

Abbreviation X in Table 1₁、X₂、X₃、X₄And X₅Each representing a substituent attached to the corresponding position R in the formula set forth in the table¹、R²、R³、R⁴And L_n-R⁵ _m。

TABLE 1

The following synthetic examples are intended to further illustrate the invention without limiting its content. The synthesis is illustrated in schemes (1) to (3).

Synthesis of the Compound of example 46 (Synthesis scheme 1)

Synthetic scheme 1

Aniline fragment 4 was prepared by:

● Compound3Preparation of

Method 1A:

100g (0.507mol) of 3-methoxy-4-nitrobenzoic acid2163g (0.508mol) O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylA suspension of tetrafluoroborate and 192mL (1.1mol) of ethyldiisopropylamine in 1.2L of dichloromethane is stirred at 25 ℃ for 1 hour. To the resulting solution was added 58g (0.508mol) of 1-methyl-4-aminopiperidine1And stirred at 20 ℃ for 16 hours. The solution was evaporated to 600mL and the organic phase was washed five times with 80mL of 1M aqueous ammonia solution. The organic phase is concentrated by evaporation and the residue is chromatographed over silica gel with dichloromethane/methanol/concentrated aqueous ammonia (15: 1: 0.1). Combined product ofThe material was fractionated, the solvent was evaporated and the product crystallized from ethyl acetate/methanol. 123g of product are obtained3。

Method 1B:

4.00kg (20.3mol) of 3-methoxy-4-nitrobenzoic acid2Placed in 54L of toluene. At standard pressure, 16L of toluene were distilled off. The mixture was cooled to 105 ℃ and 40ml of dimethylformamide dissolved in 2L of toluene were added. 2.90kg (24.3mol) of thionyl chloride were flowed in over 30 minutes at a jacket temperature of 120 ℃. And the mixture was washed with 4L of toluene. The reaction mixture was stirred at reflux for 1 hour. Then 12L of toluene was distilled off under normal pressure. The contents of the reactor were cooled. 2.55kg (22.3mol) of 1-methyl-4-aminopiperidine are introduced1A solution of 2.46kg (24.3mol) triethylamine in 2L toluene was refluxed at 55-65 ℃. The mixture was washed with 4L of toluene. The suspension was stirred for 1 hour. 20L of water were poured in and 3.08kg (30.4mol) of concentrated hydrochloric acid (36%) were added at 35-40 ℃. The mixture was rinsed with 2L of water. Phase 2 is formed at 35-40 ℃. The organic phase is separated and the aqueous phase containing the product is returned to the reactor. Rinsing was carried out with 4L of water. 3.2L of water were removed by distillation under reduced pressure at 50 ℃. 4.87kg (60.9mol) of sodium hydroxide solution (50%) were passed into the remaining solution at 40 ℃. Rinse with 4L water. The product suspension was cooled to 22 ℃ and stirred at this temperature for 30 minutes. The suspension was filtered with suction and the filter cake was washed with 40L of water. The product was dried in a vacuum oven at 40 ℃. 5.65kg of product were obtained.

● Compound4Preparation of

Method 2A:

145g (0.494mol)3A solution in 2L of methanol was hydrogenated in the presence of 2g of palladium on carbon (10%) at 4 bar. The catalyst was filtered off and the filtrate was concentrated by evaporation. 128g of product are obtained4。

Method 2B:

25L of deionized water was added to 5.00kg (17.0mol)3And 600g of activated carbon (technical grade). Further, 2.05kg (34.1mol) of acetic acid was added. The suspension was stirred at 22-25 ℃ for 15 minutes. 500g of palladium on carbon (10%) suspended in 3L of deionized water was added and the mixture was rinsed with 2L of deionized water. The contents of the reactor were heated to 40 ℃ and hydrogenated at this temperature until hydrogen uptake ceased. The reaction mixture was filtered and the filter cake was washed with 10L of deionised water.

