亚硫酸二甲酯

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:41.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 250 mL, 3 neck flask equipped with a mechanical agitator, thermocouple, heating mantle, condenser, nitrogen inlet and vent, 5-(1,3-dioxolan-2-yl)-(S)-2-amino-pentanoic acid (100 g), methanol (1200 mL) and dimethyl sulfite (44.8 mL) were charged. Chlorotrimethyl silane (168 mL) was added to the resulting slurry and the reaction mixture was heated at 40 to 42° C. for about 8 hours, followed by stirring at ambient temperature for eight hours to afford a solution of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester hydrochloride salt (in-process quantitation 100.9 g, 93 M %). Potassium bicarbonate (208.6 g) was slurried in methanol (400 mL) contained in a 5-L three neck flask and the reaction mixture containing the hydrochloride salt of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester, was neutralized by adding it to the potassium bicarbonate slurry slowly (over 1.5 hours) maintaining the pH of mixture above 6.9. The solvent of the resulting slurry was replaced with n-butyl acetate by vacuum distillation (50 to 60 mmHg and 30 to 40° C.) maintaining a pot volume of about 2 L. After 2.25 L of n-butyl acetate was distilled, methanol (1.25 L) was added to the distillation vessel and the distillation was continued, maintaining a pot volume of NLT 2 L, until the water content of the slurry supernatant was<0.05 wt % and the methanol level was<5 relative area %. Hexane (1.5 L) was charged to the resulting slurry and it was then cooled to -5° C. After stirring the mixture for 1 hour, it was filtered and the filter-cake was washed with hexane (2×100 mL). The resulting hazy filtrate was polish filtered to afford a clear filtrate. The clear filtrate was warmed to 20 to 25° C. and a methanolic (1333 mL) solution of oxalic acid dihydrate (33.3 g) was added slowly over about 2 hours. The resulting slurry of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester oxalic acid salt (2:1) was agitated for 18 hours at ambient temperature and the product was collected on a filter. The product wet-cake was washed with acetonitrile (4×100 mL) and died under vacuum at 45° C. to afford 103.2 g (78 M %) of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester oxalic acid salt (2:1) having a free base potency of 84 wt % (vs. lab standard, theo.=82 wt %) and an HPLC AP of 100. To a 250 mL, 3 neck flask equipped with a mechanical agitator were charged

反应条件: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under nitrogen, chlorotrimethyl silane (28.0 g) was added to a slurry of 5-(1,3-dioxolan-2-yl)-(S)-2-amino-pentanoic acid (20.0 g) and dimethyl sulfite (12.0 g) in methanol (240 mL) to afford a homogeneous solution. Following the observation of an exotherm to 29° C., the solution was heated to 40-45° C., stirred at that temperature for 8 h and at ~22° C. for up to 72 hours. In-process HPLC analysis showed that the reaction was complete (~93 M % conversion to product) and the resulting solution was cooled to -5 to -10° C. With stirring, the apparent pH of the mixture was adjusted to 11.7 to 11.9 by the slow careful addition of 32% (or 4.45 M) methanolic potassium methoxide solution (70 mL) maintaining the temperature in the range -5 to 0° C. Analysis of the product slurry (NMR) indicated that the neutralization was complete (chemical shift of the alpha proton of BMS-205787 was<3.36 ppm). The solvent of the product slurry was exchanged with ethyl acetate by first concentrating the thin slurry under vacuum at<30° C. to 300 mL volume followed by the addition of ethyl acetate until the removal of methanol was completed as judged by in-process GC analysis (<1 AP). Upon completion of the solvent exchange, the batch volume was adjusted to ~400 mL with ethyl acetate and the resulting slurry was filtered. Poly(acrylic acid co-acrylamide), potassium salt (3.0 to 3.2 g) and water (30-32 mL) were added to the filtrate. The mixture was stirred for ~35 minutes and filtered. Optionally, the Poly(acrylic acid co-acrylamide), potassium salt treatment can be repeated on the filtrate if the quantity of ethylene glycol exceeds 0.15 equivalents, as judged by in-process GC analysis. Following in-process HPLC analysis, (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester (17.4 g) was obtained as an ethyl acetate solution in 80.8 M % yield. to afford a homogeneous solution to 29° C. the resulting solution was cooled to -5 to -10° C With stirring maintaining the temperature in the range -5 to 0° C by first concentrating the thin slurry under vacuum at<30° C. to 300 mL volume followed by the addition of ethyl acetate until the removal of methanol the resulting slurry was filtered Poly(acrylic acid co-acrylamide), potassium salt (3.0 to 3.2 g) and water (30-32 mL) were added to the filtrate The mixture was stirred for ~35 minutes filtered

