TW201006803A - Process for the preparation of N-phenyl-2-pyrimidine-amine derivatives - Google Patents

Abstract

Disclosed is a novel method of preparing an N-phenyl-2-pyrimidine-amine derivative. As compared to a conventional method, the disclosed preparation method is efficientin that the method requires low production cost due to production process reduction, a simplified purification method, and high yield/purity by a selective reaction, and also is environmentally friendly and consistent.

Description

201006803 6. Description of the Invention: [Technical Field of the Invention] The present invention relates to a novel preparation method of the N-phenyl-2-pyrimidine-amine derivative of the following formula 1.

In the above formula, 'Rl疋 is substituted or unsubstituted, sold, squid, uranyl (substituent is amino or lower alkyl); R2 is hydrogen, halogen, lower alkyl or alkoxy; R4 is a lower alkyl group substituted by a lower alkyl group or 1 to 3 ketones; R5 represents a C5 to C10_ aliphatic group, or is a heterocyclic atom containing a ring, which is substituted with an atmosphere, oxygen and sulfur, and contains 5~ 7 monocyclic groups (_〇cyciic radical) are fused to acyclic or tricydicradica of a benzene ring or pyridazinyl or oxazinyl homopiperazinyl ° substituted by a lower alkyl group [Prior Art] A compound is disclosed in the Republic of Korea Patent Registration No. 1 (5). The compound of the formula 1 is preferably a 4-f group 1 [ 3 —( 4·indolyl-1 -yl)-5-trifluorodecyl-phenyl]_3_(4_11 than 嗓_2_yl_money_2_methane Benzoamine. The compound of the formula 1 is an acetoin, which inhibits, for example, 201006803 c-Abl 'Bcr-AW, the receptor-dependent tyrosine kinases pdgF-R, Flt3, VEGF-R, EGF-R and c-Kit. The compound of formula 1 is used in the treatment of various cancers of warm-blooded animals, for example, for lung cancer, gastric cancer, colon cancer, pancreatic cancer, liver cancer, prostate cancer, breast cancer, chronic or acute leukemia, blood cancer, brain tumor, bladder cancer, rectal cancer. , treatment of cervical cancer, lymphoma, etc. The conventional synthesis method of the compound of the formula 1 is carried out by reacting with aniline after acid hydrolysis of ethyl acetate, and diethyl cyanophosphonate is used as a cyclizing agent. (Refer to the reaction formula u

(1) Reaction formula 1 The above process requires the hydrolysis of ethyl ester (2) to carboxylic acid (3) throughout the process in the same manner as in Reaction Scheme 1, and it takes a long time to prepare and refine the compound for obtaining the compound of Formula 3. Further, in the above condensation reaction, since the yield of the compound of the formula 1 is 30 to 40%, there is a problem that the production cost is high. In particular, the solubility of the carboxylic acid (3) in a general organic solvent is very low, so that the purification and the 201006803 reaction treatment are too _. And in the condensation reaction towel, (4) aryl sulphate diethyl sulphur 8 is a high-priced, environmentally harmful, very toxic reagent 'Ld5 〇 in rodent mice and rabbits respectively 2 〇 mg / kg And 40mg/kg. Therefore, there is a need for a new method which is non-hazardous to humans and the environment, and at the same time, produces a high-purity compound of formula 1 at a relatively low cost, simple, stable, efficient and rapid. [Summary of the Invention]

❿ The object of the present invention is to provide a novel process for the preparation of the compound of formula 1 with high stability, high yield and high purity. Another object of the present invention is to reduce the manufacturing cost by producing a compound of the formula 1 with a low-cost reagent. It is yet another object of the present invention to provide a method for preparing a compound of formula 1 using a safer reagent for non-hazardous contamination of humans and the environment. The shortcomings of the existing synthetic method of this type of overcoming type 1 towel reached 7G_9G%. The present invention is a novel process comprising the preparation of the N-phenyl-2.transamine derivative of the compound of the formula 1 by the direct condensation reaction using the compound of the formula 2 and the compound of the formula 4 as a catalyst as shown in the reaction formula 2.