To crystallize it, the filtrate was transferred to a reactor and the transfer vessel was rinsed with 5L of deionized water. The contents of the reactor were heated to 50 ℃. A mixture of 5.45kg (68.2mol) sodium hydroxide solution (50%, technical grade) and 7L of deionized water was added. The mixture was stirred at 45-50 ℃ for 10 minutes. The suspension is cooled to 20 ℃ and stirred at this temperature for 1-1.5 hours. The product was suction filtered, washed with 30L of deionized water and dried in a vacuum oven at 45 ℃. 4.13kg of product are obtained4。

Dihydropteridinone fragments9By preparing

● amino acid ester6a-dPreparation of

Preparation of the methyl ester according to methods known in the literature6aEthyl ester of (I) to (II)6bAnd 2-propyl ester6cFor example: according to e.g. WO03/020722 a 1. Preparation of tert-butyl esters by transesterification with tert-butyl acetate in the presence of perchloric acid6d(J.Med.Chem.，Vol 37，No 20，1994，3294-3302)。

In the following nucleophilic substitution reaction, the amino acid may be used in the form of a base or a hydrochloride.

● amino acid amides6e，fPreparation of

Aminolysis of methyl esters by 40% aqueous methylamine at room temperature6aTo prepare amino acid amides6e. In a five-fold excess of a 2 molar solution of dimethylamine in tetrahydrofuran in the presence of O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylPreparation of amino acid amides by formation of amides from free amino acids in the presence of fluoroborates as coupling agents6f。

● Compound7Preparation of

● Compound7aPreparation of

Methyl ester7aPreparation of

457g (2.06mol) of amino acid methyl ester6aAnd a suspension of 693g (8.25mol) of powdered sodium bicarbonate in 10L of cyclohexane was stirred at room temperature for 15 minutes. 440g (2.27mol) of 2, 4-dichloro-5-nitropyrimidine are added5And 1.5L cyclohexane and the mixture was stirred at room temperature for 3 days. The reaction was monitored by HPLC. To redissolve the crystallized product, 4L of dichloromethane were added to the suspension. After addition of 335g of magnesium sulfate, the suspension is filtered off with suction and the filter cake is washed once more with dichloromethane. The filtrate was evaporated under reduced pressure to 3.1kg and the resulting suspension was heated to reflux. The solution was allowed to cool slowly and stirred at 10-15 ℃ for one hour. The suspension is filtered off with suction and the filter cake is washed with cyclohexane. The product was dried in a vacuum oven at 40 ℃. To give 582g of7a(X＝OCH₃) Dark yellowA colored solid.

Preparation of the Compounds in analogy to this preparation7b-f. In amino acid amides7e，fDuring the reaction, a suitable polar solvent, such as ethyl acetate or dichloromethane, is added to improve solubility.

● Compound8Preparation of

560g (1.63mol) of freshly prepared7aAnd a suspension of 185g Raney nickel in 2.8L acetic acid at 75 ℃. After the absorption of hydrogen had ceased, the catalyst was filtered off and the hydrogenation solution was evaporated under reduced pressure. To the residue were added 4L of deionized water and 4L of ethyl acetate. A precipitate containing the product formed between the two phases. The aqueous phase was separated. And 2L of ethyl acetate are added to the organic phase and the precipitate is filtered off with suction. The precipitate was suspended in 600mL of deionized water, stirred at room temperature for 1 hour, filtered with suction and washed with deionized water. 110g of wet product A are obtained.

The filtrate was washed three times with sodium chloride solution. The organic phase is concentrated by evaporation. 380g of a reddish brown residue B are obtained, which are combined with the wet product A. The combined crude products A and B were dissolved in 1.5L of ethanol at reflux temperature. The solution was clarified by filtration and the filter washed with 150mL ethanol. To this solution was added 550mL of deionized water at reflux. The mixture was allowed to cool and stirred at room temperature for 16 hours and then at 0-5 ℃ for 3 hours. The precipitate was filtered off with suction and washed with deionized water/methanol (1: 1) and then with deionized water. The product was dried in a vacuum oven at 50 ℃. 266g of product are obtained8Is a solid of (2).