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 30 ml of dimethylformamide was added 0.6 g of approximately 55 % sodium hydride, and the solution was stirred for 20 minutes at room temperature. To this was added 2.2 g of dimethyl sulfite and stirring was further continued for 4 hours at room temperature. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure. The residue thus obtained was mixed with water to precipitate a crude product. This product was recrystallized from methanol to afford 2.8 g of 1-(m-nitrophenyl)-3-methylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 242°-243° C. stirring was further continued for 4 hours at room temperature the solvent was removed from the reaction mixture by distillation under reduced pressure The residue thus obtained to precipitate a crude product This product was recrystallized from methanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 206.6 g (0.47 mol) of a 35 percent mixture of 4-chloroacetoacetyl chloride in methylene chloride was cooled to -10° C. Under nitrogen, 102.4 g (3.2 mol) of methanol was added in 30 minutes and then 83.3 g (0.7 mol) of thionyl chloride was added in 30 minutes (formation of dimethyl sulfite). The temperature was raised to room temperature and the solution was stirred for 3 hours at 20° to 25° C. The excess methanol and methylene chloride were then distilled off at reduced pressure. The residue (raw 4-chloro-3,3-dimethoxybutanoic acid methyl ester) was mixed with 0.21 g of methanesulfonic acid and warmed to 125° to 130° C. at a pressure of 100 mbars. Thus, the formed methanol and the excess dimethyl sulfite was distilled off. The residue (raw 4-chloro-3-methoxy-but-2E-enoic acid methyl ester) was taken up in 110.2 g (120 ml) of toluene and the organic phase was washed with 69.8 g of aqueous 16 percent HCl for 30 minutes, with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes, with 134 g of aqueous 10 percent NaOH for 75 minutes and finally with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes. The toluene was then evaporated off and the residue was distilled at a pressure of 20 mbars and a temperature of 95° to 97° C. 4-chloro-3-methoxybut-2E-enoic acid methyl ester was obtained in a yield of 61.7 g (80 percent) in a purity of 99.5 percent (GC). The excess methanol and methylene chloride were then distilled off at reduced pressure The residue (raw 4-chloro-3,3-dimethoxybutanoic acid methyl ester) was mixed with 0.21 g of methanesulfonic acid warmed to 125° to 130° C. at a pressure of 100 mbars Thus, the formed methanol and the excess dimethyl sulfite was distilled off the organic phase was washed with 69.8 g of aqueous 16 percent HCl for 30 minutes, with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes, with 134 g of aqueous 10 percent NaOH for 75 minutes and finally with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes The toluene was then evaporated off the residue was distilled at a pressure of 20 mbars a temperature of 95° to 97° C

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 206.6 g (0.47 mol) of a 35 percent mixture of 4-chloroacetoacetyl chloride in methylene chloride was cooled to -10° C. Under nitrogen, 102.4 g (3.2 mol) of methanol was added in 30 minutes and then 83.3 g (0.7 mol) of thionyl chloride was added in 30 minutes (formation of dimethyl sulfite). The temperature was raised to room temperature and the solution was stirred for 3 hours at 20° to 25° C. The excess methanol and methylene chloride were then distilled off at reduced pressure. The residue (raw 4-chloro-3,3-dimethoxybutanoic acid methyl ester) was mixed with 0.21 g of methanesulfonic acid and warmed to 125° to 130° C. at a pressure of 100 mbars. Thus, the formed methanol and the excess dimethyl sulfite was distilled off. The residue (raw 4-chloro-3-methoxy-but-2E-enoic acid methyl ester) was taken up in 110.2 g (120 ml) of toluene and the organic phase was washed with 69.8 g of aqueous 16 percent HCl for 30 minutes, with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes, with 134 g of aqueous 10 percent NaOH for 75 minutes and finally with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes. The toluene was then evaporated off and the residue was distilled at a pressure of 20 mbars and a temperature of 95° to 97° C. 4-chloro-3-methoxybut-2E-enoic acid methyl ester was obtained in a yield of 61.7 g (80 percent) in a purity of 99.5 percent (GC). The excess methanol and methylene chloride were then distilled off at reduced pressure The residue (raw 4-chloro-3,3-dimethoxybutanoic acid methyl ester) was mixed with 0.21 g of methanesulfonic acid warmed to 125° to 130° C. at a pressure of 100 mbars Thus, the formed methanol and the excess dimethyl sulfite was distilled off the organic phase was washed with 69.8 g of aqueous 16 percent HCl for 30 minutes, with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes, with 134 g of aqueous 10 percent NaOH for 75 minutes and finally with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes The toluene was then evaporated off the residue was distilled at a pressure of 20 mbars a temperature of 95° to 97° C

反应条件: temp:41.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-α-Amino-1,3-dioxolane-2-pentanoic acid (100 g), methanol (1200 ml) and dimethyl sulfite (44.8 ml) were charged to a 250 ml, three neck flask equipped with a mechanical agitator, thermocouple, heating mantle, condenser, nitrogen inlet, and vent. Chlorotrimethylsilane (168 ml) was added to the resulting slurry and the reaction mixture was heated at 40 to 42° C. for about 8 hours, followed by stirring at ambient temperature for 8 hours to afford a solution of (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester, hydrochloride salt. Potassium bicarbonate (208.6 g) was slurried in methanol (400 ml) contained in a 5 liter three neck flask and the reaction containing the hydrochloride salt of (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester was neutralized by adding it to the potassium bicarbonate slurry slowly over 1.5 hours while maintaining the pH of the mixture above 6.9. The solvent of the resulting slurry was replaced with n-butyl acetate by vacuum distillation (50 to 60 mm Hg and 30 to 40° C.) maintaining a pot volume of about 2 liters. After 2.25 liters of n-butyl acetate was distilled, methanol (1.25 l) was added to the distillation vessel and the distillation was continued, maintaining a pot volume of not less than 2 liters, until the water content of the slurry supernatant was less than 0.05 weight percent and the methanol level was less than 5 relative area percent by gas chromatography. Hexane (1.5 1) was charged to the resulting slurry and it was then cooled to −5° C. After stirring the mixture for 1 hour, it was filtered and the filter-cake was washed with hexane (2×100 ml). The resulting hazy filtrate was polish filtered to afford a clear filtrate. The clear filtrate was warmed to 20 to 25° and a methanolic (1333 ml) solution of oxalic acid dihydrate (33.3 g) was added slowly over about 2 hours. The resulting slurry of (S)-2-amino-6,6-dimethoxy-hexanoic acid, methyl ester, oxalic acid salt (2:1) was agitated for 18 hours at ambient temperature and the product was collected on a filter. The product wet-cake was washed with acetonitrile (4×100 ml) and dried under vacuum at 45° C. to afford 103.2 g of the desired product. equipped with a mechanical agitator thermocouple, heating mantle, condenser, nitrogen inlet, and vent

反应条件: temp:41.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-α-Amino-1,3-dioxolane-2-pentanoic acid (100 g), methanol (1200 ml) and dimethyl sulfite (44.8 ml) were charged to a 250 ml, three neck flask equipped with a mechanical agitator, thermocouple, heating mantle, condenser, nitrogen inlet, and vent. Chlorotrimethylsilane (168 ml) was added to the resulting slurry and the reaction mixture was heated at 40 to 42° C. for about 8 hours, followed by stirring at ambient temperature for 8 hours to afford a solution of (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester, hydrochloride salt. Potassium bicarbonate (208.6 g) was slurried in methanol (400 ml) contained in a 5 liter three neck flask and the reaction containing the hydrochloride salt of (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester was neutralized by adding it to the potassium bicarbonate slurry slowly over 1.5 hours while maintaining the pH of the mixture above 6.9. The solvent of the resulting slurry was replaced with n-butyl acetate by vacuum distillation (50 to 60 mm Hg and 30 to 40° C.) maintaining a pot volume of about 2 liters. After 2.25 liters of n-butyl acetate was distilled, methanol (1.25 l) was added to the distillation vessel and the distillation was continued, maintaining a pot volume of not less than 2 liters, until the water content of the slurry supernatant was less than 0.05 weight percent and the methanol level was less than 5 relative area percent by gas chromatography. Hexane (1.5 1) was charged to the resulting slurry and it was then cooled to −5° C. After stirring the mixture for 1 hour, it was filtered and the filter-cake was washed with hexane (2×100 ml). The resulting hazy filtrate was polish filtered to afford a clear filtrate. The clear filtrate was warmed to 20 to 25° and a methanolic (1333 ml) solution of oxalic acid dihydrate (33.3 g) was added slowly over about 2 hours. The resulting slurry of (S)-2-amino-6,6-dimethoxy-hexanoic acid, methyl ester, oxalic acid salt (2:1) was agitated for 18 hours at ambient temperature and the product was collected on a filter. The product wet-cake was washed with acetonitrile (4×100 ml) and dried under vacuum at 45° C. to afford 103.2 g of the desired product. equipped with a mechanical agitator thermocouple, heating mantle, condenser, nitrogen inlet, and vent

反应条件: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under nitrogen, chlorotrimethyl silane (28.0 g) was added to a slurry of (S)-α-amino-1,3-dioxolane-2-pentanoic acid (20.9 g) and dimethyl sulfite (12.0 g) in methanol (240 ml) to afford a homogeneous solution. Following the observation of an exotherm to 29° C., the solution was heated to 40-45° C., stirred at that temperature for 8 hours and at about 22° C. for up to 72 hours. In-process HPLC analysis showed that the reaction was complete (about 93 M % conversion to product) and the resulting solution was cooled to −5 to −10° C. With stirring, the apparent pH of the mixture was adjusted to 11.7 to 11.9 by the slow careful addition of 32% (or 4.45 M) methanolic potassium methoxide solution (70 ml) maintaining the temperature in the range of −5 to 0° C. Analysis of the product slurry (1H-NMR) indicated that the neutralizaiton was complete. The solvent of the product slurry was exchanged with ethyl acetate by first concentrating the thin slurry under vacuum at less than 30° C. to 300 ml volume followed by the addition of ethyl acetate until the removal of methanol was completed as judged by in-process GC analysis (less than 1 AP). Upon completion of the solvent exchange, the batch volume was adjusted to about 400 ml with ethyl acetate and the resulting slurry was filtered. Poly(acrylic acid co-acrylamide), potassium salt (3.0 to 3.2 g) and water (30-32 ml) were added to the filtrate. The mixture was stirred for about 35 minutes and filtered. Optionally, the poly (acrylic acid co-acrylamide), potassium salt treatment can be repeated on the filtrate if the quantity of ethylene glycol exceeds 0.15 equivalents, as judged by in-process GC analysis. Following in-process HPLC analysis, 17.4 g of the title product was obtained as an ethyl acetate solution in 80.8 M % yield. to afford a homogeneous solution to 29° C. the resulting solution was cooled to −5 to −10° C With stirring maintaining the temperature in the range of −5 to 0° C by first concentrating the thin slurry under vacuum at less than 30° C. to 300 ml volume followed by the addition of ethyl acetate until the removal of methanol the resulting slurry was filtered Poly(acrylic acid co-acrylamide), potassium salt (3.0 to 3.2 g) and water (30-32 ml) were added to the filtrate The mixture was stirred for about 35 minutes filtered

反应条件: temp:41.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 250 mL, 3 neck flask equipped with a mechanical agitator, thermocouple, heating mantle, condenser, nitrogen inlet and vent, 5-(1,3-dioxolan-2-yl)-(S)-2-amino-pentanoic acid (100 g), methanol (1200 mL) and dimethyl sulfite (44.8 mL) were charged. Chlorotrimethyl silane (168 mL) was added to the resulting slurry and the reaction mixture was heated at 40 to 42° C. for about 8 hours, followed by stirring at ambient temperature for eight hours to afford a solution of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester hydrochloride salt (in-process quantitation 100.9 g, 93 M %). Potassium bicarbonate (208.6 g) was slurried in methanol (400 mL) contained in a 5-L three neck flask and the reaction mixture containing the hydrochloride salt of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester, was neutralized by adding it to the potassium bicarbonate slurry slowly (over 1.5 hours) maintaining the pH of mixture above 6.9. The solvent of the resulting slurry was replaced with n-butyl acetate by vacuum distillation (50 to 60 mmHg and 30 to 40° C.) maintaining a pot volume of about 2 L. After 2.25 L of n-butyl acetate was distilled, methanol (1.25 L) was added to the distillation vessel and the distillation was continued, maintaining a pot volume of NLT 2 L, until the water content of the slurry supernatant was <0.05 wt % and the methanol level was <5 relative area %. Hexane (1.5 L) was charged to the resulting slurry and it was then cooled to −5° C. After stirring the mixture for 1 hour, it was filtered and the filter-cake was washed with hexane (2×100 mL). The resulting hazy filtrate was polish filtered to afford a clear filtrate. The clear filtrate was warmed to 20 to 25° C. and a methanolic (1333 mL) solution of oxalic acid dihydrate (33.3 g) was added slowly over about 2 hours. The resulting slurry of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester oxalic acid salt (2:1) was agitated for 18 hours at ambient temperature and the product was collected on a filter. The product wet-cake was washed with acetonitrile (4×100 mL) and dried under vacuum at 45° C. to afford 103.2 g (78 M %) of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester oxalic acid salt (2:1) having a free base potency of 84 wt % (vs. lab standard, theo.=82 wt %) and an HPLC AP of 100. To a 250 mL, 3 neck flask equipped with a mechanical agitator were charged

反应条件: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under nitrogen, chlorotrimethyl silane (28.0 g) was added to a slurry of 5-(1,3-dioxolan-2-yl)-(S)-2-amino-pentanoic acid (20.0 g) and dimethyl sulfite (12.0 g) in methanol (240 mL) to afford a homogeneous solution. Following the observation of an exotherm to 29° C., the solution was heated to 40-45° C., stirred at that temperature for 8 h and at ˜22° C. for up to 72 hours. In-process HPLC analysis showed that the reaction was complete (˜93 M % conversion to product) and the resulting solution was cooled to −5 to −10° C. With stirring, the apparent pH of the mixture was adjusted to 11.7 to 11.9 by the slow careful addition of 32% (or 4.45 M) methanolic potassium methoxide solution (70 mL) maintaining the temperature in the range −5 to 0° C. Analysis of the product slurry (NMR) indicated that the neutralization was complete (chemical shift of the alpha proton of BMS-205787 was <3.36 ppm). The solvent of the product slurry was exchanged with ethyl acetate by first concentrating the thin slurry under vacuum at <30° C. to 300 mL volume followed by the addition of ethyl acetate until the removal of methanol was completed as judged by in-process GC analysis (<1 AP). Upon completion of the solvent exchange, the batch volume was adjusted to ˜400 mL with ethyl acetate and the resulting slurry was filtered. Poly(acrylic acid co-acrylamide), potassium salt (3.0 to 3.2 g) and water (30-32 mL) were added to the filtrate. The mixture was stirred for ˜35 minutes and filtered. Optionally, the Poly(acrylic acid co-acrylamide), potassium salt treatment can be repeated on the filtrate if the quantity of ethylene glycol exceeds 0.15 equivalents, as judged by in-process GC analysis. Following in-process HPLC analysis, (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester (17.4 g) was obtained as an ethyl acetate solution in 80.8 M % yield. to afford a homogeneous solution to 29° C. the resulting solution was cooled to −5 to −10° C With stirring maintaining the temperature in the range −5 to 0° C by first concentrating the thin slurry under vacuum at <30° C. to 300 mL volume followed by the addition of ethyl acetate until the removal of methanol the resulting slurry was filtered Poly(acrylic acid co-acrylamide), potassium salt (3.0 to 3.2 g) and water (30-32 mL) were added to the filtrate The mixture was stirred for ˜35 minutes filtered

反应条件: temp:41.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 250 mL, 3 neck flask equipped with a mechanical agitator, thermocouple, heating mantle, condenser, nitrogen inlet and vent, 5-(1,3-dioxolan-2-yl)-(S)-2-amino-pentanoic acid (100 g), methanol (1200 mL) and dimethyl sulfite (44.8 mL) were charged. Chlorotrimethyl silane (168 mL) was added to the resulting slurry and the reaction mixture was heated at 40 to 42° C. for about 8 hours, followed by stirring at ambient temperature for eight hours to afford a solution of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester hydrochloride salt (in-process quantitation 100.9 g, 93 M %). Potassium bicarbonate (208.6 g) as slurried in methanol (400 mL) contained in a 5-L three neck flask and the reaction mixture containing the hydrochloride salt of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester, was neutralized by adding it to the potassium bicarbonate slurry (over 1.5 hours) maintaining the pH of mixture above 6.9. The solvent of the resulting slurry was replaced with n-butyl acetate by vacuum distillation (50 to 60 mmHg and 30 to 40° C.) maintaining a pot volume of about 2 L. After 2.25 L of n-butyl acetate was distilled, methanol (1.25 L) was added to the distillation vessel and the distillation was continued, maintaining a pot volume of NLT 2 L, until the water content of the slurry supernatant was <0.05 wt % and the methanol level was <5 relative area %. Hexane (1.5 L) was charged to the resulting slurry and it was then cooled to −5° C. After stirring the mixture for 1 hour, it was filtered and the filter-cake was washed with hexane (2×100 mL). The resulting hazy filtrate was polish filtered to afford a clear filtrate. The clear filtrate was warmed to 20 to 25° C. and a methanolic (1333 mL) solution of oxalic acid dihydrate (33.3 g) was added slowly over about 2 hours. The resulting slurry of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester oxalic acid salt (2:1) was agitated for 18 hours at ambient temperature and the product was collected on a filter. The product wet-cake was washed with acetonitrile (4×100 mL) and dried under vacuum at 45° C. to afford 103.2 g (78 M %) of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester oxalic acid salt (2:1) having a free base potency of 84 wt % (vs. lab standard, theo.=82 wt %) and an HPLC AP of 100. To a 250 mL, 3 neck flask equipped with a mechanical agitator were charged