* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With palladium 10% on activated carbon; hydrogen In methanol at 20℃;
Preparation of methyl 2-(2-aminophenyl)acetate (Compound 6-1) [00231j A mixture of Compound 1-2 (9.75 g, 50 mmol), 10percent palladiumlactivecarbon catalyst (dry, 530 mg, 5 mmol) in methanol (100 mL) was stirred under hydrogen atmosphere at room temperature for overnight. The reaction mixture was filtered to remove palladiumlactive carbon catalyst and the filtrate was concentrated to give Compound 6-1 (8.02 g, yield: 97percent) as a pale yellow oil. MS (ES): mlz:166[M+H]. ‘H NMR (400 MHz, DMSO-d6) ö: 6.94 (m, 2H), 6.64 (d, 1H, J 8.0 Hz),6.51 (m, 1H), 4.88 (s, 2H), 3.59 (s, 3H), 3.52 (s, 2H).
97%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃;
Preparation of methyl 2-(2-aminophenyl)acetate (Compound 11-3)[00269j A mixture of methyl 2-(2-nitrophenyl)acetate (Compound 11-2, 9.75 g, 50 mmol), 10percent palladiumlactive carbon catalyst (dry, 530 mg, 5 mmol) in methanol (100 mL) was stirred under H2 (1 atm.) at room temperature overnight. The reaction mixture was filtered to remove palladiumlactive carbon catalyst and the filtrate was concentrated to give the desired product methyl 2-(2-aminophenyl)acetate (Compound 11-3, 8.02 g, yield: 97percent) as a pale yellow oil. MS (ESI): mlz: 166[M+H]. ‘H NMR (400 MHz, DMSO-d6) ö: 6.94 (m, 2H), 6.64 (d, 1H, J= 8.0 Hz), 6.51 (m, 1H), 4.88 (s, 2H), 3.59 (s, 3H), 3.52 (s, 2H).
67%
With hydrogen In ethyl acetate at 20℃; for 2 h;
The 2-nitrophenyl acid methyl ester (1 g, 5.13 mmol) was dissolved in 20 mL of EA and 0.3 g of Pd/C 10percent was suspended into the solution, the reaction mixture was under hydrogen atmosphere at room temperature. After 2h the reaction was completed by TLC analysis (DCM: EA 60; 40) the Pd/C 10percent was removed by filtration and the solvent by reduced pressure; to yield a colorless oil 0.67 g (67percent).
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 5, p. 691 - 701
[2] European Journal of Organic Chemistry, 2017, vol. 2017, # 14, p. 1889 - 1893
[3] Patent: WO2014/106238, 2014, A1, . Location in patent: Paragraph 00231
[4] Patent: WO2014/106238, 2014, A1, . Location in patent: Paragraph 00269; 00397
[5] Patent: WO2009/3970, 2009, A1, . Location in patent: Page/Page column 42-43
[6] Journal of the American Chemical Society, 1937, vol. 59, p. 2348,2350
[7] Journal of the American Chemical Society, 1983, vol. 105, # 1, p. 74 - 79
[8] Journal of Organic Chemistry, 1995, vol. 60, # 8, p. 2326 - 2327
[9] Tetrahedron, 1997, vol. 53, # 48, p. 16521 - 16532
[10] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 17, p. 2891 - 2893
[11] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 14, p. 4396 - 4401
[12] Patent: US2005/101587, 2005, A9,
[13] Patent: WO2003/82841, 2003, A1, . Location in patent: Page/Page column 90
[14] Journal of Organic Chemistry, 2009, vol. 74, # 23, p. 9222 - 9224
[15] Patent: WO2014/418, 2014, A1, . Location in patent: Page/Page column 60
[16] RSC Advances, 2014, vol. 4, # 84, p. 44629 - 44633
[17] Patent: US2015/197511, 2015, A1, . Location in patent: Paragraph 0294; 0295
[18] European Journal of Organic Chemistry, 2015, vol. 2015, # 26, p. 5775 - 5780