● Compound9Preparation of

38g (0.95 mol.) of sodium hydride (60% in mineral oil) are added in portions to 264g (0.94 mol.) in one hour at 4-10 deg.C8And 161g (1.13mol) of methyl iodide dissolved in 2L of dimethylacetamide. The cooling bath was removed and the mixture was allowed to warm to 20 ℃ over 2 hours. It is cooled to 10 ℃ and 0.38g (9.5mol) of sodium hydride are additionally added. The mixture was stirred at 10-15 ℃ for 4 hours. To the reaction solution were added 100mL of ethyl acetate and 1kg of ice. The resulting suspension was diluted with 3L of deionized water. The suspension was stirred for 2 hours, the precipitate was filtered off with suction and the filter cake was washed with deionized water. The product was dried in a vacuum oven at 50 ℃. 273g of product are obtained9Colorless crystals.

By passing4And9reaction of (a) to prepare the compound of example 46:

201g (1.06mol) of p-toluenesulfonic acid monohydrate, 209g (706mmol)9And 183g (695mmol)4The suspension in 800mL of 2-methyl-4-pentanol was heated at reflux. 100mL of solvent was distilled off. The mixture was refluxed for 3 hours, 200mL of 2-methyl-4-pentanol were added and 120mL of the solvent was distilled off. After heating at reflux temperature for 2 hours, another 280mL of solvent was distilled off. The mixture was cooled to 100 ℃ and 1L of deionized water was added to the reaction solution followed by 0.5L of ethyl acetate. The organic phase was separated and the aqueous phase was washed once more with 0.5L of ethyl acetate. 1.5L of dichloromethane and 0.5L of ethyl acetate are added to the acidic aqueous phase. The pH of the aqueous phase was adjusted to pH9.2 with 260mL of 6 normal sodium hydroxide solution. The aqueous phase is separated and the organic phase is washed 3 times with 1L each time of a1 strength aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and the solvent is concentrated by evaporation under reduced pressure. 406g of crude product are obtained.

The crude product was dissolved in 1.5L of ethyl acetate. 2.5L of methyl-tert-butyl ether are added at a temperature of 50-55 ℃. The mixture was seeded at 45 ℃ and cooled to room temperature and stirred for 16 hours. The suspension was stirred at 0-5 ℃ for 3.5 hours and the precipitate was filtered off with suction. The filter cake was washed once more with methyl-tert-butyl ether/ethyl acetate (2: 1) and methyl-tert-butyl ether. The product was dried in a vacuum oven at 50 ℃. 236g of the compound of example 46 as anhydrate (I) were obtained as crystals.

And (3) crystallization:

46.5g of the above crystalline anhydrate (I) were dissolved in 310mL of 1-propanol and clarified by filtration. The mixture was heated to 70 ℃ and 620mL of deionized water was added. The solution was allowed to cool to room temperature, cooled to 0-10 ℃ and seeded. The resulting suspension was stirred at 0-10 ℃ for 3 hours. Filtered with suction and washed with cold 1-propanol/deionized water (1: 2) and deionized water. The product was dried in a vacuum oven at 50 ℃. 40.5g of the compound of example 46 are obtained as monohydrate in the form of crystals.

The crude reaction product can also be directly precipitated from 1-propanol/deionized water in the form of monohydrate crystals.

