1-(1,1-Dimethylethyl) (2S)-4-oxo-1,2-pyrrolidinedicarboxylate

white to off-white solid

Trichloroisocyanuric acid (75.6 g) was added to a solution of (4R)-1-(tert- butoxycarbonyl)-4-hydroxy-L-proline (Formula IV, prepared according to the process of 100 g) in ethyl acetate (1000 mL). The solution was cooled to 0°C to -5°C. A solution of TEMPO in ethyl acetate (3.38 g in 50 mL ethyl acetate) was slowly added to the reaction mixture at -5°C to 10°C, and the reaction mixture was stirred at the same temperature for 20 minutes. The reaction mixture was heated to a temperature of 25°C to 30°C, and stirred at the same temperature for 60 minutes. After completion of the reaction, the reaction mixture was quenched with deionized water (200 mL), and stirred for 60 minutes at a temperature of about 25°C to 30°C. The reaction mixture was filtered through a Hyflo® bed. The filtrate was washed with deionized water (2 x 200 mL). The layers were separated. The organic layer was washed with an aqueous solution of sodium chloride (prepared by adding 40 g sodium hydroxide to 200 mL deionized water). The organic layer was concentrated at a temperature of about 50°C under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate ( 100 mL). Hexanes (400 mL) were slowly added to the solution of ethyl acetate. The reaction mixture was stirred at 25°C to 30°C for 30 minutes. The reaction mixture was filtered to obtain a solid. The solid was washed with a mixture of ethyl acetate (20 mL) and hexanes (80 mL), and dried at 40°C to 45°C under reduced pressure to obtain 1-(tert-butoxycarbonyl)-4-oxo-L-proline. Yield: 95.9percentCommercial (2S, 4R)-1- (tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid (30g, 0. [13MOL)] was dissolved in acetone (1500ml). A mechanical stirrer was placed in the flask and the solution stirred vigorously. A freshly made solution of 8N chromic acid was prepared by dissolving chromium trioxide (66.7g, 0. [667MOL)] in water [(40ML), ] adding concentrated sulphuric acid (53. [3ML)] and adding enough water to bring the solution volume to 115ml. The 8N chromic acid solution [(115ML)] was then added dropwise over a period of 30 min with continued vigorous stirring, the reaction's exotherm being maintained at the optimal temperature of [25C] by the use of an ice bath. After the complete addition of the chromic acid, the reaction mixture was stirred for a further 15 minutes-maintaining the optimal temperature of [25C.] The reaction mixture was then quenched by the addition of methanol [(20ML).] Exotherm was controlled by the use of an ice bath and, if necessary, direct addition of a small amount of crushed ice to the reaction mixture itself. The reaction mixture was filtered through a Celite pad and then concentrated in vacuo. The resulting acidic solution was then extracted with ethyl acetate [(3X300ML)] and the combined organic layers washed with brine [(2XLOOML), ] then dried with magnesium sulfate and concentrated in vacuo. The crude product was recrystallized from ethyl acetate to give a white crystalline product, [(25)-1-(TERT-BUTOXYCARBONYL)-4-OXO-2-PYRROLIDINECARBOXYLIC] acid (22. [55G, ] 76percent) [(LA).] [(1H] NMR [(360MHZ, ] [CDC13)] : 1.4 [(M, ] 9H), 2.5-3. 0 (m, 2H), 3.7-3. 9 [(M, ] 2H), 4.75 (dd, [1H)).]To a 1 L reaction flask were added 60.0 g (0.26 mol) of N-Boc-L-hydroxyproline, (0.26 mol) of TCCA, stirred and cooled to room temperature, To the reaction flask was added 2.02 g (0.012 mol) of TEMPO (reaction exotherm) in portions, Control feeding rate, The temperature used in the -3 ° C, filtration, the filtrate was concentrated to a white solid 40.12g, yield 67percent.Example 1. Preparation of (5 l -(fert-butoxycarbonyl)-4-oxopyrrolidine-2- carboxylic acidTo a solution of (2R, 45)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2- carboxylic acid (92 g, 0.398 mol) in isopropyl acetate (460 mL) was added TEMPO (2.49 g, 0.05 eq) at 0°C. A solution of NaCIO (12.5 wtpercent, 370 mL) was added dropwise to the reaction mixture while maintaining the temperature at 0-5°C. The reaction was slowly allowed to warm to room temperature and stirred at room temperature overnight. The organic layer was separated and the aqueous layer was treated with 1M KHSOTo an ice cooled solution of Boc hydroxyproline 1 (20 g, 86.4 mmol) in ethyl acetate (300 ml_) were added a saturated aqueous solution of sodium metaperiodate (500 mL) and ruthenium oxide (115 mg, 0.864 mmol). The biphasic mixture was vigorously stirred at 35Transfer the above aqueous layer containing the intermediate carboxylate to another dry clean reaction bottle, then add 150 mL of chloroform, 0.55 g of TEMPO and 0.22 g of sodium bromide and 0.1 g of 18-crown-6-ether. Slowly reduce the temperature to 0 ° C under stirring, start to add 250 mL of aqueous solution of sodium dichloroisocyanurate with a mass concentration of 25percent, and control the temperature of the reaction system during the dropwise addition to 0 ° C ~ 10 ° C, continue after