3
[ 3740-52-1 ]
[ 35613-44-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 14, p. 4396 - 4401
[2] Tetrahedron, 1997, vol. 53, # 48, p. 16521 - 16532
[3] Journal of the American Chemical Society, 1983, vol. 105, # 1, p. 74 - 79
[4] Journal of the American Chemical Society, 1937, vol. 59, p. 2348,2350
[5] Patent: WO2014/418, 2014, A1,
[6] Patent: WO2014/106238, 2014, A1,
[7] RSC Advances, 2014, vol. 4, # 84, p. 44629 - 44633
[8] Patent: US2015/197511, 2015, A1,
[9] European Journal of Organic Chemistry, 2017, vol. 2017, # 14, p. 1889 - 1893
4
[ 30095-98-8 ]
[ 59-48-3 ]
[ 35613-44-6 ]
Reference：
[1] Liebigs Annalen der Chemie, 1985, vol. 1985, # 7, p. 1398 - 1412
[2] Organic Letters, 2009, vol. 11, # 6, p. 1345 - 1348
Stage #1: With acetic acid In dichloromethane at 20℃; for 2 h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 40℃;
Preparation of tert-butyl 4-(2-oxoindolin- 1 -yl)piperidine- 1 -carboxylate (Compound 6-2) [00232j A mixture of Compound 6-1 (3.30 g, 20 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (4.38 g, 22 mmol), acetic acid (HOAc, 600 mg, 10 mmol) in dichloromethane (DCM, 80 mL) was stirred at room temperature for 2 h, then sodium triacetoxyborohydride (6.36 g, 30 mmol) was added in portions and heated to 40°C, stirred overnight. The reaction mixture was cooled to room temperature and diluted with dichloromethane (200 mL), washed with water (200 mL x 2) and sodium bicarbonate (sat. aq., 200 mL x 2), dried over anhydrous sodium sulfate, concentrated to give the crude product, purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 5percent, V/v) to give Compound 6-2 (2.65 g, yield: 42percent) as a white solid. MS (ES): mlz: 261[M+H-56]. ‘H NMR (400 MHz, CDC13) ö: 7.24 (m, 2H), 7.01 (m, 2H), 4.41 (m, 1H), 4.28 (br s, 2H), 3.53 (s, 2H), 2.83 (br s, 2H), 2.32 (m, 2H), 1.70 (m, 2H), 1.50 (s, 9H).
42%
Stage #1: With acetic acid In dichloromethane at 20℃; for 2 h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 40℃;
Preparation of tert-butyl 4-(2-oxoindolin- 1 -yl)piperidine- 1 -carboxylate (Compound 11-4) [00270j A mixture of methyl 2-(2-aminophenyl)acetate (Compound 11-3, 3.30 g, 20 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (4.38 g, 22 mmol), acetic acid (HOAc, 600 mg, 10 mmol) in dichloromethane (DCM, 80 mL) was stirred at room temperature for 2 h, then sodium triacetoxyborohydride (NaBH(OAc)3, 6.36 g, 30 mmol) was added in portions and heated to 40°C, stirred overnight. The reaction mixture was cooled to room temperature and diluted with dichloromethane (DCM, 200 mL), washed with water (200 mL x 2) and sodium bicarbonate (sat. aq., 200 mL x 2), dried over anhydrous sodium sulfate, concentrated to give the crude product, purified by flash colunm chromatography on silica gel (ethyl acetate petroleum ether, 1 20-1 15-1 10 v v) to give the desired product tert-butyl 4-(2-oxoindolin- 1 -yl)piperidine- 1- carboxylate (Compound 11-4, 2.65 g, yield: 42percent) as a pale yellow solid. MS (ESI):mlz: 261[M+H-56]. ‘H NMR (400 MHz, CDC13) ö: 7.24 (m, 2H), 7.01 (m, 2H), 4.41 (m, 1H), 4.28 (br s, 2H), 3.53 (s, 2H), 2.83 (br s, 2H), 2.32 (m, 2H), 1.70 (m, 2H), 1.50 (s, 9H).