Synthesis of the Compounds of example 27, example 110 and example 234 (Synthesis scheme 2)

Synthesis scheme 2

11Preparation of

260g (1.32mol) of 3-methoxy-4-nitrobenzoic acid2Placed in 1.5L of toluene. 300mL of toluene was distilled off.5mL of dimethylformamide was added to the residue and 123mL (1.7mol) of thionyl chloride was added dropwise. The reaction solution was heated under reflux for 2 hours. The solvent was concentrated by evaporation under reduced pressure using a rotary evaporator. The residue is dissolved in 500mL of tetrahydrofuran and 202g (1.33mol) of trans 4-aminocyclohexanol are added dropwise10Suspension in 1.5L tetrahydrofuran and 1.38L of 30% potassium carbonate solution, maintaining the temperature between 5 ℃ and 13 ℃. The mixture was stirred at 20 ℃ for 1 hour and 5L of deionized water was added. The precipitate was filtered off with suction and washed with deionized water. The solid was dried in a circulating air dryer at 70 ℃. 380g (98% of theory) of product are obtained11。

TLC (9: 1. RTM. dichloromethane/ethanol) R_f＝0.47

13Preparation of

1g of finely divided ruthenium (III) chloride hydrate powder is added to 185g (0.63mol) in 1.8L of acetonitrile11And 234g N-methylmorpholine-N-oxide and the mixture was refluxed for 1 hour. 1.6L of acetonitrile was removed by evaporation under reduced pressure. To the residue was added 1.5L of deionized water and the suspension was cooled to 5 ℃. The precipitate was suction filtered and washed with copious amounts of deionized water. The solid was dried in a circulating air dryer at 70 ℃. 168g (91% of theory) of product are obtained13。

TLC (9: 1. RTM. dichloromethane/ethanol) R_f＝0.64

14aPreparation of

164g (0.51mol) in 1.4L of tetrahydrofuran13(90%) 80.1mL (0.65mol) of cis-2, 6-dimethylmorpholine12And 60g of sodium acetate were heated under reflux for 1 hour. The mixture was cooled to 20 ℃ and 120g (0.57mol) of sodium triacetoxyborohydride were added in portions to maintain the temperature between 18 ℃ and 22 ℃. The mixture was stirred at 20 ℃ for 16 hours. The solvent was concentrated by evaporation under reduced pressure. The residue was dissolved in 2 normal hydrochloric acid. To the solution was added 10g of activated carbon and filtered under suction. 300mL of diisopropyl ether and aqueous ammonia were added to the filtrate until the aqueous phase was basic. The mixture was stirred for one hour and the suspension was cooled to 5 ℃. The suspension was filtered off with suction and the solid was washed with deionized water. The crude product was crystallized from 1.2L of isopropanol. The crystalline product filtered off with suction was dried in a circulating air drier at 50 ℃. 84g (43% of theory) of product are obtained14a。

TLC (9: 1. RTM. dichloromethane/ethanol) R_f＝0.45

14bPreparation of

65.3g (223mmol) were separated with a water separator1323.6mL (268mmol) morpholine12bAnd a suspension of 0.4mL methanesulfonic acid in 600mL toluene was heated to reflux until all enamine was formed. The solvent was distilled under reduced pressure to a residual volume of 100 mL. The residue was dissolved in 400mL of ethanol at 80 ℃ and cooled to 0 ℃ to 5 ℃. At this temperature, 10.1g of sodium borohydride are added in portions and the mixture is stirred for a further 16 hours at 20 ℃. Ice was added to the solution and it was adjusted to pH 8 to 9 by addition of semi-concentrated hydrochloric acid. The solvent was concentrated by evaporation under reduced pressure. The residue is suspended in dichloromethane and chromatographed on silica gel with a solvent mixture of dichloromethane/ethanol/ammonia (49: 1: 0.25 to 19: 1: 0.25). The cis compound [ TLC (19: 1: 0.25. dichloromethane/ethanol/ammonia) R ] is eluted first_f＝0.23]. Will contain transFraction of compound [ TLC (dichloromethane/ethanol/ammonia 19: 1: 0.25) R_f＝0.12]Combined and concentrated by evaporation. The residue was suspended in 350mL of methanol at boiling temperature. At about 50 ℃ 2 molar equivalents of trimethylchlorosilane are added, followed by 500mL of tert-butyl methyl ether. The suspension was filtered off with suction and the solid was dried.

