甘氨酸甲酯 盐酸盐

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

实验步骤: A mixture of (1R,10S,11S,16S)-3-methoxy-11,15,15-trimethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (61) (0.20 g, 0.49 mmol), HATU (0.37 g, 0.98 mmol), N-methylmorpholine (0.20 mL, 3.0 mmol) and glycine methyl ester hydrochloride (0.18 g, 1.5 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 10:1) to give methyl 2-{[(1R,10R,11S,16S)-3-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-5-yl]formamido}acetate (92) (0.10 g, 42%) as a white solid. 1H NMR (CDCl3): δ 8.16 (s, 1H), 7.81 (d, 1H), 7.71 (d, 1H), 7.18 (m, 1H), 4.24 (m, 2H), 3.32 (m, 3H), 2.30 (d, 1H), 1.76-1.00 (m, 16H), 0.97 (s, 3H), 0.88 (s, 3H), 0.84 (s, 3H). MS m/z 478 (C25H35NO6S+H+). The THF was evaporated under reduced pressure the residue was quenched with water the resulting solid was collected by filtration The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 10:1)

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

实验步骤: A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (65) (0.20 g, 0.49 mmol), HATU (0.37 g, 0.98 mmol), N-methyl morpholine (0.2 mL, 3 mmol) and glycine methyl ester hydrochloride (0.09 g, 2 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 10:1) to give methyl 2-{[(1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl]formamido}acetate (90) (0.05 g, 54%) as a cream solid. 1H NMR (CDCl3): δ 7.37 (s, 1H), 7.21 (d, 1H), 6.89 (d, 1H), 6.70 (m, 1H), 4.19 (m, 2H), 3.81 (s, 3H), 3.40 (m, 2H), 2.62 (m, 1H), 2.16 (m, 1H), 1.76-1.34 (m, 10H), 1.20-1.00 (m, 2H), 0.98-0.92 (m, 4H), 0.89 (s, 3H), 0.82 (s, 3H). MS m/z 476 (C25H35NO6S−H+). The THF was evaporated under reduced pressure the residue was quenched with water the resulting solid was collected by filtration The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 10:1)

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

实验步骤: {[1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid methyl ester (5.0 g) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (5.0 g), glycine methyl ester hydrochloride (1.76 g), HBTU (5.8 g), and DIEA (3.34 mL).

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 1-cyano-4-methoxy-8-phenoxy-isoquinoline-3-carboxylic acid (483 mg, 1.51 mmol), triethylamine (466 μL, 3.32 mmol), and dichloromethane (12 mL) was added isobutylchloroformate (211 μL, 1.62 mmol) at 0° C. The mixture was stirred at 0° C. for twenty-five minutes before glycine methyl ester hydrochloride (208 mg, 1.66 mmol) was added. The mixture was stirred at 0° C. for twenty-five minutes and at room temperature for 5.5 hours before it was concentrated. The residue was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow solid (343 mg): MS: (+) m/z 391.95 (M+1). was added was concentrated The residue was partitioned between ethyl acetate and 1N HCl The organic layer was washed with saturated sodium bicarbonate, brine dried over anhydrous sodium sulfate concentrated in vacuo the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes

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

实验步骤: Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (50 mg) and glycine methyl ester hydrochloride (20 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118 the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 574.8 (M+H)+.

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

实验步骤: The compound of example 362 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and glycine methyl ester hydrochloride.

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

实验步骤: The compound of example 332 was prepared analogous to compound of example 329 by reaction of the compound of example 328 and glycine methyl ester hydrochloride.

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

实验步骤: DMAP (1.222 g, 0.01 mol) and EDAC (2.680 g, 0.014 mol) were added as solids to a solution of 1-methylindole-2-carboxylic acid (1.752 g, 0.01 mol) and glycine methyl ester hydrochloride (1.256 g, 0.01 mol) in methylene chloride (30 mL) and DMP (5 mL) under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and then for 3 hours at room temperature. The reaction mixture was partitioned with ethyl acetate and 5% KHSO4 solution and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solution was washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) solution and brine, dried over sodium sulfate, and concentrated to give a purple powder as crude product. Trituration of the powder with ether afforded the title product (1.734 mg, 70%). TLC: (methanol/methylene chloride 1:9): Rf=0.61, 1H NMR (CDCl3): δ7.65 (dt, J=8.0, 1.1, 1H), 7.41-7.31 (m, 2H), 7.16 (dd, J=6.6, 1.4, 1H) 6.96 (d, J=0.5, 1H), 6.67 (bs, 1H), 4.25 (d, J=5.2, 2H), 4.05 (s, 3H), 3.82 (s, 3H). for 3 hours at room temperature The reaction mixture was partitioned with ethyl acetate and 5% KHSO4 solution the aqueous layer was extracted with ethyl acetate The combined ethyl acetate solution was washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) solution and brine dried over sodium sulfate concentrated to give a purple powder as crude product