62%
With sodium tris(acetoxy)borohydride; sodium hydrogencarbonate; acetic acid In dichloromethane
C. 4-(2-Oxo-2.3-dihydro-indol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester. Methyl 2-aminophenylacetate (3.0 g, 18.2 mmol) and 1-tert-butoxycarbonyl-4-piperidone (4.5 g, 22.6 mmol) were set stirring in 50 mL of CH2Cl2 under an atmosphere of nitrogen. Sodium triacetoxyborohydride (5.4 g, 25.5 mmol) was added followed by 1 mL of acetic acid. After 20 h at rt the mixture was quenched by the slow addition of saturated NaHCO3. After stirring for 30 min, the organics were separated, dried (MgSO4), and evaporated to afford 7.5 g of a purple oil. Purification by column chromatography (silica, 10-50percent EtOAc/hexanes) gave 3.9 g (62percent) of the title compound. TLC (silica, 25percent EtOAc/hexanes): Rf=0.15. 1H NMR (400MHz, CDCl3): 7.25 (m, 2H), 7.01 (m, 2H), 4.40 (m, 1H), 3.53 (s, 2H), 2.83 (m, 2H), 2.32 (m, 2H), 1.70 (m, 2H), 1.51 (s, 9H).
With palladium on activated charcoal; hydrogen; In toluene; at 5℃; under 760.051 Torr;
Compound 2 (97.6 g, 0.5 mol),Pd/C (0.98g) and toluene (200mL) were placed in the reaction flask.Hydrogen was passed through a hydrogenation reaction at normal pressure of 5 C overnight.After the reaction,filter,Wash with a small amount of toluene,Combine the filtrate and the wash solution,Recovering toluene,Precipitating solids,Vacuum drying,The pale yellow liquid was Intermediate 3 (80.9 g, 98%).
97%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;
Preparation of methyl 2-(2-aminophenyl)acetate (Compound 6-1) [00231j A mixture of Compound 1-2 (9.75 g, 50 mmol), 10% palladiumlactivecarbon catalyst (dry, 530 mg, 5 mmol) in methanol (100 mL) was stirred under hydrogen atmosphere at room temperature for overnight. The reaction mixture was filtered to remove palladiumlactive carbon catalyst and the filtrate was concentrated to give Compound 6-1 (8.02 g, yield: 97%) as a pale yellow oil. MS (ES): mlz:166[M+H]. ?H NMR (400 MHz, DMSO-d6) oe: 6.94 (m, 2H), 6.64 (d, 1H, J 8.0 Hz),6.51 (m, 1H), 4.88 (s, 2H), 3.59 (s, 3H), 3.52 (s, 2H).
97%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 760.051 Torr;
Preparation of methyl 2-(2-aminophenyl)acetate (Compound 11-3)[00269j A mixture of methyl 2-(2-nitrophenyl)acetate (Compound 11-2, 9.75 g, 50 mmol), 10% palladiumlactive carbon catalyst (dry, 530 mg, 5 mmol) in methanol (100 mL) was stirred under H2 (1 atm.) at room temperature overnight. The reaction mixture was filtered to remove palladiumlactive carbon catalyst and the filtrate was concentrated to give the desired product methyl 2-(2-aminophenyl)acetate (Compound 11-3, 8.02 g, yield: 97%) as a pale yellow oil. MS (ESI): mlz: 166[M+H]. ?H NMR (400 MHz, DMSO-d6) oe: 6.94 (m, 2H), 6.64 (d, 1H, J= 8.0 Hz), 6.51 (m, 1H), 4.88 (s, 2H), 3.59 (s, 3H), 3.52 (s, 2H).
