2-methoxybenzamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2-methoxybenzamide in 1,2-di-chloroethane (24.5 ml/g) is brought to reflux in the presence of 3 equivalents of freshly distilled pyruvic acid in a round-bottomed flask surmounted by a system which makes it possible to remove the water formed during the reaction. When the formation of water has finished 15 (approximately 7 hours), the reaction mixture is left at room temperature. After filtering off the insoluble materials, the filtrate is extracted with an aqueous sodium bicarbonate solution. The combined aqueous phases are extracted with dichloromethane and then acidified with hydrochloric acid. The precipitate formed is filtered off, dried and then taken up in ethyl acetate. After filtering off the insoluble material, the filtrate is concentrated under vacuum, dissolved in dichloromethane and then precipitated with heptane, thus providing pure N-(2-methoxybenzoyl)dehydroalanine. (Nonoptimized yield 8.5%). to remove the water formed during the reaction 15 (approximately 7 hours) the reaction mixture is left at room temperature After filtering off the insoluble materials the filtrate is extracted with an aqueous sodium bicarbonate solution The combined aqueous phases are extracted with dichloromethane The precipitate formed is filtered off dried After filtering off the insoluble material the filtrate is concentrated under vacuum dissolved in dichloromethane precipitated with heptane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 40 Parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate were boiled in 160 parts of methanol. The product was filtered off while hot and crystallized twice from a mixture of 600 parts of tetrachloromethane and 400 parts of trichloromethane. The product was filtered off, dried and recrystallized from 4-methyl-2-pentanone. The product was filtered off and dried (water-separator) yielding 18.5 parts of cis-4-amino-5-chloro-N-[2-chloro-4-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]aminocarbonyl]-5-methoxyphenyl]-2--methoxybenzamide; mp. 181.5° C. (compound 239). The product was filtered off while hot and crystallized twice from a mixture of 600 parts of tetrachloromethane and 400 parts of trichloromethane The product was filtered off dried recrystallized from 4-methyl-2-pentanone The product was filtered off dried (water-separator)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 40 Parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate were boiled in 160 parts of methanol. The product was filtered off while hot and crystallized twice from a mixture of 600 parts of tetrachloromethane and 400 parts of trichloromethane. The product was filtered off, dried and recrystallized from 4-methyl-2-pentanone. The product was filtered off and dried (water-separator) yielding 18.5 parts of cis-4-amino-5-chloro-N-[2-chloro-4-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]aminocarbonyl]-5-methoxyphenyl]-2--methoxybenzamide; mp. 181.5° C. (compound 239). The product was filtered off while hot and crystallized twice from a mixture of 600 parts of tetrachloromethane and 400 parts of trichloromethane The product was filtered off dried recrystallized from 4-methyl-2-pentanone The product was filtered off dried (water-separator)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combine 2-methoxy benzamide (10.0 g, 66.2 mmol) with phosphorus pentasulfide (10.1 g, 22.7 mmol) and THF (200 mmol) in a sealed vessel and stir for 30 minutes at room temperature. Sonicate the mixture for 1 hour and then allow the mixture to stand at room temperature. Decant the THF solution from the solids and concentrate. Chromatograph the resulting residue over silica gel (MeOH/CH2Cl2) to give 2-methoxy-thiobenzamide (7.05 g, 64%). Sonicate the mixture for 1 hour to stand at room temperature Decant the THF solution from the solids concentrate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (141 mg, 0.319 mmol), 4-[(benzylamino)carbonyl]-3-methoxyphenylboronic acid (100 mg, 0.351 mmol), palladium tetrakistriphenyphosphine (22 mg, 0.019 mmol) and sodium carbonate (81 mg, 0.765 mmol) were mixed with ethylene glycol dimethyl ether (4 mL) and water (2 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give cis-N1-benzyl-4-44-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (126 mg, 71%). 1H NMR (CDCl3) δ 1.83 (m, 6H), 2.34 (s, 3H), 2.45 (m, 11H), 4.02 (s, 3H), 4.43 (d, J=5.66 Hz, 2H), 4.95 (m, 1H), 5.52 (bs, 2H), 7.37 (m, 7H), 8.18 (m, 1H), 8.41 (m, 1H); LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+=555.5, Rt=2.65 min. The reaction mixture was heated at reflux overnight Organic solvent was removed under reduced pressure the aqueous layer was extracted with dichloromethane The combined organic layer was washed with water brine, dried over MgSO4 filtered evaporated The residue was purified by flash column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (141 mg, 0.319 mmol), 4-[(benzylamino)carbonyl]-3-methoxyphenylboronic acid (100 mg, 0.351 mmol), palladium tetrakistriphenyphosphine (22 mg, 0.019 mmol) and sodium carbonate (81 mg, 0.765 mmol) were mixed with ethylene glycol dimethyl ether (4 mL) and water (2 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give cis-N1-benzyl-4-44-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (126 mg, 71%). 