KR20100021321A - Process for the preparation of n-phenyl-2-pyrimidine-amine derivatives - Google Patents

Abstract

The present invention relates to a novel method for preparing an N-phenyl-2-pyrimidin-amine derivative of the general formula (1).

[Formula 1]

Wherein R ₁ , R ₂ , R ₄ and R ₅ are as defined in the specification.

The manufacturing method according to the present invention can provide a more environmentally friendly, consistent and efficient manufacturing method and a lower production cost according to high yield and purity through a shorter manufacturing process and a selective reaction than the conventional manufacturing method.

Description

Process for producing Ν-phenyl-2-pyrimidine-amine derivatives {PROCESS FOR THE PREPARATION OF N-PHENYL-2-PYRIMIDINE-AMINE DERIVATIVES}

The present invention relates to a novel method for preparing an N-phenyl-2-pyrimidin-amine derivative of the general formula (1).

[Formula 1]

Where

R ₁ represents substituted or unsubstituted thiazole, imidazole, pyrazine, wherein the substituent is an amino group, or lower alkyl,

R ₂ is hydrogen, halogen, lower alkyl, or lower alkoxy,

R ₄ is lower alkyl or lower substituted by 1 to 3 halogens Alkyl,

R ₅ represents an aliphatic having 5 to 10 carbon atoms, or a saturated or unsaturated monocyclic radical or any benzene ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur and containing 5 to 7 ring members. Exhibits, or is lower than, fused non- or tri-cyclic radicals Substituted piperazinyl or homopiperazinyl by alkyl.

The compound of Formula 1 is disclosed in Korean Patent Registration No. 10-0674813. Preferred compounds of formula 1 are 4-methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidine -2-ylamino) benzamide. Compounds of Formula 1 have been shown to inhibit one or more tyrosine kinases, such as c-Abl, Bcr-Abl, receptor tyrosine kinases PDGF-R, Flt3, VEGF-R, EGF-R and c-Kit. Therefore, the compound of Formula 1 may be used for various cancers in warm-blooded animals, such as lung cancer, stomach cancer, colon cancer, pancreatic cancer, liver cancer, prostate cancer, breast cancer, chronic or acute leukemia, hematologic cancer, brain tumors, bladder cancer, rectal cancer, cervical cancer, lymphoma, and the like. It can be used for the treatment of.

Existing synthesis of compounds of formula 1 involves hydrolysis of ethyl esters to carboxylic acids and subsequent reaction with aniline, wherein diethylcyanophosphonate is used as coupling agent. (See Scheme 1)

Scheme 1

This method requires a step of hydrolyzing ethyl ester (2) to carboxylic acid (3) in the whole process. As in Scheme 1, a long preparation process and a purification time are required to obtain the compound of Formula 3. In addition, the yield of the compound of Chemical Formula 1 in the condensation reaction has a problem such as high production cost in the low production. In particular, the carboxylic acid (3) has a very low solubility in a general organic solvent, it is very difficult to process after purification and reaction. In addition, diethylcyanophosphonate used in the condensation reaction is an expensive reagent, and is an environmentally harmful and highly toxic substance, and has an LD50 of 25 mg / Kg and 4 mg / Kg in rodent rats and rabbits, respectively. Therefore, there is a need for an alternative method for producing a high purity of the compound of Formula 1 in a simple, consistent, efficient, and rapid manner with low production costs without harming human and environmental pollution.

It is an object of the present invention to provide an alternative method for efficiently preparing a compound of formula 1 of high purity in a consistent and high yield.

A further object of the present invention is to prepare a compound of formula 1 from cheap reagents to lower the manufacturing cost.

It is another object of the present invention to provide a process for the preparation of the compound of formula 1 using safer reagents that do not harm humans and environmental pollution.

Overcoming the problems presented by the existing synthesis methods shown in Scheme 1 of the present invention, typically results in a 70 to 90% increase in overall yield.

The present invention is a reaction in which the compound of formula 2 and the compound of formula 4 are directly condensed using a strong base as a catalyst and a compound of formula 1, as shown in Scheme 2 below, and the compound of formula 1 is N-phenyl-2-pyrimidin-amine Provided are novel methods comprising the reaction to prepare derivatives.

Scheme 2

In the above formula

R ₁ represents substituted or unsubstituted thiazole, imidazole, pyrazine, wherein the substituent is an amino group, or lower alkyl,

R ₂ is hydrogen, halogen, lower alkyl, or lower alkoxy,

R ₃ is lower alkyl, phenyl, phenyl-lower alkyl or substituted phenyl,

R ₄ represents lower alkyl or lower alkyl substituted with 1 to 3 halogens,

R ₅ represents an aliphatic having 5 to 10 carbon atoms, or a saturated or unsaturated monocyclic radical or any benzene ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur and containing 5 to 7 ring members. Exhibits, or is lower than, fused non- or tri-cyclic radicals Substituted piperazinyl or homopiperazinyl by alkyl.