67%
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; at 20℃; for 2h;
The 2-nitrophenyl acid methyl ester (1 g, 5.13 mmol) was dissolved in 20 mL of EA and 0.3 g of Pd/C 10% was suspended into the solution, the reaction mixture was under hydrogen atmosphere at room temperature. After 2h the reaction was completed by TLC analysis (DCM: EA 60; 40) the Pd/C 10% was removed by filtration and the solvent by reduced pressure; to yield a colorless oil 0.67 g (67%).
8.5 g (100%)
palladium-carbon; In methanol;
B. Methyl 2-aminophenylacetate. Methyl 2-nitrophenylacetate (10.1 g, 51.2 mmol) in 125 mL of methanol containing 221 mg of 10% Pd/C was placed on the Parr hydrogenator at 40 psi. After 5 h the mixture was filtered through celite and evaporated under reduced pressure to give a clear red oil. The solvent was evaporated under reduced pressure to give 8.5 g (100%) of methyl 2-aminophenylacetate as a clear red oil. TLC (silica, EtOAc/hexanes): Rf=0.24. 1H NMR (400MHz, CDCl3): 7.21 (m, 2H), 6.86 (m, 2H), 3.81 (s, 3H), 3.70 (s, 2H).
With hydrogen;platinum(IV) oxide; In methanol; under 2585.81 - 2844.39 Torr; for 25.5h;
B. (2-Amino-phenyl) acetic acid methyl ester; The title A compound, (2-nitro-phenyl)-acetic acid methyl ester (5.0 g, 25.6 mmol) is dissolved in MeOH (125 mL) in a Parr Bottle. It is purged with nitrogen, then added Pt02 (185 mg), then placed on a Parr Shaker under 50 to 55 psi of hydrogen with shaking for 25.5 h. The reaction is opened and filtered through celite, and concentrated to yield (2-amino- phenyl) acetic acid methyl ester as an amber oil : [M+1] + = 166.
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;Inert atmosphere;
Add Pd/C (10%, 800 mg) to a solution of methyl 2-(2-nitrophenyl)acetate (7.5 g, 38.5 mmol) in methanol (50 mL) under N2, then flush with H2, stir the reaction under atmosphere at room temperature overnight. Remove the hydrogen; filter off the solid, concentrate the filtrate under reduced pressure to obtain the crude product (4.8 g, 76.2%) which is used directly without further purification. MS: (M+l):166
With palladium 10% on activated carbon; hydrogen; In methanol; at 25℃;Inert atmosphere;
Add Pd/C (10%, 800 mg) to a solution of methyl 2-(2-nitrophenyl)acetate (7.5 g, 38.5 mmol) in methanol (50 mL) under N2, then flush with H2, stir the reaction under H2 atmosphere at room temperature overnight. Remove the hydrogen; filter off the solid, concentrate the filtrate under reduced pressure to obtain the crude product (4.8 g, 76.2%) which is used directly without further purification. MS: (M+1):166.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Stir the mixture of <strong>[35613-44-6]methyl 2-(2-aminophenyl)acetate</strong> (4.8 g, 29.1 mmol) and potassium carbonate (8.0 g, 58.2 mmol) in DMF (15 mL) at room temperature overnight. TLC (PE:EtOAc=2:l) shows the reaction is complete. Concentrate the reaction mixture under reduced pressure to give the crude product. Purify by chromatography (silica gel, EtOAc:PE=l:2) to afford the title compound (4.0 g, 95%). MS: (M+l): 134.2.
4 g
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃;
Stir the mixture of <strong>[35613-44-6]methyl 2-(2-aminophenyl)acetate</strong> (4.8 g, 29.1 mmol) and potassium carbonate (8.0 g, 58.2 mmol) in DMF (15 mL) at room temperature overnight. TLC (PE:EtOAc=2:1) shows the reaction is complete. Concentrate the reaction mixture under reduced pressure to give the crude product. Purify by chromatography (silica gel, EtOAc:PE=1:2) to afford the title compound (4.0 g, 95%). MS: (M+1): 134.2.