24g (27% of theory) of the compound are obtained as the hydrochloride salt14b。

TLC (dichloromethane/ethanol/ammonia 19: 1: 0.25) R_f＝0.12

14cPreparation of

112g (383mmol) were separated using a water separator13108g (770mmol) of N- (cyclopropylmethyl) piperazine12cAnd 4.5mL of methanesulfonic acid in toluene were heated at reflux for 3 hours (about 76mL of water was separated). 900mL of toluene were evaporated off under reduced pressure and the residue was suspended in 1.2L of ethanol. 15g of sodium borohydride are added to the suspension in portions over one hour at from 15 ℃ to 25 ℃. The mixture was stirred at 20 ℃ for 3 hours and an additional 4g of sodium borohydride were added. The mixture was stirred at 20 ℃ for 16 hours. 650mL of ethanol were evaporated under reduced pressure. 2L of purified water and 300mL of cyclohexane were added. The mixture was cooled to 5 ℃ and the suspension was filtered under suction. The residue was dissolved in 1 normal hydrochloric acid. 5g of activated carbon were added and the mixture was filtered off with suction. 400mL of tert-butyl methyl ether was added to the filtrate and basified with aqueous ammonia solution. It was allowed to cool to 4 ℃, the precipitate was filtered off with suction and washed with deionized water. The residue was heated to reflux in 400mL of tert-butyl methyl ether. The solid was cooled, filtered with suction and washed with tert-butyl methyl ether. After drying at 60 ℃ in a circulating air dryer, 73g (46% of theory) of product are obtained14c。

TLC (methylene chloride-Ethanol ═ 9: 1) R_f＝0.2

15aPreparation of

108.5g (277mmol)14aA solution in 900mL of acetic acid was hydrogenated in the presence of 10g of Raney nickel at 20 ℃ and 50psi of hydrogen. The catalyst was filtered off and the solution was concentrated by evaporation under reduced pressure. The residue was dissolved in 500mL of isopropanol and basified by addition of aqueous ammonia solution. Enough ice water was added to make the volume 1.5L. The precipitate was suction filtered and washed with 400mL deionized water, 160mL isopropanol, and 300mL t-butyl methyl ether. The solid was dried in a circulating air dryer at 50 ℃. 92g (92% of theory) of product are obtained15a。

TLC (9: 1. RTM. dichloromethane/ethanol) R_f＝0.25

15bPreparation of

23g (57.5mmol)14bA solution of hydrogen chloride in 200mL of deionized water was hydrogenated in the presence of 5g of palladium on carbon (10%) at 20 deg.C and 50psi of hydrogen pressure. The catalyst was filtered off and the filtrate was slowly adjusted to pH 11 by addition of 1 normal sodium hydroxide solution. The suspension was stirred at 20 ℃ for 2 hours, filtered off with suction and the solid was washed with deionized water. Drying in a vacuum drying oven gave 17.5g of product15b。

15cPreparation of

72.5g (174mmol)14cA solution of 700mL of methanol and 145mL of dimethylformamide was hydrogenated at 20 ℃ in the presence of 10g of Raney nickel under a hydrogen pressure of 50 psi. The catalyst was filtered off and the methanol was evaporated off under reduced pressure. To the residue was added 500mL of deionized water and the suspension was cooled to 5 ℃. The precipitate was filtered off with suction and washed with deionized water. After drying at 60 ℃ in a circulating air dryer, 60.5g (90% of theory) of product are obtained15c。

TLC (dichloromethane/ethanol/ammonia 9: 1: 0.1) R_f＝0.58

17aPreparation of (corresponding to the compound of example 234)