In the production method of the present invention, the direct condensation of the aniline (4) and the ester (2) can produce a compound of the formula (1) by, for example, catalysis by a strong base such as potassium tert-butoxide. Other bases such as metal hydrides, metal halides, bulky alkyl lithium, metal alkoxides, metal bis (trimethylsilyl) amides or lithium dialkylamides, or mixtures thereof may also be used. The metal may be lithium, sodium, magnesium or potassium.

In the preparation method of the present invention, the organic solvent used is not particularly limited, but tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, toluene, N, N-dimethylacetamide, xylene, benzene and N-methyl One or more organic solvents selected from the group consisting of pyrrolidinone can be used.

In a preferred embodiment of the preparation method of the invention, it is selected from the group consisting of tetrahydrofuran, dimethylformamide, dimethylsulfoxide, toluene, N, N-dimethylacetamide, xylene, benzene and N-methylpyrrolidinone In the presence of at least one organic solvent at a temperature of -50 ℃ to 50 ℃, preferably -20 ℃ to 30 ℃, in the presence of 3.0 to 5.0 equivalents, preferably 3.5 to 4.5 equivalents of the base, Dissolving 1.0 equivalent in a selected organic solvent, dropwise and stirring; And 1.0 to 1.2 equivalents, preferably 1.1 equivalents, of the compound of Formula 2 dissolved in a selected organic solvent, and then added dropwise thereto, followed by stirring. The compound of Formula 1 may be generated.

In a preferred embodiment of the invention, the method comprises the following reaction.

Scheme 3

Where

R ₁ represents substituted or unsubstituted thiazole, imidazole, pyrazine, wherein the substituent is an amino group, or lower alkyl,

R ₃ is lower alkyl, phenyl, phenyl-lower alkyl or substituted phenyl.

The compound of Formula 4a may be prepared using the method disclosed in Korean Patent Registration No. 10-0674813. It is intended that the disclosure of this application be incorporated herein.

As in Scheme 3 according to the embodiment of the present invention, aniline (4a) and ester (2a) as a starting material through the condensation reaction of a single step of the catalysis of the strong base N-phenyl-2-pyrimidin-amine derivative 1a) can be prepared.

The manufacturing method according to the present invention is an efficient manufacturing method that can lower the production cost with high yield and purity through a shorter manufacturing process, a simple purification method and a selective reaction than the conventional method.

Except where expressly stated otherwise herein, the following terms used in this application each will have the meaning set forth below.

Lower alkyl contains 1 to 6 carbon atoms and is linear or branched, and preferred lower alkyl moieties include butyl (eg n-butyl, sec-butyl, isobutyl, tert-butyl), propyl (eg n -Propyl or isopropyl), ethyl or methyl. Particularly preferred lower alkyl moieties are methyl, ethyl, n-propyl or tert-butyl. In addition, aliphatic means alkenyl, alkynyl, or alkyl. Lower alkoxy is also preferably a group containing straight or branched chain saturated aliphatic hydrocarbon residues containing 1 to 6 carbon atoms, specifically methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and t-butoxy, pentoxy, isopentoxy, hexoxy and the like.

Halogen is fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine.

Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples illustrate the present invention, but do not limit the present invention in any way.

Example  One

4-Methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-cyazol-2-yl-pyrimidin-2-ylamino Synthesis of Benzamide

Method A

Potassium tert-butoxide (20.9 g, 186.56 mmol) was dissolved in tetrahydrofuran (167 ml) in the reactor and cooled to -20 ± 5 ° C. To the reaction was added 3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenylamine (10 g, 41.46 mmol) dissolved in tetrahydrofuran (80 ml) and stirred for 30 minutes. . When stirring is complete, 4-methyl-3- (4-thiazol-2-yl-pyrimidin-2-ylamino) benzoic acid ethyl ester (15.5 g, 45.60 mmol) is dissolved in tetrahydrofuran (90 ml) to the reaction product. Added slowly. After addition, the temperature of the reaction was slowly warmed to room temperature and stirred until the reaction was complete. At the end of the reaction the reaction was cooled to 5-10 ° C. and 15% aqueous sodium chloride solution (337 ml) was added slowly to the reaction. After the addition, the temperature of the reactant was gradually warmed to room temperature, water (170 ml) was added thereto, and the organic layer was extracted and separated. Ethyl acetate (400 ml) was added to the organic layer, washed with water (200 ml), separated, and concentrated under reduced pressure. After concentration was complete, methanol (220ml) was added thereto, and the mixture was stirred under reflux for 1 hour, cooled to room temperature, and stirred for 2 hours.