Preparation of tert-butyl 4-(2-oxoindolin- 1 -yl)piperidine- 1 -carboxylate (Compound 6-2) [00232j A mixture of Compound 6-1 (3.30 g, 20 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (4.38 g, 22 mmol), acetic acid (HOAc, 600 mg, 10 mmol) in dichloromethane (DCM, 80 mL) was stirred at room temperature for 2 h, then sodium triacetoxyborohydride (6.36 g, 30 mmol) was added in portions and heated to 40C, stirred overnight. The reaction mixture was cooled to room temperature and diluted with dichloromethane (200 mL), washed with water (200 mL x 2) and sodium bicarbonate (sat. aq., 200 mL x 2), dried over anhydrous sodium sulfate, concentrated to give the crude product, purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 5%, V/v) to give Compound 6-2 (2.65 g, yield: 42%) as a white solid. MS (ES): mlz: 261[M+H-56]. ?H NMR (400 MHz, CDC13) oe: 7.24 (m, 2H), 7.01 (m, 2H), 4.41 (m, 1H), 4.28 (br s, 2H), 3.53 (s, 2H), 2.83 (br s, 2H), 2.32 (m, 2H), 1.70 (m, 2H), 1.50 (s, 9H).
42%
Preparation of tert-butyl 4-(2-oxoindolin- 1 -yl)piperidine- 1 -carboxylate (Compound 11-4) [00270j A mixture of <strong>[35613-44-6]methyl 2-(2-aminophenyl)acetate</strong> (Compound 11-3, 3.30 g, 20 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (4.38 g, 22 mmol), acetic acid (HOAc, 600 mg, 10 mmol) in dichloromethane (DCM, 80 mL) was stirred at room temperature for 2 h, then sodium triacetoxyborohydride (NaBH(OAc)3, 6.36 g, 30 mmol) was added in portions and heated to 40C, stirred overnight. The reaction mixture was cooled to room temperature and diluted with dichloromethane (DCM, 200 mL), washed with water (200 mL x 2) and sodium bicarbonate (sat. aq., 200 mL x 2), dried over anhydrous sodium sulfate, concentrated to give the crude product, purified by flash colunm chromatography on silica gel (ethyl acetate petroleum ether, 1 20-1 15-1 10 v v) to give the desired product tert-butyl 4-(2-oxoindolin- 1 -yl)piperidine- 1- carboxylate (Compound 11-4, 2.65 g, yield: 42%) as a pale yellow solid. MS (ESI):mlz: 261[M+H-56]. ?H NMR (400 MHz, CDC13) oe: 7.24 (m, 2H), 7.01 (m, 2H), 4.41 (m, 1H), 4.28 (br s, 2H), 3.53 (s, 2H), 2.83 (br s, 2H), 2.32 (m, 2H), 1.70 (m, 2H), 1.50 (s, 9H).
3.9 g (62%)
With sodium tris(acetoxy)borohydride; sodium hydrogencarbonate; acetic acid; In dichloromethane;
C. 4-(2-Oxo-2.3-dihydro-indol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester. Methyl 2-aminophenylacetate (3.0 g, 18.2 mmol) and 1-tert-butoxycarbonyl-4-piperidone (4.5 g, 22.6 mmol) were set stirring in 50 mL of CH2Cl2 under an atmosphere of nitrogen. Sodium triacetoxyborohydride (5.4 g, 25.5 mmol) was added followed by 1 mL of acetic acid. After 20 h at rt the mixture was quenched by the slow addition of saturated NaHCO3. After stirring for 30 min, the organics were separated, dried (MgSO4), and evaporated to afford 7.5 g of a purple oil. Purification by column chromatography (silica, 10-50% EtOAc/hexanes) gave 3.9 g (62%) of the title compound. TLC (silica, 25% EtOAc/hexanes): Rf=0.15. 1H NMR (400MHz, CDCl3): 7.25 (m, 2H), 7.01 (m, 2H), 4.40 (m, 1H), 3.53 (s, 2H), 2.83 (m, 2H), 2.32 (m, 2H), 1.70 (m, 2H), 1.51 (s, 9H).