1H NMR (CDCl3) δ 1.83 (m, 6H), 2.34 (s, 3H), 2.45 (m, 11H), 4.02 (s, 3H), 4.43 (d, J=5.66 Hz, 2H), 4.95 (m, 1H), 5.52 (bs, 2H), 7.37 (m, 7H), 8.18 (m, 1H), 8.41 (m, 1H); LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+=555.5, Rt=2.65 min. The reaction mixture was heated at reflux overnight Organic solvent was removed under reduced pressure the aqueous layer was extracted with dichloromethane The combined organic layer was washed with water brine, dried over MgSO4 filtered evaporated The residue was purified by flash column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a solvent mixture of 50 ml of aqueous 28% ammonia and 450 ml of ethanol, 13.9 g of ethyl 2-(2-methoxyphenyl)-4-methylthiazole-5-carboxylate which had been prepared by heating a mixture of o-methoxybenzamide, ethyl α-chloroacetoacetate and phosphorus pentasulfide under a reflux condenser for 5 hours was dissolved. Then in a similar manner as in Example 3 the object was obtained as colourless minute aciculate melting at 191° to 192.5° C. in an amount of 8.7 g corresponding to the yield of 70%. had been prepared by heating was dissolved Then in a similar manner as in Example 3 the object was obtained as colourless minute aciculate melting at 191° to 192.5° C. in an amount of 8.7 g corresponding to the yield of 70%

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2-methoxybenzamide in 1,2-di-chloroethane (24.5 ml/g) is brought to reflux in the presence of 3 equivalents of freshly distilled pyruvic acid in a round-bottomed flask surmounted by a system which makes it possible to remove the water formed during the reaction. When the formation of water has finished 15 (approximately 7 hours), the reaction mixture is left at room temperature. After filtering off the insoluble materials, the filtrate is extracted with an aqueous sodium bicarbonate solution. The combined aqueous phases are extracted with dichloromethane and then acidified with hydrochloric acid. The precipitate formed is filtered off, dried and then taken up in ethyl acetate. After filtering off the insoluble material, the filtrate is concentrated under vacuum, dissolved in dichloromethane and then precipitated with heptane, thus providing pure N-(2-methoxybenzoyl)dehydroalanine. (Nonoptimized yield 8.5%). to remove the water formed during the reaction 15 (approximately 7 hours) the reaction mixture is left at room temperature After filtering off the insoluble materials the filtrate is extracted with an aqueous sodium bicarbonate solution The combined aqueous phases are extracted with dichloromethane The precipitate formed is filtered off dried After filtering off the insoluble material the filtrate is concentrated under vacuum dissolved in dichloromethane precipitated with heptane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2-methoxybenzamide in 1,2-di-chloroethane (24.5 ml/g) is brought to reflux in the presence of 3 equivalents of freshly distilled pyruvic acid in a round-bottomed flask surmounted by a system which makes it possible to remove the water formed during the reaction. When the formation of water has finished 15 (approximately 7 hours), the reaction mixture is left at room temperature. After filtering off the insoluble materials, the filtrate is extracted with an aqueous sodium bicarbonate solution. The combined aqueous phases are extracted with dichloromethane and then acidified with hydrochloric acid. The precipitate formed is filtered off, dried and then taken up in ethyl acetate. After filtering off the insoluble material, the filtrate is concentrated under vacuum, dissolved in dichloromethane and then precipitated with heptane, thus providing pure N-(2-methoxybenzoyl)dehydroalanine. (Nonoptimized yield 8.5%). to remove the water formed during the reaction 15 (approximately 7 hours) the reaction mixture is left at room temperature After filtering off the insoluble materials the filtrate is extracted with an aqueous sodium bicarbonate solution The combined aqueous phases are extracted with dichloromethane The precipitate formed is filtered off dried After filtering off the insoluble material the filtrate is concentrated under vacuum dissolved in dichloromethane precipitated with heptane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a manner similar to that described for the preparation of 2-n-propoxybenzamidine hydrochloride in Preparation 7, 2-methoxybenzamindine hydrochloride, m.p. 150°-152° was prepared from 2-methoxybenzamide.