methyl 2-(methylamino)acetate;hydrochloride

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

Procedure: To a solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-dimethylcarbamoyl-4-formylphenyl)amide (137 mg) and N-methylglycine methyl ester hydrochloride (45 mg) in dichloromethane (2 mL) was added sodium triacetoxyborohydride (97 mg). The mixture was stirred at room temperature for 4 hours, diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:1, v/v) to give the title compound (120 mg). washed successively with saturated aqueous sodium bicarbonate and saturated brine dried over anhydrous sodium sulfate concentrated in vacuo The residue was purified by column chromatography on silica gel (chloroform

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

Procedure: The crude 6-methoxy-5-(pentafluoroethyl)-1-naphthalene carboxylic acid (3.65 g, 11.4 mmol), 1-hydroxybenzotriazole (2.31 g, 17.1 mmol), dry distilled dimethylformamide (35 ml) and dicyclohexylcarbodiimide (2.82 g, 13.7 mmol) were stirred at room temperature for 1 hour. The mixture was cooled to 0° C., a solution of sarcosine methyl ester hydrochloride (3.18 g, 22.8 mmol) in dimethylformamide (30 ml) and N-ethyl morpholine (2.92 ml, 22.8 mmol) was added and stirring continued for 2 hours at room temperature. After cooling to 0° C., the precipitate (dicyclohexyl urea) was removed by filtration, the filtrate evaporated and the residue purified by HPLC (ethyl acetate/hexane 1:1, Waters Prep LC 500A). 1.5 g of pure, and 2.5 g of less pure N-[[6-methoxy-5-(pentafluoroethyl)-1-naphthalenyl]carbonyl]-N-methylglycine, methyl ester were obtained. nmr (DMSO): δ2.75 & 3.25 (2s, 3H, N--CH3, rotamers); δ3.75 (s, 3H, OCH3); δ3.97 (s, 3H, OCH3); δ4.35 (broad, 2H, N--CH2 --CO); δ7.7 (m, 5H, Har). ms: m/e 405 (M+), 303, 195, 102. The mixture was cooled to 0° C. stirring continued for 2 hours at room temperature After cooling to 0° C. the precipitate (dicyclohexyl urea) was removed by filtration the filtrate evaporated the residue purified by HPLC (ethyl acetate/hexane 1:1, Waters Prep LC 500A)

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

Procedure: 4-Nitrophenyl[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]carbamate (125 mg) was dissolved in absolute THF (5 ml), and sarcosine methyl ester hydrochloride and triethylamine were added dropwise with stirring. After stirring for 5 h, the reaction mixture was freed of the solvent, and the residue was admixed with water and 2 N hydrochloric acid and refluxed for 2 h. After standing overnight, the reaction mixture was concentrated and admixed with ethyl acetate, water and saturated potassium carbonate solution. After separation of the phases, the organic phase was washed five times with saturated potassium carbonate solution and twice with saturated sodium chloride solution. Drying over magnesium sulfate and filtration were followed by concentration. The residue was purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was taken up with water/hydrochloric acid and freeze-dried. 60 mg of the title compound were obtained. After stirring for 5 h refluxed for 2 h the reaction mixture was concentrated After separation of the phases the organic phase was washed five times with saturated potassium carbonate solution Drying over magnesium sulfate and filtration were followed by concentration The residue was purified by means of preparative HPLC the acetonitrile was removed on a rotary evaporator extracted three times with ethyl acetate After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered concentrated to dryness freeze-dried

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

Procedure: 4-Nitrophenyl[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]carbamate (125 mg) was dissolved in absolute THF (5 ml), and sarcosine methyl ester hydrochloride and triethylamine were added dropwise with stirring. After stirring for 5 h, the reaction mixture was freed of the solvent, and the residue was admixed with water and 2 N hydrochloric acid and refluxed for 2 h. After standing overnight, the reaction mixture was concentrated and admixed with ethyl acetate, water and saturated potassium carbonate solution. After separation of the phases, the organic phase was washed five times with saturated potassium carbonate solution and twice with saturated sodium chloride solution. Drying over magnesium sulfate and filtration were followed by concentration. The residue was purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was taken up with water/hydrochloric acid and freeze-dried. 60 mg of the title compound were obtained. After stirring for 5 h refluxed for 2 h the reaction mixture was concentrated After separation of the phases the organic phase was washed five times with saturated potassium carbonate solution Drying over magnesium sulfate and filtration were followed by concentration The residue was purified by means of preparative HPLC the acetonitrile was removed on a rotary evaporator extracted three times with ethyl acetate After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered concentrated to dryness freeze-dried