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 50℃; for 19h;
C. [2- (t-Butoxycarbonylmethyl-amino)-phenyl]-acetic acid methyl ester; The title B compound, (2-amino-phenyl) acetic acid methyl ester (4.2 g, 25.4 mmol) is dissolved in DMF (30 mL). Powdered potassium carbonate (8.78 g, 63.5 mmol) and t-butyl bromoacetate (4.12 mL, 27.9 mmol) are added and the reaction is stirred at room temperature for 18 h and then at 50C for 1 h. The reaction is diluted with water (300 mL) and extracted with EtOAc (2 x 200 mL). Combined EtOAc layers are washed with water (2 x 100 mL) then brine (100 mL), dried over anhydrous MgS04, filtered and concentrated to give a viscous brown oil. This residue is chromatographed on a 110 g silica gel RediSep (Isco Inc.) column with a 30 mUmin gradient elution of 10: 90 (EtOAc: hexane) to 25: 75 over 30 min. Fractions containing product are combined and evaporated to yield [2-(t-butoxy- carbonylmethyl-amino)-phenyl]-acetic acid methyl ester as a clear amber oil : [M+1] + = 280.
methyl 2-(methylsulfonylamino)phenylacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With magnesium sulfate; triethylamine;palladium; In toluene;
To a solution of methyl 2-nitrophenylacetate, (6.04 kg) in toluene (100 l) is added anhydrous magnesium sulfate (2.00 kg) and then 5% palladium-on-charcoal (125 g). The mixture is then stirred and hydrogenated, keeping the temperature below 40 by regulation of the stirring rate and input of hydrogen gas. After the addition is complete, the mixture is filtered. The filtrate containing <strong>[35613-44-6]methyl 2-aminophenylacetate</strong> is cooled to -20 and triethylamine (3.75 kg) is added all at once with stirring. This is followed by the slow addition of a solution of methanesulfonyl chloride (3.91 kg) in toluene (4.5L), keeping the temperature between -2 and 5. After stirring at -2 for 1 hour, the mixture is filtered and washed with toluene (10 l). The filter cake is then slurried with water (90 l) for 90 minutes, filtered, and washed with water (45 l) and methanol (8 l). The solid is dried at 50 in vacuo overnight to yield methyl 2-(methylsulfonylamino)phenylacetate, mp 73-75.
(C) Methyl 2-(2-[(trifluoromethyl)sulfonyl]aminophenyl)acetate The methyl 2-(2-aminophenyl)acetate obtained in (B) (1.32 g, 7.99 mmol) was dissolved in methylene chloride (50 ml), and the solution was added dropwise with triethylamine (1.23 ml, 8.79 mmol) under ice cooling, and slowly added dropwise with trifluoroacetic anhydride (1.34 ml, 7.99 mmol). After the reaction mixture was stirred for 15 minutes at the same temperature, the organic layer was separated, and the layer was washed with 10% aqueous citric acid, saturated aqueous sodium hydrogencarbonate and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the title compound as pale orange oil (1.41 g, 59.4%). 1H-NMR (CDCl3) delta: 3.75 (2H, s), 3.77 (3H, s), 7.17-7.45 (3H, m), 7.48-7.65 (1H, m)
A mixture of 160 g of 4,7-dichloroquinoline, 80 g of <strong>[35613-44-6]methyl 2-aminophenylacetate</strong> and 500 mL of acetonitrile is heated at reflux temperature for 24 hours. The solvent is evaporated under reduced pressure and the residue extracted 4 times with 750 mL portions of hot water. The aqueous extract is rendered basic (pH 8) with 10% ammonium hydroxide whereupon [2- (7-Chloro-quinolin-4-ylamino)-phenyl]-acetic acid methyl ester separates as an oil which crystallizes upon addition of ethanol. The product may be recrystallized from aqueous methanol, M.P.147-148C.[0114] The hydrochloride of £2-(7-Chloro-quinolin-4-ylamino)-phenyl]-acetic acid methyl ester may be prepared in conventional manner by treating a solution of the free base in ether with gaseous hydrochloric acid; M.P. 224-226C. [0115] To a solution of 6 g of [2-(7-Chloro-quinolin-4-ylamino)-phenyl]-acetic acid methyl ester in 100 mL of hot methanol is added 3 g of methanesulfonic acid. The solution is cooled to room temperature and 750 mL of ether is added. The product precipitates as off-white crystals and is collected by filtration. The resulting methanesulfonate of the above-mentioned compound is recrystallized from methanol-ether, M.P. 179-1810C.