20.2g (55.9mmol)15a、16.5g(61.4mmol)16And a solution of 15.9g (83.6mmol) of p-toluenesulfonic acid hydrate in 400mL of 2-methyl-4-pentanol was heated under reflux for 9 hours while a total of 360mL of solvent was distilled off over the entire time. The residue was cooled and the solidified oil was dissolved in 300mL of deionized water. The aqueous phase was washed three times with ethyl acetate. To the aqueous phase was added 400mL of ethyl acetate and sufficient sodium hydroxide solution was added to bring the pH to 11 to 12. The organic phase was washed twice with deionized water. The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in 82mL of dimethylacetamide and a solution of 60mL of concentrated aqueous ammonia in 1.4L of deionized water was added slowly dropwise with thorough stirring. The mixture was stirred at 20 ℃ for 4 hours, the precipitate was filtered off with suction and washed with copious amounts of deionized water. Drying in a vacuum drying oven at 60 deg.C in the presence of sodium hydroxide pellets to give 30.3g of product17a。

The base obtained was crystallized from acetone/1-normal hydrochloric acid as the monohydrochloride salt, having a melting point of about 320 ℃ (decomposition, DSC: 10K/min).

17bPreparation of (corresponding to the compound of example 27)

16.2g (48.6mmol)15b、14.5g(54mmol)16And a solution of 13g (68.3mmol) of p-toluenesulfonic acid hydrate in 250mL of 2-methyl-4-pentanol and 20mL of N-methylpyrrolidone was heated to reflux. 180mL of solvent was distilled off over one hour. 100mL of 2-methyl-4-pentanol was added and the solution was heated to reflux for 5 hours. It was cooled to 80 ℃ and 40mL of methanol and 12g of trimethylchlorosilane were added. 400mL of acetone was flowed in at 60 ℃. The suspension was heated to reflux and cooled to 30 ℃. The precipitate was filtered off with suction and washed with acetone/methanol (85: 15) and acetone. After drying at 50 ℃ in a vacuum drying cabinet, 22.7g (78% of theory) of the product are obtained as the hydrochloride salt17b。

After the hydrochloride salt was dissolved in deionized water and transferred to an aqueous solution of potassium carbonate and common salt, the free base was extracted with dichloromethane. Make it17bThe base (2) was crystallized from acetone/deionized water (1: 1) (melting point 150 ℃ C., DSC: 10K/min).

17cPreparation of (corresponding to Compound example 110)

23g (59.5mmol) were separated using a water separator15c、16.8g(62.5mmol)16And a solution of 28.3g (149mmol) of p-toluenesulfonic acid hydrate in 350mL of 2-methyl-4-pentanol was heated under reflux for 22 hours. Adding 1g of16After that, the mixture was refluxed for another 2 hours. 300mL of solvent was distilled off and the viscous oil was allowed to evaporateCooling to 60 ℃. 300mL of dichloromethane and 300mL of deionized water were added and the pH was raised to pH9 by adding about 20mL of 10 normal sodium hydroxide solution. The organic phase was washed twice with deionized water and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in 200mL of ethyl acetate at 65 ℃. The mixture was slowly cooled to 20 ℃, the precipitate was filtered with suction and washed with cold ethyl acetate. Drying at 60 ℃ in a vacuum drying oven gives 24.4g of product17c(melting point 182 ℃ C., DSC: 10K/min, there is an additional endothermic effect in the DSC plot before melting).

Or a compound14cIt can also be prepared by the following method (synthetic scheme 3).

Synthetic scheme 3

19Preparation of

22g (142mmol) of 4-acetamido-cyclohexanone dissolved in 175mL of toluene1839.7g (283mmol) of N-cyclopropylmethylpiperazine12cAnd 0.71mL of methanesulfonic acid were heated in a water separator under reflux until no more water precipitated. The mixture was allowed to cool and 175mL of ethanol was added at 50 ℃ and cooled to 20 ℃. With thorough stirring, 5.37g (142mmol) of sodium borohydride were added in portions and the mixture was stirred at 20 ℃ for 16 hours. 200mL of 4-normal hydrochloric acid were added dropwise to the reaction mixture. 200mL of solvent were evaporated under reduced pressure. 100mL of saturated potassium carbonate solution and 200mL of methyl isobutyl ketone were added to the residue. The two-phase mixture was cooled to 5 ℃ with thorough stirring. The product was suction filtered and dissolved in 90mL of methyl isobutyl ketone at reflux. After the addition of the activated carbon, the reaction mixture is,it was filtered hot. The mixture was allowed to cool and the precipitate was filtered off with suction. After drying, 16.2g (41% of theory) of the trans compound are obtained19。

