(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol

[(3RR3AS, 6AR)-3-HYDROXYHEXAHYDROFULO] [2, 3- [B] FURAN (I)] : To a solution containing 250 mg (1.95 mmol) (3aS, 6aR)-3-oxyhexahydrofuro [[2, ] 3-b] furan (6) [IN ETOH] (25 mL) was added mg (2. 35 mmol) NaBH4 at -18C. The reaction mixture was stirred [AT-18C] for 2.5 hours, then the reaction was quenched with saturated [NH4CL] solution (5 mL) and warmed to room temperature. The resulting mixture was concentrated under reduced pressure, and then 10 mL water was added. The aqueous layer was extracted with ethyl acetate (3 x 50 mL) and a solution of [70%] CHCl3, 20% MeOH, and [10%] water (3 x 50 mL). The combined organic extracts were dried over [NA2SO4. COLUMN] chromatography (silica gel 80 g, MeOH in [CHC13] [7%)] gave compound [(I)] (178 mg. [70%)] as a colorless solid, Rf=0. 3, [a] 25D-12.4, c 1.3, MeOH. IR (neat) [2951, ] 1641, 1211 [CM-1] ; [1H-NMR] (400 MHz [CDC13)] 5 : 1.85 (mc, 1H), 1.94 (bs, [1H), ] 2.27 [(ME, ] 1H), 2.84 [(ME, ] 1H), 3.63 (dd, 1H, J=7.1 Hz, J=9.2 Hz), 3.89 [(ME, ] 1H), 3.97 [(ME, ] 1H), 4.43 (dd, 1H, J=6.8 Hz, J=14. 5' Hz), 5.68 (d, 1H, J=5. [2] Hz). [13C-NMR] (125.8 MHz, CDC13, Dept) [5] : 25.27 (-), 46.97 (+), 70.31 (-), 71.26 (-), 73.50 [(+), ] 109. [93.] (+). [C6H1003I] Exact Mass: 130. 06 ; Mol. Wt.: 130.14 ; C, 55.37, H, 7.74, [0, ] 36.88.26.3 g of tert-butyl methyl ether, 35.09 g (135 mmol) of di (N-succinimidyl) carbonate, And 20.00 g (the content of the compound (II-1): 73.0%) of the compound (II-1) and the compound (III-2) obtained in the same manner as in were mixed at room temperature And the temperature was raised to 40 C. 11.89 g (150 mmol) of pyridine was added dropwise to the obtained solution at 40 C., and the mixture was stirred at 40 C. for 22 hours. The whole amount of the solution was cooled to 20 C., 73.0 g of 2-propanol was added dropwise at 20 C. to precipitate compound (I-1), cooled to 0 to 5 C. and then cooled to 0 to 5 C. for 19 hours Followed by stirring.The precipitated compound (I-1) was filtered and washed to obtain 27.83 g of compound (I-1) (content: 97.8%, yield 90%, enantiomeric excess of compound (I-1) Rate> 99.9% ee). 30.0 g of tert-butylmethyl ether, 11.87 g of the compound (II-0)(The diastereomer ratio of the compound (II-1) to the 3S, 3aS, 6aR-OH form: 91.1 / 8.9 containing 84.3% diastereomer) and the enzyme (CHIRAZYME L-2c, -flyo, manufactured by Roche Diagnostics) was added to the mixture at a temperature of 25 C. 3.31 g (38.4 mmol) of vinyl acetate was added dropwise to the mixture, After stirring at 25 C. for 40 hours, insoluble matter was filtered off.The filtrate was concentrated to obtain 12.73 g of a mixture containing compound (II-1) and compound (III-2) (yield of compound (II-1): 90% 3S, 3aS, 6aR-OH isomer: 100.0 / 0.0). (II-1) and the compound (III-2) obtained in the same manner as in Example 2, 26.3 g of tert-butyl methyl ether, 35.09 g (135 mmol) of di (N-succinimidyl carbonate) And 20.00 g of the compound (II-1) in an amount of 73.0%) were mixed at room temperature, and the mixture was heated to 40 C. To the resulting solution, 11.89 g (150 mmol) of pyridine was added dropwise at 40 C. And the mixture was stirred for 22 hours at 40 C. The total amount of the solution was cooled to 20 C. and 73.0 g of 2-propanol was dropwise added at 20 C. to precipitate the compound (I-1) and cooled to 0 to 5 C. , And the mixture was stirred for 19 hours at 0 to 5 C. The precipitated compound (I-1) was filtered, (Yield: 97.8%, yield: 90%, enantiomer excess of compound (I-1)> 99.9% ee) was obtained by filtration and washing with water to obtain 27.83 g of compound (I-1).