The resulting solid was filtered, washed sufficiently with methanol (100 ml) and dried to obtain the target compound (17.51 g, yield 81%) as an off-white solid.

¹ H-NMR (DMSO-d ₆ , δ) = 2.19 (s, 3H), 2.36 (s, 3H), 7.24 (s, 1H), 7.35 (m, 2H), 7.47 (s, 1H), 7.64 ( d, 1H), 7.71 (d, 1H), 7.92 (d, 1H), 8.01 (s, 1H), 8.11 (s, 1H), 8.30 (s, 2H), 8.47 (d, 1H), 9.00 (s , 1H), 10.49 (s, 1H)

Method B

4-Methyl-3- (4-thiazol-2-yl-pyrimidin-2-ylamino) benzoic acid instead of 4-methyl-3- (4-cyazol-2-yl-pyrimidin-2- Similar to Method A of Example 1, except that monoamino) -benzoic acid methyl ester (14.9 g, 45.60 mmol) was used, 3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl -Phenylamine (10 g, 41.46 mmol) and 4-methyl-3- (4-cyazol-2-yl-pyrimidin-2-ylamino) -benzoic acid methyl ester to react the off-white solid (17.8 g, Yield 80%).

Method C

Similar to Method A of Example 1 using sodium tert-butoxide instead of potassium tert-butoxide 3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenylamine (10 g , 41.46 mmol) and 4-methyl-3- (4-thiazol-2-yl-pyrimidin-2-ylamino) benzoic acid methyl ester (14.9 g, 45.60 mmol) were reacted to give an off-white solid (17.3 g). , Yield 78%).

Method D

4-Methyl-3- (4-thiazol-2-yl-pyrimidin-2-ylamino) benzoic acid instead of 4-methyl-3- (4-cyazol-2-yl-pyrimidin-2- Similar to Method A of Example 1, except for using monoamino) -benzoic acid phenyl ester (17.7 g, 45.60 mmol) 3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl Phenylamine (10 g, 41.46 mmol) and 4-methyl-3- (4-cyazol-2-yl-pyrimidin-2-ylamino) -benzoic acid phenyl ester to react the off-white solid (15.53 g, Yield 70%).

Example  2

4-Methyl-N- [3- (4-methylimidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) Synthesis of Benzamide

Method A

4-Methyl-3- (4-pyrazin-2-yl-pyrimidin-2-yl instead of 4-methyl-3- (4-cyazol-2-yl-pyrimidin-2-ylamino) benzoic acid ethyl ester Similar to Method A of Example 1, except that amino) -benzoic acid ethyl ester (15.3 g, 45.60 mmol) was used, 3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl -Phenylamine (10 g, 41.46 mmol) and 4-methyl-3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzoic acid ethyl ester were reacted to give a pale solid (18.7 g, yield). 85%).

¹ H-NMR (DMSO-d ₆ , δ) = 2.21 (s, 3H), 2.38 (s, 3H), 7.35 (s, 1H), 7.39 (s, 1H), 7.54 (s, 1H), 7.63 ( d, 1H), 7.75 (d, 1H), 8.14 (d, 2H), 8.38 (d, 2H), 8.54 (d, 2H), 8.68 (s, 1H), 9.06 (s, 1H), 9.45 (s , 1H), 10.56 (s, 1H)

Method B

4-Methyl-3- (4-pyrazin-2-yl-pyrimidin-2-yl instead of 4-methyl-3- (4-cyazol-2-yl-pyrimidin-2-ylamino) benzoic acid ethyl ester Similar to Method A of Example 1, except that amino) -benzoic acid methyl ester (14.7 g, 45.60 mmol) was used, 3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl- Reaction of phenylamine (10 g, 41.46 mmol) with 4-methyl-3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzoic acid methyl ester (18.3 g, yield 83) %) Was obtained.

Method C

Similar to Method A of Example 1, except that sodium tert-butoxide was used instead of potassium tert-butoxide 3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenyl Amine (10 g, 41.46 mmol) and 4-methyl-3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) benzoic acid methyl ester (14.7 g, 45.60 mmol) were reacted to give an off-white solid. 17.2 g, yield 78%) was obtained.

Method D

4-Methyl-3- (4-pyrazin-2-yl-pyrimidin-2-yl instead of 4-methyl-3- (4-cyazol-2-yl-pyrimidin-2-ylamino) benzoic acid ethyl ester Similar to Method A of Example 1, except that amino) -benzoic acid phenyl ester (17.5 g, 45.60 mmol) was used, 3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl- Reaction of phenylamine (10 g, 41.46 mmol) with 4-methyl-3- (4-pyrazin-2-yl-pyrimidin-2-ylamino) -benzoic acid phenyl ester to give a target compound (16.1 g, yield 73). %) Was obtained.

