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With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 2 - 7℃; for 2h;Large scale;
To (2S)-1-tert-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (Compound 8a) (60.0 kg),thiazolidine (30.3 kg) and N,N-diisopropylethylamine ( 118kg) in ethyl acetate and propylphosphonic anhydride (595kg) (cyclic trimer) was added 28w% at 2 -7 C in ethyl acetate (446kg) was added and the reaction mixture was 2 -4 C stirred for 2 hours. To this reaction mixture was added 15w% aqueous citric acid (600kg) for distribution, and the aqueous layer with ethyl acetate (271kg) extract. The ethyl acetate layer obtained was mixed, and sequentially washed with 10w% aqueous solution of diammoniumphosphate (600kg) and water (300kg). The ethyl acetate layer was concentrated to a residual volume 300L, n-heptane (739kg) at 23 -25 C added, and the mixture wasstirred at 23 -25 C 1 hour and stirred at 1 -5 C. The precipitated crystals were collected by filtration, with n-heptane (164 kg) were washed and driedunder reduced pressure to yield 3-[(2S)-1-tert-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine (compound 9a) (67.8 kg, yield 86 %)
86%
(2S) -1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (Compound 3a)(250.0 kg), N, N-diisopropylethylamine (DIPEA) (141 kg) in ethyl acetate (2242.5 kg) was added with pivaloyl chloride (131.5 kg) at 10 C. or lower, and the reaction mixture was added. The mixture was stirred at 10 C. or lower for 30 minutes.After thiazolidine (97.2 kg) was added to the reaction mixture at 10 C. or lower,The reaction mixture was stirred at 0-10 C. for 1 hour.To this reaction mixture, water (500.0 kg) was added for liquid separation,Ethyl acetate layer was prepared with diammonium hydrogen phosphate aqueous solution (prepared from 144.0 kg ammonium hydrogen phosphate and water (750.0 kg)) and saline (prepared from salt (75.0 kg) and water (425.0 kg)). Washed sequentially.After concentrating the ethyl acetate layer to a residual amount of 1250 L,2-Propanol (976.3 kg) was added and concentrated again.After the remaining amount was 1000 L, n-heptane (1368 kg) was added at 40 to 45 C., and the mixture was stirred at -5 C. or lower for 1 hour.The precipitated crystals were collected by filtration and washed with n-heptane (684.0 kg).2-Propanol (429.6 kg) was added to the obtained crystals, n-heptane (1521.9 kg) was added at 40 to 45 C., and the mixture was stirred at -5 C. or lower for 1 hour.The precipitated crystals are collected by filtration, washed with n-heptane (769.8 kg), and then dried under reduced pressure.3-[(2S) -1-t-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl] thiazolidine283.1 kg of (Compound 2a) was obtained.(Yield 86%)
81.7%
A solution of DCC (107.8 g) in toluene (300 mL) was added to a solution of 1-(tert-butoxycarbonyl)-4-oxo-L-proline (prepared according to the process of Example 2; 100 g) in toluene (900 mL) at -5C to - 10C, and the reaction mixture was stirred for 30 minutes at the same temperature. Dimethylaminopyridine (1 g) and thiazolidine (46.7 g) were slowly added to the reaction mixture at a temperature of about -6C to -2C over a period of about 15 to 20 minutes. The reaction mixture was allowed to warm to a temperature of 0C to 5C, and stirred at the same temperature for 60 minutes. When the reaction was complete, the reaction mixture was quenched with deionized water (20 mL), and stirred at 20C to 25C for 30 minutes. The resulting mixture was filtered through a Hyflo bed. The filtrate was washed with aqueous sodium bicarbonate solution (50 g sodium carbonate in 500 mL deionized water). The organic layer was separated and washed with an aqueous solution of sodium chloride (50 g sodium chloride in 500 mL deionized water). Activated carbon (10 g) was added to the organic layer, and the reaction mixture was stirred at 25C to 30C for 30 minutes. The reaction mixture was filtered through a Hyflo bed, and concentrated at a temperature of 50C under reduced pressure. The residue obtained was dissolved in ethyl acetate (200 mL) at 50C to 55C. Hexanes (800 mL) were added at 50C to 55C over a period of 1 to 2 hours. The reaction mixture was further cooled to a temperature of 0C to 5C, and stirred at the same temperature for 3 hours. The reaction mixture was filtered to obtain a solid. The solid was washed with a pre-cooled (0C to 5C) mixture of ethyl acetate (80 mL) and hexanes (320 mL), and dried at a temperature of 40C to 45C under reduced pressure to obtain tert-Butyl (2S)-4-oxo-2-(1.3-thiazolidin-3- ylcarbonyl)pyrrolidine-1-carboxylate. Yield: 81.7%
81.7%
With dmap; dicyclohexyl-carbodiimide; In toluene; at -6 - 5℃; for 1.33333h;