(5) Under nitrogen protection, To cleanliness, The dried 2000 L reactor was charged with 800 kg of dichloromethane and 80 kg of furanol (molar amount 130.06, mole number 615 mol). 189 kg DSC (molar amount 256.17, mole number 738 mol), 74.8 kg of triethylamine (molar amount 101, mole number 740.6 mol), the temperature was refluxed, and the TLC controlled reaction was completed; (6) After the reaction is completed, the temperature is lowered to 10 C or lower. Washed twice with saturated brine, and the organic phase is dried and concentrated; (7) The obtained crude product was concentrated, and added 360 kg of ethyl acetate, 480 kg of isopropanol, and refluxed to recrystallize; (8) Cooling, centrifuging, drying, Got 104.0kg (3R, 3aS, 6aR)-hydroxyhexahydrofuro[2, 3-beta]furanyl succinimidyl carbonate, The yield was 62%, the purity was >98%, and the unknown single impurity was impurity was <0.1%, which was qualified.3) Preparation of l-( [[f3R-, 3aS., 6aR)hexahv(irofuro[2, 3-blfuran-3-yloxylcarbonyll- oxy)-2, 5-pyrrolidinedione; In a glass-lined reactor 17.7 kg (3R, 3aS, 6aR)-hexahydrofuro [2, 3-b] furan-3-ol in acetonitrile (30%) was added, then 3.9 kg of triethylamine. 9 kg of solid disuccinimidyl carbonate (DSC) was added in portions, while keeping the reaction temperature below 350C. The reaction mixture was stirred at 2O0C for 3 hours. The temperature was lowered to 20C and 45 kg of ice-water was added to the reactor.Precipitation was observed and the precipitate was filtered off. The cake was dissolved in 41 kg of chloroform and the aqueous phase was separated. The solution was evaporated to dryness and 18.8 kg of petroleum ether was added to the reactor containing the residue. The mixture was stirred at 0-50C for 1 hour. The resulting white precipitation was filtered off and rinsed with about 2 kg of petroleum ether. l-([[(3R, 3aS, 6aR)hexahydrofuro[2, 3-b]furan-3-yloxy]carbonyl]oxy)-2, 5-pyrrolidine- dione was obtained as an off-white solid, weight 3.69 kg (yield 39.9%, purity 68.7% by HPLC area, mobile phase: CH3CN/15mmol/L Na2HPO4, pH 3.0 by H3PO4 (35/65); speed:0.8mL/min; retention time: 7.730 min.).To a stirred solution of [3R, 3aS, 6aS]-3-hydroxyhexahydrofuro[2, 3-b]furan 25 (65 mg, 0.5 mmol) in dry CH3CN (5 mL) at 23 C. were added disuccinimidyl carbonate (192 mg, 0.75 mmol) and triethylamine (0.25 mL). The resulting mixture was stirred at 23 C. for 12 h. The reaction was quenched with saturated aqueous NaHCO3 (10 mL) and the mixture was concentrated under reduced pressure. The residue was extracted with CH2Cl2 (2×25 mL) and the combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent under reduced pressure gave a residue, which was chromatographed over silica gel (50% ethyl acetate/hexane) to furnish (3R, 3aS, 6aR) 3-hydroxyhexahydrofuro[2, 3-b]furanyl-succinimidyl carbonate 31 (70 mg) as a brown oil. Carbonate 33 (65 mg) was prepared from 60 mg of alcohol 27 by following a similar procedure.1. (3R, 3aS, 6aR)-hexahydrof ro [2, 3-b]furan-3-ol (100 mg) was added into a pre-dried 25ml round bottom flask under nitrogen. Disuccinimidyl carbonate (DSC) (295 mg) was then added followed by acetonitrile (3ml). Et3N (155 mg) was added while stirring, until the suspension became clear. The resulting solution was stirred at ambient temperature for 5 hours under TLC control. The solvent was then removed, saturated solution of NaHC03 (4 ml) was added, and extracted with EtOAc (3*20 ml). The combined organic fractions were dried with Na2S04, filtered, and concentrated to an oily residue. MeOH (4 ml) was added, and the resulting suspension was