the completion of the dropwise addition. After the reaction was completed for 2.0 h, after the reaction was completed, the pH of the system was adjusted to 3 to 4 by adding a potassium bisulfate aqueous solution having a mass concentration of 25percent to carry out acidification. After the pH value was substantially stabilized in the range, the product was stirred and analyzed for 30 minutes. The crude product is obtained by suction filtration, and the crude product has a purity of 99percent. The crude product is added to 100 mL of water and beaten at room temperature for 30 min, filtered to obtain a wet product, and after drying, the final product is obtained.N-tert-butoxycarbonyl-keto-L-proline 38.1 g, purity 99.6percent, the total yield of the two steps reached 86.5percent.To synthesize intermediate compound 16b, saturated NaHCO3 solution (200 mL) is added to a solution of trans-4-hydroxy-L-proline (5 g, 38.0 mmol) in dioxane and water (1 : 1 , 100 mL). The solution is cooled to 0°C and (Boc)1 kg of L-hydroxyproline was dissolved in 50 kg of water to obtain a reaction liquid;The temperature of the reaction solution was lowered to -5 ° C, and 1.9 kg of trichloroisocyanuric acid was taken.Adding to the reaction solution, controlling the reaction temperature to be less than 0 ° C, taking 238 g of tetramethylpiperidine oxynitride (TEMPO), Slowly added to the reaction solution;After the addition, keep the temperature of the reaction solution below 0 ° C, carry out the reaction, and control the temperature of the reaction solution after the TLC monitoring reaction is completed.Less than 0 ° C, the pH of the reaction solution was adjusted to 8-9 with triethylamine;2 kg of di-tert-butyl dicarbonate was dissolved in 2 L of tetrahydrofuran to obtain a solution of the amino-protecting agent in THF, and dissolved therein.The liquid is slowly added to the reaction solution, and the pH is maintained at 8-9 during the feeding;After the addition is completed, the temperature of the reaction solution is slowly raised to 25 ° C, and the reaction is carried out for 4-5 hours;After TLC monitors the reaction, the temperature of the reaction solution is lowered to -5 ° C, and 5 kg of 10percent aqueous sodium thiosulfate solution is taken.Slowly added to the reaction solution;After the addition, 10 kg of ethyl acetate was added, and the pH of the system was adjusted to 3-4 with a 6 M hydrochloric acid solution to separate the organic phase;The aqueous phase was extracted twice with 5 kg of ethyl acetate. After the aqueous phase extraction by TLC, the organic phase was saturated with 10 kg.The solution was washed once with anhydrous sodium sulfate and concentrated under reduced pressure to remove solvent.This gave 1.3 kg of a white solid.Yield: 75percent;To a solution of compound S1 (0.16 g, 0.5 mmol) in anhydrous EtOH (10 mL) was added 10percent Pd/C (0.05 g). The resulting mixture was degassed twice and stirred under an atmosphere of HIntermediate 1: (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic Acid Intermediate 1: (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic Acid To a solution of (2R, 4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (20 g, 86.6 mmol) in isopropylacetate (100 mL) was added TEMPO (675 mg, 4.3 mmol) at 0° C. A solution of aq. NaClO (10 wt percent, 61.8 g, 104.0 mmol) was added dropwise to the reaction mixture at 0-5° C. The reaction was allowed to warm to room temperature and stirred at room temperature for 1 hr. The organic layer was separated and the aqueous layer was treated with 1 M aq. KHSOCompound 1a (16.4 g, 100 mmol), 1b (22.92 g, 100 mmol), DIPEA (19.4 g, 150 mmol)HATU (45.6 g, 120 mmol) was added at room temperature, and the reaction was stirred for 4 hours.The reaction was detected by TLC, and after completion of the reaction, water (200 ml) was added to quench the reaction.Ethyl acetate extraction (300 ml x 2), the organic layers were combined and the organic layer dried.Filter, thicken, Column chromatography gave 26.3 g of an off-white solid.The yield was 70.1%.The difference from is that Step 3 specifically includes the synthesis of Compound 4:1 equivalent of compound 3 and a third organic solvent are sequentially added to the reactor, the third organic solvent is methyl tert-butyl ether, and the weight of the third organic solvent is 6 times that of compound 3, and mechanical stirring is started.0.4 equivalent of 4-dimethylaminopyridine was added, and then a solution dissolved in a third organic solvent and containing 1.1 equivalents of Boc anhydride was added dropwise.The weight of the third organic solvent is twice that of the compound 3. After the addition, the mixture is heated to reflux for 3 hours, and 60 g of water is added to the reaction flask.The layers were separated and concentrated to a liquid-free liquid to give a brown-yellow oil, which was recrystallized from n-heptane to afford compound 4.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%.