A solution of DCC (107.8 g) in toluene (300 mL) was added to a solution of 1- (tert-butoxycarbonyl)-4-oxo-L-proline (Formula V, prepared according to Example 2; 100 g) in toluene (900 mL) at -10C to -5C. The reaction mixture was stirred for 30 minutesat -10C to -5C. 4-Dimethylaminopyridine (1 g) and thiazolidine (46.7 g) were slowly added to the reaction mixture at -6C to -2C over a period of 15 minutes to 20 minutes. The reaction mixture was allowed to warm to 0C to 5C, then stirred at the same temperature for 60 minutes. When the reaction was complete, the reaction mixture was quenched with deionized water (20 mL), then stirred at 20C to 25C for 30 minutes. Theresulting mixture was filtered through a Hyflo bed. The filtrate was washed with an aqueous sodium bicarbonate solution (50 g sodium carbonate in 500 mL deionized water). The organic layer was separated, then washed with an aqueous solution of sodium chloride (50 g sodium chloride in 500 mL deionized water). Activated carbon (10 g) was added to the organic layer, then the reaction mixture was stirred at 25C to 30C for 30 minutes.The reaction mixture was filtered through a Hyflo bed, then concentrated at 50C under reduced pressure. The residue obtained was dissolved in ethyl acetate (200 mL) at 50C to 55C. Hexanes (800 mL) were added at 50C to 55C over a period of one hour to 2 hours. The reaction mixture was further cooled to 0C to 5C, then stirred at the same temperature for 3 hours. The reaction mixture was filtered to obtain a solid. The solidwas washed with a precooled (0C to 5C) mixture of ethyl acetate (80 mL) and hexanes (320 mL), then dried at 40C to 45C under reduced pressure to obtain tert-butyl (2S)-4- oxo-2-( 1,3 -thiazolidin-3 -ylcarbonyl)pyrrolidine- 1 -carboxylate.Yield: 81.7% HPLC Purity: 98.97 %
50 kg
6) Add 500 kg of toluene to a dry 2000 L reactor and add N-Boc-4-oxo-L-proline in batches.50 kg (molar amount: 229.23, molar amount: 218 mol), after stirring and dissolved, the system was cooled to below 0 C. Slowly add EDC hydrochloric acidSalt 50kg (molar amount 191.7, molar amount 261mol), and kept below 0 C for 3h;7), control system temperature below 0 C, dropwise addition of 23.4 kg of tetrahydrothiazole (molar amount 89.16, molar amount 260 mol) andA mixture of 533 g of 4-dimethylaminopyridine (molar amount 122.17, mole number 4.36) was added in about 1 h. Incubate for 1 h below 0 C;The end of the reaction of controlling N-Boc-4-oxo-L-proline in HPLC can be post-treated;8), post-treatment: the reaction solution is centrifuged, the filter cake is beaten with toluene, the organic phase is combined, 500 kg of water is added to stir, hydrochloric acid is added.Adjust the pH to about 3. The aqueous phase is separated, and the organic phase is washed with water and saturated brine, respectively, and dried and filtered;9), the organic phase is concentrated under reduced pressure at 50 C to obtain a solid and dried with an oil pump;10), the solid was recrystallized from a mixed solvent of ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:4), 250 kg.The temperature is raised from 55 C to 60 C, stirred and dissolved, and the temperature is lowered by 0 C. Centrifugation and drying gave a solid 50 kg. Yield: 76.3%. HPLC>99%, single miscellaneous <0.3%.
With formaldehyd; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; at -10 - 20℃;
The tert-butoxycarbonyl-N-4-oxo-proline obtained in step S7 and the cysteine hydrochloride were dissolved in a polar proton solvent. Then, carried out reaction again with formaldehyde aqueous solution at -10 ~ 20 C under the action of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and triethylamine , followed by post-treatment to give (2S) - tert-butyl - 4-oxo-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate , standby
In a dry and clean 1L four-port bottle, add 500ml of dichloromethane and stir.Further 50.0 g (218 mmol) of compound IV and 27.3 g (240 mmol) of compound III are added,Cool the system to 10-20 C and add 32.4 g (240 mmol)1-Hydroxybenzotriazole, 46.0 g 240 mmol1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, under N2 protection,Temperature control 10 ~ 20 C, 59.2g (458mmol) N, N diisopropylethylamine was added dropwise, control 0.5-1h finished. After the completion of the dropwise addition, the temperature was maintained at 0 to 10C for 2 hours, and the HPLC was followed until the compound IV was ? 1%.The reaction solution was concentrated to 80-120 ml remaining, and 19.6 g (262 mmol) of compound II (40% formaldehyde aqueous solution) was added dropwise to the system.After 10 hours of incubation at 10 to 20C, the treatment was started, 250 ml of tap water was added, and the mixture was extracted with ethyl acetate (300 ml each time, extracted twice),,The organic phases were combined and washed once with 150 ml of 1 mol/L hydrochloric acid.Then wash it once with 100ml 20% aqueous sodium chloride,The organic phase is concentrated to 60-100 ml and 250 ml of n-heptane are added dropwiseCrystallization, precipitation of white solids, cooling to 0-5 C between 1h, filtration,The compound (S)-tert-butyl 4-oxo-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate (I) was obtained in a yield of 89.0%. The HPLC purity was 99.2%.
Put 350.0g of intermediate III into the three-necked bottle, add 2800g of dichloromethane, reduce the temperature to -5~0C , add 162.8g of triethylamine A dropwise, stir at 0~5C for 0.5hThen add 204.1g of pivaloyl chloride and keep at 0~5C for 2h.Add 210.0g of thiazolidine hydrochloride at a temperature of -5~5 C, stir for 0.5h, add 234.5g of triethylamine B dropwise, and keep stirring for 1.5h after the completion of the drip. After the stirring is complete, add 1400g of water and stir until dissolved The layers were separated and the organic layer was washed with 1400g 3.75% hydrochloric acid solution, then with 1400g 5.66% sodium bicarbonate solution, and then with 1400g water. After the organic phase was concentrated to dryness,Add 1700g of isopropanol and stir, lower the temperature to 3 5 , stir for 1.5h and then filter with suction.After drying, 390.3g of product was obtained with a yield = 85.1%.
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