Reaction formula 2 5 201006803 • In the above formula

Ri is substituted or unsubstituted carbazole, imidazole, pyridinium (substituent is amino or lower alkyl); heart is hydrogen, dentate, lower alkyl or lower alkoxy; & lower alkyl, Phenyl, phenyl-lower alkyl or substituted phenyl; ^4 is lower alkyl substituted by lower alkyl or 1 to 3 dentate, R5 represents a C5 to c1G aliphatic group, or contains nitrogen, 1 to 3 heterocyclic atoms to be substituted in oxygen and sulfur, a saturated or unsaturated monocyclic group having 5 to 7 rings or an acyclic or _tricyclic group fused to a benzene ring, or substituted by a lower alkyl group The fox ° Qinji or the South fox scorpion homopiperazinyl. The production method of the present invention 'directly condenses aniline (4) and ester (2) by a catalyst such as a strong base such as potassium tert-t-butoxy group to give a compound of the formula 1. Other domains such as metal hydrides, metal halides, bulky alkyllithium, metal alkoxides, bis (trimethylsilyl) amide or substituted amine clocks JJNR2 , or ® use its mixture. The metals listed above are barium, sodium, magnesium or unloaded. The preparation method of the present invention, the organic solvent to be used is not limited, and may be selected from the group consisting of tetrahydrofuran, diammonium decyl aldehyde, dimethyl sulfoxide, toluene, N,N-monodecylamine, diphenylbenzene, benzene, N-methylpyrrolidone and mixtures thereof. The specific process scheme of the preparation method of the present invention comprises: at _5 (rc~5〇t: (preferably -20 ° C~3 (TC), the domain basis amount is 3.0 to 5. 〇 equivalent (preferably 3.5~) In the case of 4.5 equivalents, 1 〇 equivalent of the compound of the above formula 4 is dissolved in an organic solvent, and the organic solvent used is selected from the group consisting of tetrahydrofuran, dimethylamino decanoic acid, dimercapto sulfhydryl, hydrazine, and N. N-dimercaptoacetamide, bis 6 201006803 • terpene, stupid 'N-methylpyrrolidone and mixtures thereof' are stirred while being added; while 1.0 to 1.2 equivalents, preferably u equivalents of the compound of formula 2 above It is dissolved in an organic solvent, and then added to the compound of the above formula 4 while stirring dropwise to form a compound of the above formula 1. In a preferred embodiment of the invention, the above method comprises the following reaction.

(2a) (4a) (1a) In the above formula, R1 is a substituted or unsubstituted thiazole, imidazole or pyrazine (the substituent is an amino group or a lower alkyl group). The docking station is a lower alkyl group, a phenyl group, a phenyl group-lower alkyl group or a substituted phenyl group. The compound of the formula 4a can be produced by the method disclosed in Korean Patent Registration No. 1 〇 〇 674 813. The present invention includes the disclosure of this application. In the same manner as in the above Reaction Formula 3 of the present invention, an N-phenyl-2-pyrimidine-amine derivative (formula la) is produced by a reaction-condensation reaction in which aniline (4a) and ester (2a) are used as starting materials. <The preparation method of the present invention shortens the preparation process, employs a simpler purification method, and improves the yield and purity by a preferred reaction process as compared with the prior art, and is a highly efficient preparation method which can reduce the production cost. The following term 201006803 used in the present invention has the following meanings in addition to the present invention. The lower stage base contains 1 to 6 carbon atoms, linear or branched, and the preferred lower alkyl residue is butyl (eg, n-butyl, sec sec-butyl, isobutyl, tert t-butyl) ), propyl (eg, propyl or isopropyl), ethyl or f-based. Particularly preferred low-wei corrections are methyl, ethyl, &propyl or tert tert-butyl. Further, the aliphatic group means an alkenyl group, an alkynyl group or an alkyl group. Further, the 'lower alkoxy group (Alkoxy) is preferably a group containing a main chain of 6 carbon atoms (nonnalchail(R) or branched chain saturated aliphatic hydrocarbon residue, which may be a methoxy group, Ethoxy, propoxy, propoxy, butoxy, isobutoxy, t-butoxy, pentoxy, isopentoxy, hexyloxy, etc. Halogen means Fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine. [Embodiment] The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention: Example 1