A mixture of 7.2 g of 4-chloro-7-trifluoromethylquinoline, 5.4 g of methyl 2- aminophenylacetate and 250 mL of acetonitrile is heated under reflux for 18 hours. The solvent is evaporated under reduced pressure and the residue extracted 3 times with 200 mL portions of hot water. The aqueous extract is rendered basic with 10% ammonium hydroxide whereupon the desired compound precipitated; it was recrystallized from aqueous ethanol yielding colorless needles with a melting point of 140-1410C.
2-(2-(3,4-Dichlorophenylsulfonamido)phenyl)acetic acid methyl ester; 2-Aminophenylacetic acid methyl ester (10.2 g, 39.45 mmol) was dissolved in DCM (200 ml). There were then added first pyridine (12.4 ml, 151.71 mmol) and 3,4-dichlorobenzenesulfonyl chloride (11.8 ml, 75.87 mmol) in DCM (50 ml). The reaction solution was stirred overnight and then diluted with DCM and washed in succession with 0.5 M KHSO4 solution, saturated NaHCO3 solution and saturated NaCl solution, dried over sodium sulfate and concentrated. Purification was carried out by column chromatography on silica gel (DCM).Yield: 14.3 g (96%)
2-(2-(3,4-Dichloro-N-methylphenylsulfonamido)phenyl)-acetic acid S2; Thionyl chloride (5.2 ml, 71.4 mmol) was added dropwise, with stirring and while cooling with ice, to a solution of 2-aminophenylacetic acid (7.2 g, 47.6 mmol) in methanol (150 ml). The reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated, and thionyl chloride residues were removed by dragging out with toluene and DCM. 10.3 g (contaminated with starting material) of the were obtained in the form of a brown solid. The crude product was used further without being purified further.
With hydrogenchloride; sodium nitrite; In water; at -5℃;Cooling with acetone/ice;
The 2-aminophenyl acid methyl ester (3 g, 0.018 mol) was dissolved in water(4OmL) with concentrated HCl (9 mL) and the solution was cooled in an ice/acetone bath to -5 0C, afterward sodium nitrite (1.32 g, 0.019 mol) in ImL of water was added dropwise. At that point the diazonium salt was formed and the solution took a pale yellow color. A spatula of urea was added to neutralize the excess of sodium nitrite (oxidant) and the diazonium salt solution was added dropwise into a solution of phenol (1.68 g, 0.018 mol), sodium acetate (2.88 g, 0.036 mol) and ammonia solution (5 mL) in water (40 mL), which was at -5 0C, after 5 minutes. After the addition was done glacial acetic acid (eq, 5 mL) was added and the reaction mixture was filtered. The filter cake was dissolved in EA and dried over sodium sulfate, the solvent removed under reduced pressure and the product purified by flash chromatography (DCM 100 mL, DCM: EA 80: 20) to yield 2.7 g (56%): m.p. 158- 160 0C, IRvm(rc(KBr): 3221.84 (OH), 1695.48 (C=O) cm"1. 1H-NMR (400MHz, Acetone) delta: 9.14 (IH, s), 7.86 (2H, d, J 8.50 Hz), 7.72 (IH, d, J 8 Hz), 7.45 (3H, m, J 7.52 Hz), 7.03 (2H, d, J 8.50 Hz), 4.16 (2H, s), 3.62 (3H, s). 13C-NMR (400MHz, Acetone) delta: 204.91 (C=O, Acetone), 171.22 (C=O, C-8), 160.29 (C, C-4'), 149.64 (c, C-2), 146.20 (C, C-I '), 134.13 (CH, C-6), 131.13 (CH, C-5), 129.97 (QC-I), 127.42 (CH, C-4), 124.65 (CH,C-3, C-6', C-2'), 115.38 (CH, C-5'), 114.73 (CH, C-3'), 50.65 (CH3, C-9), 36.41 (CH2, C-7), 28.52 (Acetone, CH3).
