HK1151794B - Process for the preparation of 5-(2-amino-pyrimidin-4-yl)-2-aryl-1h-pyrrole-3-carboxamides - Google Patents

Description

Process for the preparation of 5- (2-amino-pyrimidin-4-yl) -2-aryl-1H-pyrrole-3-carboxamides

The present invention relates to a process for the preparation of 5- (2-amino-pyrimidin-4-yl) -2-aryl-1H-pyrrole-3-carboxamides and to intermediate compounds useful in this process.

WO2007110344 describes and claims heteropolylanes, processes for their preparation, pharmaceutical compositions containing them and their use as therapeutic agents, particularly in the treatment of cancer and cell proliferative disorders.

Representative of the heteroalane compounds, optionally in the form of pharmaceutically acceptable salts, are, for example:

5- (2-amino-pyrimidin-4-yl) -2-phenyl-1H-pyrrole-3-carboxylic acid amide;

5- (2-amino-pyrimidin-4-yl) -2-o-tolyl-1H-pyrrole-3-carboxylic acid amide;

5- (2-amino-pyrimidin-4-yl) -2- (4-fluoro-2-methyl-phenyl) -1H-pyrrole-3-carboxylic acid amide;

5- (2-amino-pyrimidin-4-yl) -2- (2, 3-dimethyl-phenyl) -1H-pyrrole-3-carboxylic acid amide;

5- (2-amino-pyrimidin-4-yl) -2- (2, 3-difluoro-phenyl) -1H-pyrrole-3-carboxylic acid amide;

5- (2-amino-pyrimidin-4-yl) -2- (2, 4-difluoro-phenyl) -1H-pyrrole-3-carboxylic acid amide;

5- (2-amino-pyrimidin-4-yl) -2- (2, 5-difluoro-phenyl) -1H-pyrrole-3-carboxylic acid amide;

5- (2-amino-pyrimidin-4-yl) -2- (2-chloro-phenyl) -1H-pyrrole-3-carboxylic acid amide;

5- (2-amino-pyrimidin-4-yl) -2- (2-chloro-4-fluoro-phenyl) -1H-pyrrole-3-carboxylic acid amide;

5- (2-amino-pyrimidin-4-yl) -2- (2, 4-dichloro-phenyl) -1H-pyrrole-3-carboxylic acid amide;

5- (2-amino-pyrimidin-4-yl) -2- (2-fluoro-4-methyl-phenyl) -1H-pyrrole-3-carboxylic acid amide;

5- (2-amino-pyrimidin-4-yl) -2- (2, 3-dichloro-phenyl) -1H-pyrrole-3-carboxylic acid amide;

5- (2-amino-pyrimidin-4-yl) -2- (2-fluoro-3-methoxy-phenyl) -1H-pyrrole-3-carboxylic acid amide and

5- (2-amino-pyrimidin-4-yl) -2- (2-fluoro-4-chloro-phenyl) -1H-pyrrole-3-carboxylic acid amide.

These compounds have protein kinase inhibitory activity, more specifically Cdc7 or Cdc7/Cdks inhibitory activity.

More specifically, these compounds prepared according to the present invention may be used for the treatment of various cancers and cell proliferative disorders.

These compounds are also active as inhibitors of other protein kinases and are therefore useful in the treatment of diseases associated with other protein kinases.

These compounds and their analogs can be prepared according to known chemical methods, essentially comprising the condensation of a carboxylic acid derivative with an activated form of ammonia or with an amine to give the desired amide. In their turn, these carboxylic acid derivatives are prepared according to a process comprising coupling of a halogenated ketone with a β -ketoester, a Hantzsch reaction and hydrolysis. This method is described, for reference, in the above-mentioned patent application WO 2007110344.

In this respect, we have now surprisingly found that the said heteropolylane compounds can be advantageously prepared by a process which allows to obtain the desired products in higher yields and purities and with a limited number of steps.

Accordingly, a first object of the present invention is a process for the preparation of 5- (2-amino-pyrimidin-4-yl) -2-aryl-1H-pyrrole-3-carboxamides of formula (I):

wherein R is₁And R₂Independently represent hydrogen, a halogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aroyl group, a carboxyl ester, a cyano group or a nitro group, which comprises:

(a) in the presence of a Lewis acid, reacting a compound of formula (I) wherein R₁And R₂Pyrrole of formula (II) as defined above:

reacting with acetyl chloride;

(b) subjecting the resulting compound wherein R₁And R₂A compound of formula (III) as defined above:

with a dialkyl acetal of N, N-dimethylformamide,

(c) subjecting the resulting compound wherein R₁And R₂An enaminoketone (enaminone) of formula (IV) as defined above:

with guanidine or a salt thereof, and then,

(d) hydrolyzing under acidic conditions the resulting compound wherein R₁And R₂Cyano groups of the compounds of formula (V) as defined above,

to obtain the amide of formula (I) in the form of a salt as defined above;

and, if desired, converting the resulting salt to the free base under basic conditions.