4-mercapto-N-[ 3-(4-mercaptoimidazo-1)yl-5-trifluoromethyl-phenyl]-3-(4-oxazol-2-yl, pyridine-2-yl Synthesis of Amino) Benzoic Acid A A tetrahydrogen π Nan (167 ml) was dissolved in a reactor to dissolve tert-t-butoxy (20.9, 185.611111111) and cooled to -20 ± 5 ° (: To the above reaction, 3-(4-mercapto-indol-1-yl)-5-trifluoromethyl-p-aminoamine (i〇g, 41.46 mmol) dissolved in tetrahydron-flucene (8 ml) was added. After stirring for 30 minutes, 8 201006803. After stirring, tetramethylfuran (4~嗟 -2--2-yl-chryt-2-ylamino)benzoic acid ethyl ester (15.5 g, was dissolved in tetrahydrofuran (90 ml). After 45.6 mmol), slowly add dropwise to the above reactants. After the addition, the temperature of the reaction was slowly heated to 4 normal temperature and stirred until the reaction was completed. After completion of the reaction, the reaction was cooled to 5 - 1 ° C, and a 15% aqueous sodium chloride solution (337 ml) was slowly added. After the addition, the temperature of the reactant was slowly heated to normal temperature, and after adding water (170 ml), the organic layer was separated and extracted. After the organic layer was added ethyl acetate (400 ml). After completion of concentration, methanol (220 ml) was added and refluxed for 1 hour, then cooled to normal temperature and stirred for 2 hours. The resulting solid was filtered, washed with hexane (100 ml), and dried to give the title compound (17.51 g, yield 81%). ^-NMRC DMSO-dg, δ) = 2.19 (s, 3H), 2.36 (s, 3H), 7.24 (s, lH), 7.35 (m, 2H), 7.47 (s, lH),

7.64(d,lH), 7.71(d,lH), 7.92(cUH),8.01(s,1H),8.11(s,1H), 8.30(s,2H),8.47(d,lH),9.00(s ,1H),1〇.49(s,1H)

Method B In place of methyl 4-methyl-3-(4-thiazol-2-yl-pyrimidin-2-ylamino)benzoate, 4-methyl-3-(4-thiazol-2-yl-pyrimidine- In the same manner as the method A of Example 1, except for the 2-ethylamino) benzoic acid ethyl ester, 3-(4-mercapto imidazol-1-yl)-5-trifluoromethyl-phenylamine (10 g, 41.46 mmol) Reaction with methyl 4-mercapto-3-(4-indolyl)--2-yl-o-pyridin-2-ylamino)benzoate to give the beige title compound (17,8 g, yield 80%) .

Method C Instead of sodium tert tert-butoxy using potassium tert t-butoxy, similar to Method A of Example 9 201006803 1 'with 3-(4-methylimidazolium +yl)-5-trifluoromethylanilide (10 g, 41.46 mmol) and 4-mercapto-3-(4-indolazole!-ylpyrimidin-2-ylamino)benzoic acid methyl vinegar (14.9 g, 45.6 mmol) were reacted to give a beige solid compound ( 17.3 g, yield 78%).

Method D Instead of 4-mercapto-3-(4-oxazol-2-yl-x-indole-2-ylamino)benzoic acid ethyl ester using 4-mercapto-3-(4-thiazol-2-yl- In addition to ethylpyrimidin-2-ylamino)benzoate, hydrazine is similar to Method A of Example 1, using 3-(4-methyl.mazole-1-yl)-5-tris-decyl-aniline ( 10g, 41.46mmol) and 4-methyl_3_(4_ sinter-sodium-2-yl-pyridin-2-ylamino)benzoic acid phenyl ester to give the beige target solid compound (15.53g, yield 70%) ). Example 2 4-Mercapto-N-[3-(4-nonylimidazol-1-yl)-5-trifluorodecyl-phenyl]-3-(4-pyrazin-2-yl-pyrimidine- Synthesis of 2-aminoamino)benzoic acid.