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

Procedure: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (7.91 g, 1.2 eq) was added to a stirred solution of 2-bromo-6-methoxy-5-trifluoromethyl-1-naphthoic acid, prepared by the process of Example 14, Step 2 (12.00 g, 34.4 mmol) and 1-hydroxybenzotriazole (6.97 g, 1.5 eq) in anhydrous DMF (105 mL) at room temperature under a dry nitrogen atmosphere. Dissolution occurred after 20 minutes. After 1 hour, a suspension of methyl sarcosinate hydrochloride (9.56 g, 2.0 eq) in anhydrous DMF (60 mL) was added to the reaction mixture followed by triethylamine (15.8 mL, 3.3 eq). After 21/2 hours, more triethylamine (4.8 mL, 1.0 eq) was added. The reaction was diluted with water (1.6 L) after 181/2 hours. The aqueous phase was extracted with ether (4×250 mL). The extracts were combined and washed with 0.5N sodium hydroxide solution (1×200 mL) and saturated aqueous sodium chloride (1×200 mL). The ether phase was dried with magnesium sulfate and the ether was removed. The crude product was flash chromatographed (3:2 to 2:3 petroleum ether:ethyl acetate eluent gradient, silica) then reflash chromatographed (99:1 to 9:1 methylene chloride:acetonitrile eluent gradient, silica) to provide the product as a white foam (11.16 g, 75%). Dissolution After 1 hour was added to the reaction mixture The aqueous phase was extracted with ether (4×250 mL) washed with 0.5N sodium hydroxide solution (1×200 mL) and saturated aqueous sodium chloride (1×200 mL) The ether phase was dried with magnesium sulfate the ether was removed chromatographed (3:2 to 2:3 petroleum ether:ethyl acetate eluent gradient, silica) then reflash chromatographed (99:1 to 9:1 methylene chloride:acetonitrile eluent gradient, silica)

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

Procedure: 1-Hydroxybenzotriazole (5.05 g, 1.5 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (5.74 g, 1.2 eq) were added to a stirred solution of 6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)naphthoic acid, prepared by the process of Example 14 (9.18 g, 24.9 mmol) in anhydrous DMF (90 mL) at room temperature under a dry nitrogen atmosphere. After 11/4 hours, a suspension of methyl sarcosinate hydrochloride (6.96 g, 2.0 eq) in anhydrous DMF (40 mL) was added to the reaction followed by triethylamine (11.12 mL, 3.2 eq). After 30 minutes, the reaction was diluted with water (1.5 L) and extracted with ether (3×250 mL). The extracts were combined, dried with magnesium sulfate, and the ether was removed. The crude product was flash chromatographed (13:7→1:1 petroleum ether:ethyl acetate, silica) to provide the product as a clear oil (9.15 g, 81%). A small sample was triturated in petroleum ether to provide a white solid for analysis, m.p. 91.5°-93° C. was added to the reaction extracted with ether (3×250 mL) dried with magnesium sulfate the ether was removed chromatographed (13:7→1:1 petroleum ether:ethyl acetate, silica)

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

Procedure: In the same manner as described in Examples 24 and 33, methyl (2-aminoindan-5-yl)acetate hydrochloride, 4-chlorophenylsulfonyl chloride and methyl N-methyl-glycinate hydrochloride are treated to give 2-[N-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetyl-N-methylamino]-acetic acid are treated

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

Procedure: 0.303 g (1.773 mmol) of 2-(chloromethyl)imidazo[1,2-a]pyridine were dissolved in 15 ml of dimethylformamide with magnetic stirring and then 0.253 g (1.773 mmol) of sarcosine methylester hydrochloride and 0.741 ml (5.32 mmol) of triethylamine were added. The mixture was stirred at r.t. for 16 h, and then treated with 30 ml of a saturated NaCl aqueous solution. The aqueous phase was concentrated in vacuo. The residue was triturated in 75 ml of isopropanol, the salts were removed by filtration and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/methanol, 95/5, v/v). 0.107 g (yield=26%) of methyl 2-((imidazo[1,2-a]pyridin-2-ylmethyl)(methyl)amino)acetate were obtained as a pale yellow oil. LC-MS: m/z=234 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.49 (d, J=6.8 Hz, 1H), 7.79 (s, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.18 (ddd, J=9.0, 6.7, 1.2 Hz, 1H), 6.84 (td, J=6.7, 1.1 Hz, 1H), 3.76 (s, 2H), 3.61 (s, 3H), 2.32 (s, 3H). The mixture was stirred at r.t. for 16 h The aqueous phase was concentrated in vacuo The residue was triturated in 75 ml of isopropanol the salts were removed by filtration the filtrate was concentrated in vacuo The crude residue was purified by flash chromatography on a silica gel cartridge (eluent

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

Procedure: The title compound was prepared in analogy to Example 29, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and sarcosine methylester hydrochloride (commercially available, CAS RN 945218-53-1) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) as eluant. Light brown foam (33%). MS (ESI): m/z=569.135 [M+H]+.

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

Procedure: The title compound was prepared in analogy to Example 29, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and sarcosine methylester hydrochloride (commercially available, CAS RN 945218-53-1) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) as eluant. Light brown foam (33%). MS (ESI): m/z=569.135 [M+H]+.

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

Procedure: To a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-({[(4-nitrophenoxy)carbonyl]amino}methyl)-1,4-oxazepane-4-carboxylate (94 mg) in THF (2.0 mL) were added sarcosine methyl ester hydrochloride (36 mg) and potassium carbonate (72 mg), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (79 mg). the mixture was extracted with ethyl acetate The organic layer was washed with water and brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The residue was purified by silica gel chromatography (hexane/ethyl acetate)

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

Procedure: Amide coupling of 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylic acid (2.0 g, 5.49 mmol) with methyl 2-(methylamino)acetate hydrochloride (1.53 g, 10.9 mmol) analogously to the protocol 244c). White solid. Yield: 0.6 g (24% of theory)