TLC (dichloromethane/ethanol/ammonia 9: 1: 0.1) R_f＝0.39

20Preparation of

44g (157mmol)19Heated to reflux in 500mL of 24% hydrochloric acid for 6 hours. The solvent was concentrated by evaporation under reduced pressure and the residue was crystallized from 700mL of isopropanol. The precipitate is filtered off with suction, washed with tert-butyl methyl ether and dried in a vacuum drying cabinet at 60 ℃. 54.7g of product are obtained as the trihydrochloride salt20(containing 5% water).

14cPreparation of

33g (90.4mmol) of 3-methoxy-4-nitrobenzoic acid2Suspended in 80mL of toluene. 0.5mL of dimethylformamide and 16g (134mmol) of thionyl chloride were added. The mixture was heated to reflux for 1 hour. The solution was concentrated by evaporation under reduced pressure and the crude acid chloride was dissolved in 50mL of tetrahydrofuran. The solution was added dropwise to 18.7g (94.9mmol, 95%) of20Trihydrochloride and 49g (397mmol) of diisopropylethylamine in 150mL of tetrahydrofuran. The completeness of the reaction was checked using TLC. After the reaction was terminated, water was added to the suspension and the pH was adjusted to 10 by adding sodium hydroxide solution. The organic phase was separated and washed with saturated brine. The combined aqueous phases were extracted once with tetrahydrofuran. The combined organic phases are concentrated by evaporation under reduced pressure. The residue was taken up in 300mLTert-butyl methyl ether is heated and refluxed. The mixture was cooled to 20 ℃ and the precipitate was filtered off with suction. After drying at 45 ℃ in a vacuum drying oven 31.3g (83% of theory) are obtained14c。

Claims (17)

1. A process for the preparation of dihydropteridinones of the general formula (I),

wherein

R¹、R²Which may be the same or different, represent hydrogen or optionally substituted C₁-C₆-alkyl, or

R¹And R²Together represent a 2-to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms,

R³represents hydrogen or is selected from optionally substituted C₁-C₁₂Alkyl radical, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl and C₆-C₁₄A radical of an aryl group, or

Selected from optionally substituted C₃-C₁₂-cycloalkyl, C₃-C₁₂-cycloalkenyl radical, C₇-C₁₂-polycycloalkyl, C₇-C₁₂-polycyclic alkenyl radical, C₅-C₁₂Spirocycloalkyl, C containing 1 to 2 heteroatoms₃-C₁₂Heterocycloalkyl, and C containing 1 to 2 hetero atoms₃-C₁₂-a heterocycloalkenyl group, or

R¹And R³Or R²And R³Together represent saturated or unsaturated C₃-C₄An alkyl bridge, which may optionally contain 1 heteroatom,

R⁴represents a group selected from hydrogen, -CN, hydroxy, -NR⁶R⁷And halogen, or

Selected from optionally substituted C₁-C₆Alkyl radical, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₅-alkoxy, C₂-C₅-alkenyloxy, C₂-C₅-alkynyloxy, C₁-C₆Alkylthio radical, C₁-C₆-alkylsulfinyl and C₁-C₆-a group of alkylsulfonyl groups,

l represents a linker selected from optionally substituted C₂-C₁₀Alkyl radical, C₂-C₁₀-alkenyl, C₆-C₁₄-aryl, -C₂-C₄-alkyl-C₆-C₁₄-aryl, -C₆-C₁₄-aryl-C₁-C₄Alkyl radical, C₃-C₁₂Cycloalkyl and optionally heteroaryl containing 1 or 2 nitrogen atoms,

n represents a number of 0 or 1,

m represents a number of 1 or 2,

R⁵represents a compound selected from the group consisting of optionally substituted morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropanyl, R⁸-diketomethylpiperazine, 4-oxothiomorpholinyl, 4-dioxothiomorpholinyl, thiomorpholinyl, -NR⁸R⁹And the group of azepinyl,