stirred, then filtered and dried to give 152 mg of compound III as a white solid.Nu, Nu'-Disuccinimidyl carbonate compound of formula- 13 (148 gm) was added to the mixture of Procedure for Formula 22; Disuccinimidyl DicarbonatePyridine Formula 10 Formula 22A flask is charged with 14.8 g of disuccidimidylcarbonate, CH2Cl2 (25 mL), 5.0 g of Formula 10 as a solution in CH2Cl2 (20 mL), and pyridine (7.8 mL). The solution is heated at gentle reflux for several hours until reaction completes. Heating is removed and water (35 mL) is added, the mixture agitated several minutes, the layers are separated. The organic phase is washed sequentially with water (35 mL) and brine (30 mL). The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is redissolved in dichlorome thane CH2Cl2 (13 mL) with heating and heptane (10 mL) added to the warm solution. The mixture is gradually cooled to approximately 100C, the solid filtered, rinsed with heptane and dried to constant weight providing ~8.9 g 87.5%.A flask is charged with crude Formula 22 (106g), activated carbon (23g) and toluene (5.7 Kg). After agitation for 2h the mixture is filtered through celite and the filtrate evaporated to afford 100 g (94.3 % recovery) of Formula 22 as an off-white solid. A flask is charged with Formula 22 (12g) of Formula 22, acetone (24g) and heated to 52C to obtain a solution. Heptane (6Og) is added to the warm solution under agitation. The mixture is cooled over two hours to approximately 100C, the solid collected, washed the with 3:1 acetonerheptane and dried to constant weight, providing Formula 22, 11.4 g, 95 % recovery, as a white solid. 1H NMR (CDCl3) 5.75 (d, IH), 5.21-5.30 (dd, IH), 3.90-4.16 (m, 4H), 3.07-3.18 (m, IH), 2.85 (s, 4H), 2.10-2.22 (m, IH), 1.92-2.06 (m, IH).Succinimidyl carbonate 7: To a stirred solution of [3R, 3aS, 6alphai?]-3- hydroxyhexahydrofuro[2, 3-]furan (650 mg, 5 mmol; prepared according to the procedure of Ghosh et. al. in dry CH3CN (50 mL) at 23C were added disuccinimidyl carbonate (1.92 g, 7.5 mmol) and triethylamine (2.5 mL). The resulting mixture was stirred at 230C for 12 h. The reaction was quenched with saturated aqueous NaHCO3 (20 mL) and the mixture was concentrated under reduced pressure. The residue was extracted with CH2CI2 (2 x 50 mL) and the combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent 26.3 g of tert-butyl methyl ether, 35.09 g (135 mmol) of di (N-succinimidyl) carbonate, And 20.00 g (the content of the compound (II-1): 73.0%) of the compound (II-1) and the compound (III-2) obtained in the same manner as in were mixed at room temperature And the temperature was raised to 40 C. 11.89 g (150 mmol) of pyridine was added dropwise to the obtained solution at 40 C., and the mixture was stirred at 40 C. for 22 hours. The whole amount of the solution was cooled to 20 C., 73.0 g of 2-propanol was added dropwise at 20 C. to precipitate compound (I-1), cooled to 0 to 5 C. and then cooled to 0 to 5 C. for 19 hours Followed by stirring.The precipitated compound (I-1) was filtered and washed to obtain 27.83 g of compound (I-1) (content: 97.8%, yield 90%, enantiomeric excess of compound (I-1) Rate> 99.9% ee). 