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

实验步骤: 1-(tertButoxycarbonyl)-2-piperidinecarboxylic acid (11.46 g, 1.2 eq), glycine methyl ester hydrochloride (9.42 g), 1-(dimethylaminopropyl)-3-(ethyl)carbodiimide hydrochloride (8.00 g, 1.0 eq) and Et3N (16.3 mL) were reacted as described in Example 1 to give 5.6 g of the title compound as a colorless crystallinesolid: mp 118.5-119.5° C. (EtOAc/isooctane 1:3);

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

实验步骤: To a mixture of glycine methyl ester hydrochloride (2.07 g, 16.5 mmol), and 4-benzyloxy-benzaldehyde (3.18 g, 15 mmol) in CH2Cl2 (50 mL) at 0° C. was added sodium triacetoxyborohydride (3.81 g, 18 mmol). The mixture was allowed to warm to room temperature and stirred overnight. Aqueous NaHCO3 was added, and the mixture was stirred for 30 minutes. The aqueous layer was extracted 3 times with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography (ethyl acetate) gave 1.98 g (46%) of the title compound as a white solid; mp 57-58° C. the mixture was stirred for 30 minutes The aqueous layer was extracted 3 times with CH2Cl2 The combined organic extracts were washed with brine dried over MgSO4 concentrated

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

实验步骤: To a mixture of glycine methyl ester hydrochloride (2.07 g, 16.5 mmol) and 4-benzyloxybenzaldehyde (3.18 g, 15.0 mmol) in CH2Cl2 (50 mL) at 0° C. was added sodium triacetoxyborohydride (3.81 g, 18.0 mmol). The mixture was allowed to warm to room temperature and stirred for 4 hours. Aqueous NaHCO3 was added, and the mixture was stirred for 30 minutes. The aqueous layer was extracted three times with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSo4, and concentrated. Flash chromatography (75% ethyl acetate/hexane) gave 1.98 g (46%) of the title compound as a white solid; mp 57-58° C. the mixture was stirred for 30 minutes The aqueous layer was extracted three times with CH2Cl2 The combined organic extracts were washed with brine dried over MgSo4 concentrated

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 31.72 g (250 mmol) of glycine methyl ester hydrochloride was added in a single portion to a solution of 10.13 g (250 mmol) of sodium hydroxide in 80 ml of methanol at 0° C. The temperature dropped to -10° C. The mixture was stirred for 10 minutes, during which time the temperature rose again to 0° C. 108.25 g (a 26.6 percent strength solution in toluene, 250 mmol) of methyl pentanimidate was added, and the mixture was stirred at room temperature for 3 hours. 35.64 g (about 92 percent strength, 275 mmol) of dimethylformamide dimethyl acetal then was added, during the course of 5 minutes. The reaction mixture was stirred for an additional 3 hours. 200 ml of toluene was added, and methanol and water were removed from the mixture by distillation in vacuo. Of the remaining 203.5 g, 91.68 g (corresponding to 112 mmol of methyl pentanimidate) was initially introduced at room temperature and treated with 65.09 g (416 mmol) of POCl3. The mixture was heated 15 100° C. for 1.5 hours and then 118.5 g of POCl3 /toluene was distilled off and the residue was treated with 121 ml of ethyl acetate and 408 ml of water. The pH was adjusted to 1, by addition of 18 ml of 30 percent strength sodium hydroxide solution, and the phases were separated. The aqueous phase was extracted twice, each time with 200 ml of ethyl acetate, and the combined organic phases were washed with 200 ml of water, dried (MgSO4), and filtered and concentrated. The residue was dried in a high vacuum. 14.07 g of 2-butyl-5-chloroimidazole-4-carbaldehyde (HPLC content 79.9 percent) was obtained. This corresponds to a yield of 56 percent, based on the methyl pentanimidate. The temperature dropped to -10° C rose again to 0° C the mixture was stirred at room temperature for 3 hours The reaction mixture was stirred for an additional 3 hours methanol and water were removed from the mixture by distillation in vacuo 118.5 g of POCl3 /toluene was distilled off the residue was treated with 121 ml of ethyl acetate and 408 ml of water The pH was adjusted to 1, by addition of 18 ml of 30 percent strength sodium hydroxide solution the phases were separated The aqueous phase was extracted twice each time with 200 ml of ethyl acetate, and the combined organic phases were washed with 200 ml of water dried (MgSO4) filtered concentrated The residue was dried in a high vacuum