R⁶、R⁷may be the same or different and represents hydrogen or C₁-C₄-an alkyl group,

and is

R⁸、R⁹Is represented by R⁵The above unsubstituted nitrogen substituents, which may be the same or different, are hydrogen or are selected from C₁-C₆-alkyl, -C₁-C₄-alkyl-C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₆-C₁₄-aryl, -C₁-C₄-alkyl-C₆-C₁₄Aryl, pyranyl, pyridinyl, pyrimidinyl, C₁-C₄Alkoxycarbonyl, C₆-C₁₄-arylcarbonyl group, C₁-C₄-alkylcarbonyl group, C₆-C₁₄Aryl methoxycarbonyl, C₆-C₁₄-arylsulfonyl, C₁-C₄-alkylsulfonyl and C₆-C₁₄-aryl-C₁-C₄-a group in the alkylsulfonyl group,

and wherein the one or more of the one,

optional substituents for alkyl, alkenyl and alkynyl groups are selected from fluoro;

optional substituents for aryl are selected from: OH, NO₂、CH、OMe、-OCHF₂、-OCF₃、-NH₂Halogen, C₁-C₁₀-alkyl, -O-C₁-C₃-alkyl, -COOH, -COO-C₁-C₄-alkyl, or CONH₂；

The optional substituents of the heteroaryl group are selected from: F. cl, Br, OH, OMe, methyl, ethyl, CN, CONH₂、NH₂Optionally substituted phenyl, optionally substituted heteroaryl;

optional substituents for cycloalkyl groups are selected from: OH, NO₂、CN、OMe、-OCHF₂、-OCF₃、-NH₂Or halogen, C₁-C₁₀-alkyl, -O-C₁-C₃-alkyl, -COOH, -COO-C₁-C₄-alkyl or-CONH₂；

Optional substituents for heterocycloalkyl are selected from: c₁-C₄-an alkyl group;

characterized in that a compound of formula (II) is reacted in the presence of an organic sulfonic acid as an acid catalyst

Wherein

R¹To R³As defined above and A is a leaving group,

with compounds of the formula (III)

Wherein

R⁴、R⁵L and m, n are as defined above.

2. The process as claimed in claim 1, characterized in that R is⁵Represents an N-cyclopropylmethylpiperazine group.

3. The process according to claim 1, characterized in that the dihydropteridinone is selected from the group consisting of dihydropteridinones having the following general formula (I):

abbreviations X used in the tables₂、X₃、X₄And X₅Each representing a substituent attached to the corresponding position R in the formula set forth in the table²、R³、R⁴And L_n-R⁵ _m。

4. A process as claimed in any of claims 1 to 3, characterized in that the reaction is carried out in a solvent.

5. The process of claim 4 wherein the solvent is dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone, dimethylsulfoxide, sulfolane, methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 2-propanol, 2-butanol, the isomeric secondary alcohols of pentane or hexane, the tertiary alcohols of butane, pentane or hexane, acetonitrile or 2-propylnitrile.

6. The process as claimed in any of claims 1 to 3, characterized in that the temperature of the reaction is between 18 ℃ and 180 ℃.

7. The process as claimed in claim 4, wherein the reaction temperature is from 18 ℃ to 180 ℃.

8. The process as claimed in claim 5, wherein the reaction temperature is from 18 ℃ to 180 ℃.

9. A compound of the formula

10. A compound of the formula

11. A compound of the formula

Or a salt thereof.

12. A compound of the formula

Or a salt thereof.

13. A compound of the formula

Or a salt thereof.

14. A compound of the formula

Or a salt thereof.

15. A compound of the formula

Or a salt thereof.

16. A compound of the formula

Or a salt thereof.

17. A compound of the formula

Or a salt thereof.