Method A ❹ In addition to ethyl 4-methyl-3-(4-pyrazin-2-yl-pyrimidin-2-ylamino)benzoate instead of 4-mercapto-3-(4-thiazol-2-yl In the same manner as the method A of Example 1, except for the ethyl pyrimidin-2-ylamino)benzoate, 3-(4-methylimidazol-1-yl)-5-trifluoromethyl-phenyl (10 g, 41.46 mmol) was reacted with ethyl 4-methyl-3-(4-indol-2-yl·, dimethyl-2-ylamino)benzoate to give the title compound as a beige (18.7 g, yield: 85%) . !H-NMR ( DMSO-d6 , δ ) = 2.21 (s, 3H ) , 2.38 (s, 3H), 7.35 (s, 1H), 7.39 (s, 1H), 7.54 (s, 1H), 7.63 (d) , lH), 7.75 (d, lH), 8.14 (d, 2H), 8.38 (d, 2H), 8.54 (d, 2H), 201006803 ' 8.68 (s, 1H), 9.06 (s, 1H), 9.45 ( s,1H),1〇.56(s,1H)

Method B was substituted for 4-mercapto-3-(4-oxazol-2-yl, pyridine-2-ylamino)benzoic acid ethyl ester (14.7 g, 45.6 mmol) in place of 4-mercapto-3-(4- In the same manner as the method A of Example 1, except for the pyrazin-2-yl-pyrimidin-2-ylamino) benzoic acid phthalate, the reaction 3-(4-methylm sigma-1 _)-5-three Fluoromethyl-p-aminoamine (i〇g, 4i.46mmol) and 4-mercapto-3-(4-pyrazin-2-yl-pyrimidin-2-ylamino)benzoate oxime ester gave a beige target ❹ Solid compound (18.3 g, yield 83%).

Method C is similar to Method A of Example 1, except that sodium tert-t-butoxy is used in place of potassium tert-t-butoxy, 3-(4-methylimidazol-1-yl)-5-trifluoromethyl Aniline (10 g, 41.46 mmol) was reacted with 4-methyl-3-(4·pyrazin-2-yl-pyrimidin-2-ylamino)methaneacetic acid (14.7 g, 45.6 mmol) to give a beige solid. Compound (17.2 g, yield 78%).

Method D ❹ In place of 4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)benzoic acid phenyl ester (17.5 g, 45.6 mmol) instead of 4-methyl-3-( In the same manner as Method A of Example 1, except for 4-oxazin-2-yl-pyrimidin-2-ylamino)benzoic acid ethyl acetonate, 3-(4-mercapto-amido-1·yl)-5- Trifluoromethyl-aniline (10g, 4i.46mmol) and 4-mercapto-3-(4-pyrazine-2-yl-pyrimidin-2-ylamino)benzoic acid benzene were reacted to obtain the target Solid compound (16.1 g, yield 73%). Example 3 3_(4_Mimidyl, pyridin-2-ylamino)-4-methyl-N-[3-(4-methylamisin-1-yl)-5-trifluoromethyl_ Synthesis of phenyl]benzoic acid. 11 201006803

Method A In place of 4-methyl-3-(4), ethyl 3-(4-imidazolidinyl-pyrimidin-2-ylamino)-4-indolyl-benzoate (14.75 g, 45.6 mm) was used. In the same manner as Method A of Example 1, except for -thiazol-2-yl-pyridin-2-ylamino)benzoic acid ethyl acetate, 3-(4-mercapto-imidazol-1-yl)-5-trifluoro Methyl-aniline (10 g, 41.46 mmol) and ethyl 3-(4-imidazol-1-yl-pyrimidin-2-ylamino)-4-methyl-benzoate were obtained as a beige solid title compound (15.7 g, Yield 73%). φ ^-NMR ( DMSO-d6 , δ ) = 2.27 (s, 3H ) , 2.30 (s, 3H), 6.84 (d, lH), 7.24 (s, lH), 7.39 (s, lH), 7.56 (d) , 2H), 7.89 (m, 3H), 7.92 (d, 2H), 8.07 (s, lH), 8.35 (s, lH), 8.42 (d, 1 H), 9.40 (s, 1 H), 9.89 ( s, 1H)

Method B Instead of using 4-(4-imidazolyl-1-yl-pyrimidin-2-ylamino)-4.methyl-benzoic acid decyl ester (14.1 g, 45.60 mmol) instead of 4-methyl-3_(4- In the same manner as the method a of Example 1, except for the oxime-2-keto-2-carto-2-ylamino)benzoic acid ethyl ester, the reaction • 3-(4-mercapto-amido-1-yl)-5- Trifluoromethyl-aniline (l〇g, 4i.46mmol) and 3-(4-mithio-l-yl-bine-2-ylamino)-4-methyl-benzoic acid methyl ester give beige Target solid compound (16.1 g, yield 75%).