Another object of the present invention is a process for the preparation of 5- (2-amino-pyrimidin-4-yl) -2-aryl-1H-pyrrole-3-carboxamides of formula (I) as defined above, wherein the process comprises: the cyano group of the compound of formula (V) as defined above is hydrolysed under acidic conditions and the resulting salt form of the amide of formula (I) as defined above is then converted to the free base, if desired under basic conditions.

The final compound can be isolated and purified using conventional methods, such as chromatography and/or crystallization and salt formation.

The carboxamides of formula (I) as defined above may be converted into pharmaceutically acceptable salts. The carboxamide of formula (I) as defined above or a pharmaceutically acceptable salt thereof may then be formulated together with a pharmaceutically acceptable carrier or diluent to provide a pharmaceutical composition.

Furthermore, another object of the present invention are the intermediate compounds of formulae III, IV or V as defined above, and processes for their preparation.

In this specification, the term

"halogen" means bromine, chlorine, iodine or fluorine, more preferably chlorine or fluorine;

"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms; the term refers to groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like;

"cycloalkyl" refers to cycloalkyl of 3 to 10 carbon atoms having one or more carbocyclic rings, including, but not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like;

"aryl" refers to an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl), wherein the fused rings may or may not be aromatic (e.g., 2-benzoOxazolidinyl, 2H-1, 4-benzoOxazin-3 (4H) -on-7-yl, and the like), provided that the point of attachment is at an aromatic carbon atom; preferred aryl groups include phenyl and naphthyl; in the name of the compound of formula I, aryl is R as defined above₁And R₂Substituted phenyl;

"aroyl" refers to arylcarbonyl Ar-CO-wherein aryl is as defined herein;

"carboxy ester" refers to the group-C (O) O-alkyl, -C (O) O-aryl, wherein alkyl and aryl are as defined herein;

"cyano" or "nitrile" refers to the group-CN;

"Nitro" means the radical-NO₂。

Preferred compounds according to the invention are those in which R is₁And R₂Independently represents hydrogen, a halogen atom, an alkyl or alkoxy group, more preferably a methyl, fluorine or chlorine atom.

As noted above, the present invention also provides compounds of formula (III):

wherein R is₁And R₂As defined above.

Another object of the present invention is a process for the preparation of the compound of formula (III) as defined above, comprising the reaction of the pyrrole of formula (II) as defined above with acetyl chloride in the presence of a lewis acid.

The present invention also provides compounds of formula (IV):

wherein R is₁And R₂As defined above.

Another object of the invention is a process for the preparation of the compound of formula (IV) as defined above, which comprises treating the compound of formula (III) as defined above with a dialkyl acetal of N, N-dimethylformamide.

Also provided are compounds of formula (V),

wherein R is₁And R₂As defined above.

Finally, the invention includes a process for the preparation of a compound of formula (V) as defined above, which process comprises reacting a compound of formula (IV) as defined above with guanidine or a salt thereof.

Acylation of the compound of formula (II) with acetyl chloride to give the compound of formula (III) is preferably carried out in the presence of a lewis acid such as aluminium trichloride or titanium tetrachloride in an anhydrous organic solvent such as dichloromethane, cooled at a temperature of-5 ℃ to 0 ℃ or at room temperature. Similar reactions are described in j.het.chem.1983, 20, 61.

The conversion of the compound of formula (III) to the enaminone of formula (IV) is carried out using a dialkyl acetal of N, N-dimethylformamide, such as dimethyl acetal or diisopropyl acetal. Preferably the reaction is carried out in an organic solvent such as toluene, benzene, dichloroethane or dimethylformamide at a temperature from room temperature to reflux temperature, preferably at a temperature of from 60 ℃ to 90 ℃. Similar transformations are described, for example, in Heterocycles 1998, 47, 689.

The conversion of the compound of formula (IV) into the compound of formula (V) is carried out by reaction with guanidine, guanidine hydrochloride or guanidine carbonate. Preferably the reaction is carried out in an organic solvent such as acetamide, N-methyl-2-pyrrolidone, dimethylformamide at a temperature of from 80 ℃ to 130 ℃. This type of transformation is described in the scientific literature, for example j.het.chem.1989, 26, 1147.

The hydrolysis of the nitrile derivative of the formula (V) under acidic conditions is carried out in glacial acetic acid or trifluoroacetic acid and concentrated sulfuric acid, more preferably in a ratio of 1: 1 to 5: 1, optionally in the presence of water, at a temperature of from room temperature to 120 ℃, in particular from 60 ℃ to 90 ℃, to give the carboxamide of the formula (I). Similar hydrolysis is described, for example, in j.org.chem.2005, 70, 1926.

After basification with concentrated ammonia, sodium hydroxide or potassium hydroxide, the free base is filtered off as a precipitate.

The starting compounds and reagents used in the process of the invention are known compounds or can be obtained from known compounds using known methods. In particular, the starting compounds of formula (II) defined above are known or can be obtained from known reactions starting from known compounds, see for example EP 0347,488; compounds described in EP 0312,723 and EP 0358,047 and their preparation.

The following examples illustrate but do not limit the invention.

Example 1

Step I5-acetyl-2- (2, 4-dichloro-phenyl) -1H-pyrrole-3-carbonitrile (III, R ₁ ＝R ₂ ＝Cl)

to a mixture of 2- (2, 4-dichloro-phenyl) -1H-pyrrole-3-carbonitrile (6.00g, 25.30mmol, see EP 0312,723) in 120mL of dichloromethane was added acetyl chloride (3.18 g; 40.49mmol) under nitrogen and at room temperature. The resulting mixture was cooled to +2 ℃ and anhydrous aluminium trichloride (8.10g, 60.73mmol) was added in small portions over a period of 20 minutes while maintaining the internal temperature below 5 ℃. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 3 hours. The mixture was then poured slowly into an ice-cold solution of 2M HCl (120mL) and isopropanol (28 mL). The aqueous layer was separated and extracted 2 times with dichloromethane (120mL) and isopropanol (28 mL). The combined organic extracts were concentrated under reduced pressure to a slurry, treated with isopropanol (30mL) at room temperature with stirring, and diluted with water (60 mL). The solid was collected by suction and dried under vacuum at +50 ℃ to give 6.51g of product as white, fluffy crystals. The yield was 92%.

¹H-NMR(DMSOd₆)，δppm：2.45(s，3H)7.59(m，3H)7.86(dd，1H)13.05(bs，1H)。

HRMS(M+H)⁺Calculated values: 279.0087, measurement: 279.0091.

step II 2- (2, 4-dichloro-phenyl) -5- ((E) -3-dimethylamino-propene Acyl) -1H-pyrrole-3-carbonitrile (IV, R) ₁ ＝R ₂ ＝Cl)

To a suspension of 5-acetyl-2- (2, 4-dichloro-phenyl) -1H-pyrrole-3-carbonitrile (6.2g, 22.21mmol) in 155mL of toluene was added N, N-dimethylformamide diisopropyl acetal (18.6 mL; 88.85 mmol). The mixture was stirred at 70 ℃ for 34 hours. An additional amount of reagent (4.6 mL; 22.21mmol) was then added and the mixture was heated to 80 ℃ for an additional 18 hours with thorough stirring.

After cooling to room temperature, the solid was collected under suction, washed with 25mL of toluene and dried in air to give 6.8g of product as a white solid. The yield was 91%.

¹H-NMR(DMSOd₆)，δppm：2.90(m，3H)3.15(bs，3H)5.74(d，1H)7.37(d，1H)7.57(m，2H)7.69(d，1H)7.82(dd，1H)12.64(bs，1H)。

HRMS(M+H)⁺Calculated values: 334.0509, measurement: 334.0513.

step III 5- (2-amino-pyrimidin-4-yl) -2- (2, 4-dichloro-phenyl) -1H-pyrrole -3-carbonitrile (V, R) ₁ ＝R ₂ ＝Cl)

To a suspension of 2- (2, 4-dichloro-phenyl) -5- ((E) -3-dimethylamino-acryloyl) -1H-pyrrole-3-carbonitrile (6.80g, 20.35mmol) in 82mL of N, N-dimethylformamide was added guanidine carbonate (9.17g, 101.75 mmol). The mixture was heated to 110 ℃ for 18 hours with thorough stirring. Then, an additional amount of guanidine carbonate (1.83 g; 20.35mmol) was added to the mixture and heated to 115 ℃ for an extended period of time and then for an additional 22 hours. The resulting mixture was diluted dropwise over 30 minutes with 325mL of water. The solid was isolated by filtration, washed with 100mL of water, dried in air and finally dried in a vacuum oven at 60 ℃ to give 5.58g of product as a light brown powder. The yield was 83%.

¹H-NMR(DMSOd₆)，δppm：6.48(b s，2H)7.00-8.28(m，6H)12.70(bs，1H)。

HRMS(M+H)⁺Calculated values: 330.0308, measurement: 330.0317.

step IV 5- (2-amino-pyrimidin-4-yl) -2- (2, 4-dichloro-phenyl) -1H-pyrrole -3-carboxylic acid amide (I, R) ₁ ＝R ₂ ＝Cl)

To a solution of 5- (2-amino-pyrimidin-4-yl) -2- (2, 4-dichloro-phenyl) -1H-pyrrole-3-carbonitrile (210mg, 0.636mmol) in 1.70mL trifluoroacetic acid was added, with good stirring, 0.21mL of water and 0.42mL of 98% sulfuric acid, in that order. The mixture was stirred at 70 ℃ for 8 hours, and then diluted by dropping 3mL of water over 10 minutes.

The reaction mixture was made basic (pH 10-12) by adding 30% aqueous ammonia under stirring and the free base was filtered off as a precipitate. The precipitated solid was collected by filtration, washed with 1mL of water and finally dried in a vacuum oven at 50 ℃ to give 186mg of product as an off-white solid. The yield was 84%.

¹H NMR(DMSOd₆/400MHz)δppm 6.81(bs，1H)6.95(bs，2H)7.01(d，J＝5.73Hz，1H)7.37(bs，1H)7.46(d，J＝2.68Hz，1H)7.68(dd，J＝1.77，0.55Hz，1H)8.23(d，J＝5.73Hz，1H)12.17(bs，1H)；ESI(+)MS：m/z 348(MH⁺)。

HRMS(M+H)⁺Calculated values: 348.0414, measurement: 348.0415.

example 2

The procedure is as in example 1 Steps I-IV, starting from an appropriately substituted pyrrole (R) of formula II₁＝R₂＝H；R₁＝CH₃，R₂＝H；R₁＝R₂＝CH₃；R₁＝R₂＝F；R₁＝Cl，R₂＝H；R₁＝Cl，R₂＝F；R₁＝Cl，R₂＝OCH₃And R₁＝F，R₂Cl) to give the following compound:

5- (2-amino-pyrimidin-4-yl) -2-phenyl-1H-pyrrole-3-carboxylic acid amide hydrochloride;

5- (2-amino-pyrimidin-4-yl) -2-o-tolyl-1H-pyrrole-3-carboxylic acid amide hydrochloride;

5- (2-amino-pyrimidin-4-yl) -2- (4-fluoro-2-methyl-phenyl) -1H-pyrrole-3-carboxylic acid amide hydrochloride;

5- (2-amino-pyrimidin-4-yl) -2- (2, 3-dimethyl-phenyl) -1H-pyrrole-3-carboxylic acid amide hydrochloride;

5- (2-amino-pyrimidin-4-yl) -2- (2, 3-difluoro-phenyl) -1H-pyrrole-3-carboxylic acid amide hydrochloride;

5- (2-amino-pyrimidin-4-yl) -2- (2, 4-difluoro-phenyl) -1H-pyrrole-3-carboxylic acid amide hydrochloride;

5- (2-amino-pyrimidin-4-yl) -2- (2, 5-difluoro-phenyl) -1H-pyrrole-3-carboxylic acid amide hydrochloride;

5- (2-amino-pyrimidin-4-yl) -2- (2-chloro-phenyl) -1H-pyrrole-3-carboxylic acid amide hydrochloride;

5- (2-amino-pyrimidin-4-yl) -2- (2-chloro-4-fluoro-phenyl) -1H-pyrrole-3-carboxylic acid amide hydrochloride;

5- (2-amino-pyrimidin-4-yl) -2- (2-fluoro-4-methyl-phenyl) -1H-pyrrole-3-carboxylic acid amide hydrochloride;

5- (2-amino-pyrimidin-4-yl) -2- (2, 3-dichloro-phenyl) -1H-pyrrole-3-carboxylic acid amide hydrochloride;

5- (2-amino-pyrimidin-4-yl) -2- (2-fluoro-3-methoxy-phenyl) -1H-pyrrole-3-carboxylic acid amide hydrochloride and

5- (2-amino-pyrimidin-4-yl) -2- (2-fluoro-4-chloro-phenyl) -1H-pyrrole-3-carboxylic acid amide hydrochloride.

Claims (18)

1. A process for the preparation of 5- (2-amino-pyrimidin-4-yl) -2-aryl-1H-pyrrole-3-carboxamides of formula (I):

wherein R is₁And R₂Independently represents hydrogen, a halogen atom, or an alkyl group, the process comprising:

(a) in the presence of a Lewis acid, reacting a compound of formula (I) wherein R₁And R₂Pyrrole of formula (II) as defined above:

reacting with acetyl chloride;

(b) subjecting the resulting compound wherein R₁And R₂A compound of formula (III) as defined above:

with a dialkyl acetal of N, N-dimethylformamide,

(c) subjecting the resulting compound wherein R₁And R₂An enaminone of formula (IV) as defined above:

with guanidine or a salt thereof, and then,

(d) hydrolyzing under acidic conditions the resulting compound wherein R₁And R₂Cyano groups of the compounds of formula (V) as defined above,

to obtain the amide of formula (I) in the form of a salt as defined above;

wherein the alkyl group means a straight or branched chain saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms;

and converting the resulting salt to the free base under basic conditions.

2. A process for the preparation of 5- (2-amino-pyrimidin-4-yl) -2-aryl-1H-pyrrole-3-carboxamide of formula (I) as defined in claim 1 wherein the process comprises:

-hydrolyzing the cyano group of a compound of formula (V) as defined in claim 1 under acidic conditions, and, then,

converting the obtained salt form of the amide of formula (I) as defined in claim 1 to the free base under basic conditions.

3. A process for the preparation of a pharmaceutically acceptable salt of a carboxamide of formula (I) as defined in claim 1, which process comprises: the carboxamide of formula (I) is prepared by a process according to claim 1 or 2 and is then converted into a pharmaceutically acceptable salt.

4. A compound of formula (III):

wherein R is₁And R₂As defined in claim 1.

5. A process for the preparation of a compound of formula (III) as defined in claim 4, which process comprises reacting a pyrrole of formula (II) as defined in claim 1 with acetyl chloride in the presence of a lewis acid.

6. A compound of formula (IV):

wherein R is₁And R₂As defined in claim 1.

7. A process for the preparation of a compound of formula (IV) as defined in claim 6, which process comprises treating a compound of formula (III) as defined in claim 1 with a dialkyl acetal of N, N-dimethylformamide.

8. A compound of the formula (V),

wherein R is₁And R₂As defined in claim 1.

9. A process for the preparation of a compound of formula (V) as defined in claim 8, which process comprises reacting a compound of formula (IV) as defined in claim 1 with guanidine or a salt thereof.

10. The process according to claim 1 or claim 5, characterized in that the acylation of the compound of formula (II) with acetyl chloride to give the compound of formula (III) is carried out in the presence of a Lewis acid in an anhydrous organic solvent, operating at a temperature of-5 ℃ to 0 ℃ under cooling or at room temperature.

11. The process according to claim 10, wherein the lewis acid is aluminum trichloride or titanium tetrachloride and the anhydrous organic solvent is dichloromethane.

12. The process according to claim 1 or claim 7, characterized in that the conversion of the compound of formula (III) as defined in claim 1 into the enaminone of formula (IV) as defined in claim 1 is carried out using the dialkyl acetal of N, N-dimethylformamide in an organic solvent at a temperature from room temperature to reflux temperature.

13. The process according to claim 12, wherein the organic solvent is toluene, benzene, dichloroethane or dimethylformamide and the dialkyl acetal of N, N-dimethylformamide is the dimethyl acetal or diisopropyl acetal of N, N-dimethylformamide.

14. A process according to claim 1 or claim 9, characterised in that the conversion of a compound of formula (IV) as defined in claim 1 to a compound of formula (V) as defined in claim 1 is carried out by reaction with guanidine, guanidine hydrochloride or guanidine carbonate in an organic solvent at a temperature of 80 ℃ to 130 ℃.

15. The process according to claim 14, wherein the organic solvent is acetamide, N-methyl-2-pyrrolidone or dimethylformamide.

16. Process according to claim 1, characterized in that the hydrolysis under acidic conditions of the nitrile derivative of formula (V) as defined in claim 1 is carried out in glacial acetic acid or trifluoroacetic acid and concentrated sulfuric acid, optionally in the presence of water, at a temperature ranging from room temperature to 120 ℃, to obtain the carboxamide of formula (I) as defined in claim 1.

17. A process for the preparation of the free base of the carboxamide of formula (I) as defined in claim 1, which comprises: a salt of a carboxamide of formula (I) as defined in claim 3 is converted to the free base under basic conditions by preparing a pharmaceutically acceptable salt of the carboxamide of formula (I) as defined in claim 1 by a process as defined in claim 3, dissolving the salt in a suitable solvent, adding a base, stirring in water for a suitable time, and filtering off the free base as a precipitate.

18. The process according to claim 17, wherein the suitable solvent is dimethyl sulfoxide and the base is ammonia, sodium hydroxide or potassium hydroxide.