Example  3

3- (4-imidazol-1-yl-pyrimidin-2-ylamino) -4-methyl-N- [3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenyl ] Synthesis of Benzamide

Method A

3- (4-imidazol-1-yl-pyrimidin-2-ylamino) -instead of 4-methyl-3- (4-cyazol-2-yl-pyrimidin-2-ylamino) benzoic acid ethyl ester Similar to Method A of Example 1, except that 4-methyl-benzoic acid ethyl ester (14.75 g, 45.60 mmol) was used, 3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl Phenylamine (10 g, 41.46 mmol) with 3- (4-imidazol-1-yl-pyrimidin-2-ylamino) -4-methyl-benzoic acid ethyl ester to give off a pale solid (15.7 g, Yield 73%).

¹ H-NMR (DMSO-d ₆ , δ) = 2.27 (s, 3H), 2.30 (s, 3H), 6.84 (d, 1H), 7.24 (s, 1H), 7.39 (s, 1H), 7.56 ( d, 2H), 7.89 (m, 3H), 7.92 (d, 2H), 8.07 (s, 1H), 8.35 (s, 1H), 8.42 (d, 1H), 9.40 (s, 1H), 9.89 (s , 1H)

Method B

3- (4-imidazol-1-yl-pyrimidin-2-ylamino) -instead of 4-methyl-3- (4-cyazol-2-yl-pyrimidin-2-ylamino) benzoic acid ethyl ester Similar to Method A of Example 1, except that 4-methyl-benzoic acid methyl ester (14.1 g, 45.60 mmol) was used, 3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl Phenylamine (10 g, 41.46 mmol) and 3- (4-imidazol-1-yl-pyrimidin-2-ylamino) -4-methyl-benzoic acid methyl ester to give off a pale solid (16.1 g, Yield 75%).

Method C

Similar to Method A of Example 1, except that sodium tert-butoxide was used instead of potassium tert-butoxide 3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenyl Amine (10 g, 41.46 mmol) and 3- (4-imidazol-1-yl-pyrimidin-2-ylamino) -4-methyl-benzoic acid methyl ester (14.1 g, 45.60 mmol) to react as an off-white solid Compound (16.3 g, yield 76%) was obtained.

Method D

3- (4-imidazol-1-yl-pyrimidin-2-ylamino) -instead of 4-methyl-3- (4-cyazol-2-yl-pyrimidin-2-ylamino) benzoic acid ethyl ester Similar to Method A of Example 1, except that 4-methyl-benzoic acid phenyl ester (16.9 g, 45.60 mmol) was used, 3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl Phenylamine (10 g, 41.46 mmol) and 3- (4-imidazol-1-yl-pyrimidin-2-ylamino) -4-methyl-benzoic acid phenyl ester to give off a pale solid (15.3 g, Yield 71%).

Claims (6)

A process for preparing a compound of formula 1, comprising reacting a compound of formula 2 with a compound of formula 4 by catalysis with a strong base in an organic solvent. [Formula 1]

[Formula 2]

[Formula 4]

Where R ₁ represents substituted or unsubstituted thiazole, imidazole, pyrazine, wherein the substituent is an amino group, or lower alkyl, R ₂ is hydrogen, halogen, lower alkyl, or lower alkoxy, R ₃ is lower alkyl, phenyl, phenyl-lower alkyl or substituted phenyl, R ₄ is lower alkyl or lower substituted by 1 to 3 halogens Alkyl, R ₅ represents an aliphatic having 5 to 10 carbon atoms, or a saturated or unsaturated monocyclic radical or any benzene ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur and containing 5 to 7 ring members. Exhibits, or is lower than, fused non- or tri-cyclic radicals Substituted piperazinyl or homopiperazinyl by alkyl. A process for preparing a compound of formula 1a comprising reacting a compound of formula 4a with a compound of formula 2a by catalysis with a strong base in an organic solvent. [Formula 1a]

[Formula 2a]

[Formula 4a]

Where R ₁ represents substituted or unsubstituted thiazole, imidazole, pyrazine, wherein the substituent is an amino group or lower alkyl, R ₃ is lower alkyl, phenyl, phenyl-lower alkyl or substituted phenyl. 3. The at least one of claim 1, wherein the base is selected from the group consisting of metal hydrides, metal halides, bulky alkyl lithiums, metal alkoxides, metal bis (trimethylsilyl) amides and lithium dialkylamides. How. The method of claim 3, wherein the metal is selected from the group consisting of lithium, sodium, magnesium and potassium. The method of claim 3 wherein the base is potassium tert-butoxide. The organic solvent of claim 1 or 2, wherein the organic solvent is selected from the group of tetrahydrofuran, dimethylformamide, dimethylsulfoxide, toluene, N, N-dimethylacetamide, xylene, benzene and N-methylpyrrolidinone. Which is one or more.