Method C is similar to the method A of Example 1 except that sodium tert-butoxy is used instead of the unterminated tert-butoxy group. 'Reaction 3-(4-methyl-imidazolyl)-5-trifluorodecyl-aniline ( 10 g, 41.46 mm 〇 l) and 3-(4-imidazole-1 yl-penetrating _2-ylamino)_4-methyl-benzoic acid decyl ester (14.1 g, 45.60 mmol) afforded beige colored solid compound ( 16.3 g, yield 76%). 12 201006803

Method D except for the use of 3-(4-imidazol-1-yl-pyrimidin-2-ylamino)-4-methyl-benzoic acid phenyl ester (16.9 g, 45.60 mmol) instead of 4-methyl-3-(4) In addition to ethyl thiazol-2-yl-pyrimidin-2-ylamino)benzoate, 3-(4-methyl-imidazol-1-yl)-5-trifluoroanrene was reacted similarly to Method A of Example 1. Base-aniline (10 g, 41.46 mmol) and 3-(4-imidazol-1-yl-pyrimidin-2-ylamino)-4-methyl-benzoic acid phenyl ester gave the title compound as a beige (15.3 g. The rate is 71%).

13 201006803 [Simple description of the diagram] None [Key component symbol description] 10 None

14

Claims (1)

201006803 VII. Patent application scope: 1. A method comprising reacting a compound of the formula 2 with a compound of the formula 4 under the action of a strong base in an organic solvent to produce a compound of the following formula 1, characterized in that In the above formula, Ri is substituted or unsubstituted thiazole, imidazole, pyrazine (substituent is amino or lower-grade); R2 is hydrogen, halogen, lower alkyl, lower alkoxy; A thiol, phenyl, phenyl-lower alkyl or substituted group, ^4 is a lower-grade base substituted by a lower alkyl or 1 to 3 ketone; 15 201006803 R5 represents a C5 to Ci-based aliphatic group 'Or 1 or 3 heterocyclic atoms containing nitrogen, oxygen and sulfur, a saturated or unsaturated monocyclic group containing 5 to 7 rings or an acyclic or tricyclic group fused with a benzene ring, or Lower alkyl-substituted pyridazinyl or oxazinyl homopiperazinyl 〇2, a method comprising reacting a compound of formula 2a with a compound of formula 4a under the action of a strong base in an organic solvent to produce a compound of the formula la below, Characterized by La 2 Formula 4 a 201006803. In the above formula, R1 is substituted or unsubstituted oxime, saliva, n-pyrazine (substituent is amino or lower alkyl); R3 疋 lower-grade hospital base 'benefici' Base-lower courtyard or substituted phenyl. 3. The method of claim 1 or 2, wherein the domain is selected from the group consisting of metal hydrides, dentate metals, bulky alkyllithiums, metal alkoxides, doubles. One or more of (trimethylsilyl) amide or substituted amine-based clock LiNR2. 4. The method of claim 3, wherein the metal is selected from one or more of the group consisting of bell, nano, town, and traitor. 5. The method of claim 3, wherein the metal alkoxide is potassium tert-butoxy. 6. The method according to claim 1 or 2, wherein the solvent is selected from the group consisting of tetrahydrofuran, diammonium formaldehyde, dimercapto; g wind, toluene, hydrazine, fluorenyl-difluorenyl One or more of acetamidine, diphenylbenzene, benzene, and methylpyrazine. 17 201006803 IV. Designated representative map: (1) The representative representative of the case is: None (2) The symbol of the representative figure is simple: No 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 2