Synthesis of 1 -(1 -(1-methyl-i ,2,3 ,4-tetrahydronaphthalen- 1 -yl) piperidin-4-yl) indolin2-one (Compound 17-7)[00328j To a solution of Compound 17-6 (486 mg, 2mmol) and methyl 2-(2- aminophenyl)acetate (996 mg, 6mmol) in dichloromethane (2OmL) was added acetic acid (150.0mg, 2.5 mmol). The mixture was stirred for 1.5 h at room temperature. Sodium triacetoxyborohydride (1.27 g, 6 mmol) was added into the mixture and stirred for 2 h at room temperature. Then the reaction mixture was heated to 30C and stirred overnight. The mixture was washed with sat. sodium carbonate (3OmL), brine (20 mL x 2). The organic layer were dried over anhydrous sodium sulfate and evaporated in vacuum to afford the crude product. The crude product was purified by chromatography silica gel (ethyl acetate: petroleum ether = 1: 5 to 1: 2) to obtain Compound 17-7 (500mg, yield 69 %) as a pale yellow solid. MS (ESI): mlz 361 [M+H] +
Preparation of 1 -(1 -(i-methyl-i ,2-dihydroacenaphthylen- 1 -yl)piperidin-4-yl)indolin-2- one (Compound 23-10)[00381j To a solution of 1 -(i-methyl-i ,2-dihydroacenaphthylen- 1 -yl)piperidin-4-one Compound 23-9 (132.68 mg, 0.5 mmol) and <strong>[35613-44-6]methyl 2-(2-aminophenyl)acetate</strong> (247.49 mg, 1.5 mmol) in 15 mL of dichioromethane was added acetic acid (150.0mg, 2.5 mmol). The mixture was stirred for 1.5 h at room temperature. Sodium triacetoxyborohydride (316.5 mg, 1.5 mmol) was added into the mixture and stirred2 h at room temperature. Then the reaction mixture was heated to 30C and stirred overnight. The mixture was washed with water (20 mL x 2), and sat. sodium carbonate (20 mL x 2), brine (20 mL x 2). The organic layer were dried over anhydrous sodium sulfate and evaporated in vacuum to afford the crude product. The crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1: 5 to 1: 2) to obtain 1 -(1 -(1-methyl-i ,2-dihydroacenaphthylen- 1 -yl)piperidin-4-yl)indolin-2- one(Compound 23-10, 101.5 mg, yield 53 %) as a white solid. ESIMS (mlz): 382 [M+H].
Preparation of Compound 26-7 [00408j A solution of Compound 26-6 (500 mg, 2.18 mmol, 1.0 equiv.) in DCM (10 mL) was mixed with methyl 2-(2-aminophenyl) acetate (1.08 g, 6.55 mmol) and acetic acid (650 mg, 10.90 mmol). The mixture was stirred at room temperature for 2 hours, then NaBH(OAc)3 (1.47 g, 6.54 mmol) was added in portions. The reaction mixture was stirred at room temperature for two days and monitored by LCMS. Upon completion, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried with Na2SO4, filtered and condensed. The residue was purified on silica gel (petrol/ethyl acetate) to yield Compound 26-7 (452 mg, 60%) as a solid. ESI/MS: 347 [M+H].
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