30.0 g of tert-butylmethyl ether, 11.87 g of the compound (II-0)(The diastereomer ratio of the compound (II-1) to the 3S, 3aS, 6aR-OH form: 91.1 / 8.9 containing 84.3% diastereomer) and the enzyme (CHIRAZYME L-2c, -flyo, manufactured by Roche Diagnostics) was added to the mixture at a temperature of 25 C. 3.31 g (38.4 mmol) of vinyl acetate was added dropwise to the mixture, After stirring at 25 C. for 40 hours, insoluble matter was filtered off.The filtrate was concentrated to obtain 12.73 g of a mixture containing compound (II-1) and compound (III-2) (yield of compound (II-1): 90% 3S, 3aS, 6aR-OH isomer: 100.0 / 0.0). (II-1) and the compound (III-2) obtained in the same manner as in Example 2, 26.3 g of tert-butyl methyl ether, 35.09 g (135 mmol) of di (N-succinimidyl carbonate) And 20.00 g of the compound (II-1) in an amount of 73.0%) were mixed at room temperature, and the mixture was heated to 40 C. To the resulting solution, 11.89 g (150 mmol) of pyridine was added dropwise at 40 C. And the mixture was stirred for 22 hours at 40 C. The total amount of the solution was cooled to 20 C. and 73.0 g of 2-propanol was dropwise added at 20 C. to precipitate the compound (I-1) and cooled to 0 to 5 C. , And the mixture was stirred for 19 hours at 0 to 5 C. The precipitated compound (I-1) was filtered, (Yield: 97.8%, yield: 90%, enantiomer excess of compound (I-1)> 99.9% ee) was obtained by filtration and washing with water to obtain 27.83 g of compound (I-1).(5) Under nitrogen protection, To cleanliness, The dried 2000 L reactor was charged with 800 kg of dichloromethane and 80 kg of furanol (molar amount 130.06, mole number 615 mol). 189 kg DSC (molar amount 256.17, mole number 738 mol), 74.8 kg of triethylamine (molar amount 101, mole number 740.6 mol), the temperature was refluxed, and the TLC controlled reaction was completed; (6) After the reaction is completed, the temperature is lowered to 10 C or lower. Washed twice with saturated brine, and the organic phase is dried and concentrated; (7) The obtained crude product was concentrated, and added 360 kg of ethyl acetate, 480 kg of isopropanol, and refluxed to recrystallize; (8) Cooling, centrifuging, drying, Got 104.0kg (3R, 3aS, 6aR)-hydroxyhexahydrofuro[2, 3-beta]furanyl succinimidyl carbonate, The yield was 62%, the purity was >98%, and the unknown single impurity was impurity was <0.1%, which was qualified.3) Preparation of l-( [[f3R-, 3aS., 6aR)hexahv(irofuro[2, 3-blfuran-3-yloxylcarbonyll- oxy)-2, 5-pyrrolidinedione; In a glass-lined reactor 17.7 kg (3R, 3aS, 6aR)-hexahydrofuro [2, 3-b] furan-3-ol in acetonitrile (30%) was added, then 3.9 kg of triethylamine. 9 kg of solid disuccinimidyl carbonate (DSC) was added in portions, while keeping the reaction temperature below 350C. The reaction mixture was stirred at 2O0C for 3 hours. The temperature was lowered to 20C and 45 kg of ice-water was added to the reactor.Precipitation was observed and the precipitate was filtered off. The cake was dissolved in 41 kg of chloroform and the aqueous phase was separated. The solution was evaporated to dryness and 18.8 kg of petroleum ether was added to the reactor containing the residue. The mixture was stirred at 0-50C for 1 hour. The resulting white precipitation was filtered off and rinsed with about 2 kg of petroleum ether. l-([[(3R, 3aS, 6aR)hexahydrofuro[2, 3-b]furan-3-yloxy]carbonyl]oxy)-2, 5-pyrrolidine- dione was obtained as an off-white solid, weight 3.69 kg (yield 39.9%, purity 68.7% by HPLC area, mobile phase: CH3CN/15mmol/L Na2HPO4, pH 3.0 by H3PO4 (35/65); speed:0.8mL/min; retention time: 7.730 min.).To a stirred solution of [3R, 3aS, 6aS]-3-hydroxyhexahydrofuro[2, 3-b]furan 25 (65 mg, 0.5 mmol) in dry CH3CN (5 mL) at 23 C. were added disuccinimidyl carbonate (192 mg, 0.75 mmol) and triethylamine (0.25 mL). The resulting mixture was stirred at 23 C. for 12 h. The reaction was quenched with saturated aqueous NaHCO3 (10 mL) and the mixture was concentrated under reduced pressure. The residue was extracted with CH2Cl2 (2×25 mL) and the combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent under reduced pressure gave a residue, which was chromatographed over silica gel (50% ethyl acetate/hexane) to furnish (3R, 3aS, 6aR) 3-hydroxyhexahydrofuro[2, 3-b]furanyl-succinimidyl carbonate 31 (70 mg) as a brown oil. Carbonate 33 (65 mg) was prepared from 60 mg of alcohol 27 by following a similar procedure.1. (3R, 3aS, 6aR)-hexahydrof ro [2, 3-b]furan-3-ol (100 mg) was added into a pre-dried 25ml round bottom flask under nitrogen. Disuccinimidyl carbonate (DSC) (295 mg) was then added followed by acetonitrile (3ml). Et3N (155 mg) was added while stirring, until the suspension became clear. The resulting solution was stirred at ambient temperature for 5 hours under TLC control. The solvent was then removed, saturated solution of NaHC03 (4 ml) was added, and extracted with EtOAc (3*20 ml). The combined organic fractions were dried with Na2S04, filtered, and concentrated to an oily residue. MeOH (4 ml) was added, and the resulting suspension was stirred, then filtered and dried to give 152 mg of compound III as a white solid.Nu, Nu'-Disuccinimidyl carbonate compound of formula- 13 (148 gm) was added to the mixture of Procedure for Formula 22; Disuccinimidyl DicarbonatePyridine Formula 10 Formula 22A flask is charged with 14.8 g of disuccidimidylcarbonate, CH2Cl2 (25 mL), 5.0 g of Formula 10 as a solution in CH2Cl2 (20 mL), and pyridine (7.8 mL). The solution is heated at gentle reflux for several hours until reaction completes. Heating is removed and water (35 mL) is added, the mixture agitated several minutes, the layers are separated. The organic phase is washed sequentially with water (35 mL) and brine (30 mL). The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is redissolved in dichlorome thane CH2Cl2 (13 mL) with heating and heptane (10 mL) added to the warm solution. The mixture is gradually cooled to approximately 100C, the solid filtered, rinsed with heptane and dried to constant weight providing ~8.9 g 87.5%.A flask is charged with crude Formula 22 (106g), activated carbon (23g) and toluene (5.7 Kg). After agitation for 2h the mixture is filtered through celite and the filtrate evaporated to afford 100 g (94.3 % recovery) of Formula 22 as an off-white solid. A flask is charged with Formula 22 (12g) of Formula 22, acetone (24g) and heated to 52C to obtain a solution. Heptane (6Og) is added to the warm solution under agitation. The mixture is cooled over two hours to approximately 100C, the solid collected, washed the with 3:1 acetonerheptane and dried to constant weight, providing Formula 22, 11.4 g, 95 % recovery, as a white solid. 1H NMR (CDCl3) 5.75 (d, IH), 5.21-5.30 (dd, IH), 3.90-4.16 (m, 4H), 3.07-3.18 (m, IH), 2.85 (s, 4H), 2.10-2.22 (m, IH), 1.92-2.06 (m, IH).Succinimidyl carbonate 7: To a stirred solution of [3R, 3aS, 6alphai?]-3- hydroxyhexahydrofuro[2, 3-]furan (650 mg, 5 mmol; prepared according to the procedure of Ghosh et. al. in dry CH3CN (50 mL) at 23C were added disuccinimidyl carbonate (1.92 g, 7.5 mmol) and triethylamine (2.5 mL). The resulting mixture was stirred at 230C for 12 h. The reaction was quenched with saturated aqueous NaHCO3 (20 mL) and the mixture was concentrated under reduced pressure. The residue was extracted with CH2CI2 (2 x 50 mL) and the combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent

Molecular Weight:130.14
XLogP3:-0.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:130.062994177
Monoisotopic Mass:130.062994177
Topological Polar Surface Area:38.7
Heavy Atom Count:9
Complexity:115
Defined Atom Stereocenter Count:3
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes