* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With pyridine In tert-butyl methyl ether at 25 - 40℃; for 62 h;
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): 73.0percent) of the compound (II-1) and the compound (III-2) obtained in the same manner as in Example 2 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: 97.8percent, yield 90percent, enantiomeric excess of compound (I-1) Rate> 99.9percent 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 84.3percent 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): 90percent 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 73.0percent) 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: 97.8percent, yield: 90percent, enantiomer excess of compound (I-1)> 99.9percent ee) was obtained by filtration and washing with water to obtain 27.83 g of compound (I-1).
Reference：
[1] Patent: JP2016/150901, 2016, A, . Location in patent: Paragraph 0016; 0017; 0023; 0024
[2] Journal of Organic Chemistry, 2004, vol. 69, # 23, p. 7822 - 7829
[3] European Journal of Organic Chemistry, 2016, vol. 2016, # 10, p. 1874 - 1880
[4] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1813 - 1822
[5] Patent: WO2010/23322, 2010, A1, . Location in patent: Page/Page column 29
[6] Patent: US2008/85918, 2008, A1, . Location in patent: Page/Page column 18; Sheet 3
[7] Patent: WO2011/92687, 2011, A1, . Location in patent: Page/Page column 31
[8] Patent: WO2016/207907, 2016, A1, . Location in patent: Page/Page column 23
[9] Organic Process Research and Development, 2017, vol. 21, # 1, p. 98 - 106
[10] Patent: WO2007/126812, 2007, A2, . Location in patent: Page/Page column 41
[11] Patent: WO2008/133734, 2008, A2, . Location in patent: Page/Page column 28-29
2
[ 6066-82-6 ]
[ 253265-97-3 ]
Yield
Reaction Conditions
Operation in experiment
99.6%
With triethylamine In tetrahydrofuran for 2 h; Reflux
The compounds of formula 1 obtained in Example 3 (3.8g, 0.02mol) was dissolved in 30ml of tetrahydrofuran, was added dropwise to N- hydroxyalkylSuccinimide (2.3g, 0.02mol) in 45ml of tetrahydrofuran was added triethylamine (2.02g, 0.02mol), the addition was complete, reflux, 2 hours reaction, TLC detection material disappeared, water was added to brine and extracted , take the upper concentrated to give 5.4g compound of formula 6-1 in a yield of 99.6percent.
(S)-3-[((2R,3S)-3-Amino-2-hydroxy-4-phenyl-butyl)-isobutyl-amino]-1,3-dimethyl-1,3-dihydro-indol-2-one[ No CAS ]
[ 253265-97-3 ]
{(1S,2R)-1-Benzyl-3-[((S)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acid (3R,3aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester[ No CAS ]
(R)-3-[((2R,3S)-3-Amino-2-hydroxy-4-phenyl-butyl)-isobutyl-amino]-1,3-dimethyl-1,3-dihydro-indol-2-one[ No CAS ]
[ 253265-97-3 ]
{(1S,2R)-1-Benzyl-3-[((R)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acid (3R,3aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester[ No CAS ]
{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methyl-butyl)-(3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-amino]-propyl}-carbamic acid (3R,3aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester[ No CAS ]
{(1S,2R)-1-tert-Butyl-2-hydroxy-3-[isobutyl-((R)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-amino]-propyl}-carbamic acid (3R,3aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester[ No CAS ]
{(1S,2R)-1-tert-Butyl-2-hydroxy-3-[isobutyl-((S)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-amino]-propyl}-carbamic acid (3R,3aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester[ No CAS ]
{(1S,2R)-1-Benzyl-3-[benzyl-(3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-amino]-2-hydroxy-propyl}-carbamic acid (3R,3aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester[ No CAS ]
3-Allyl-3-[allyl-((2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-amino]-1,3-dihydro-indol-2-one[ No CAS ]
[ 253265-97-3 ]
{(1S,2R)-3-[Allyl-(3-allyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid (3R,3aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester[ No CAS ]
3-[((2R,3S)-3-Amino-2-hydroxy-4-phenyl-butyl)-isobutyl-amino]-5-methoxy-3-methyl-1,3-dihydro-indol-2-one[ No CAS ]
[ 253265-97-3 ]
{(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl-((R)-5-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-amino]-propyl}-carbamic acid (3R,3aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester[ No CAS ]
{(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl-((S)-5-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-amino]-propyl}-carbamic acid (3R,3aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester[ No CAS ]
(R)-3-Allyl-3-[((2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-isobutyl-amino]-1,3-dihydro-indol-2-one[ No CAS ]
[ 253265-97-3 ]
{(1S,2R)-3-[((R)-3-Allyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid (3R,3aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester[ No CAS ]
(S)-3-Allyl-3-[((2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-isobutyl-amino]-1,3-dihydro-indol-2-one[ No CAS ]
[ 253265-97-3 ]
{(1S,2R)-3-[((S)-3-Allyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid (3R,3aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester[ No CAS ]
3-[Allyl-((2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-amino]-3-but-3-enyl-1,3-dihydro-indol-2-one[ No CAS ]
[ 253265-97-3 ]
{(1S,2R)-3-[Allyl-(3-but-3-enyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid (3R,3aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester[ No CAS ]
Procedure for formula 15, {(IS, 2R)-[l-(4-Formyl-benzyl)]-(2R)-2-hydroxy-3- [N-isobutyl-(N-4-methoxy-benzenesulfonyl)-amino]-propyl}-carbamic acid [3JR,3alphaS,6alphaJR]-hexahydrofuro[2,3-b]furan-3-yl ester; Formula 26 Formula 15A flask is charged with Formula 26 (2.0 g) and 20 mL THF. Methanesulfonic acid was added drop-wise to the solution. The solution is warmed to 4O0C until de- protection was complete. The solution was cooled to 2O0C and N-rnethylimidazole (2.39 g) was added to the reactor. Formula 22 (1.52 g) was then charged and the reaction was warmed to 500C until the reaction was complete. Ethyl acetate (150 mL) was charged and the solution was sequentially washed with 0.5 M aq. citric acid (20 g), 10% aq. NaH2PO4 (20 g), sat. NaHCO3 (20 g), and 10% aq. NaH2PO4 (20 g). The organic layer was dried over anhydrous sodium sulfate (2 g), filtered, and concentrated to a viscous oil which was purified by silica gel column chromatography <n="46"/>eluting with a mixture of ethyl acetate and heptane. The fractions containing desired Formula 15 were combined and concentrated to afford a white solid, 95%, 2.13 g, HPLC purity 97%.
N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)[1-(2-methylpropyl)benzimidazol-6-yl]sulfonamide hydrochloride[ No CAS ]
[ 253265-97-3 ]
[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)[[1-(2-methylpropyl)benzimidazol-6-yl]sulfonyl]amino]-1-(phenylmethyl)propyl]carbamic acid [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl] ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With triethylamine; In dichloromethane; at 20℃; for 4h;
Example 2; Preparation of Compound 7; Compound 7; 58 g of 3-fluoroaniline and 58 mL of benzaldehyde were heated at 80C during one hour. 200 mL of sulfuric acid were then added to the reaction mixture, cooled with an ice bath. After removing of the ice bath, the reaction mixture was further stirred at room temperature until complete dissolution of the solid. The reaction mixture was next cooled to 0C with an ice bath and 36 mL of nitric acid in 120 mL of sulfuric acid were added dropwise, maintaining the temperature at 0C. After one hour of stirring at 0C, the solid was filtered off and poured into a saturated solution of potassium carbonate in water. Ethyl acetate was then added and the two layers were separated. The aqueous phase was extracted two more times with ethyl acetate. The organic phases were collected, dried over MgS04 and evaporated. The crude compound was purified on silica gel eluting with 40% ethyl acetate in hexane, yielding 28.65 g (35%) of the desired intermediate A-2 3-fluoro-4-nitroaniline. 28.65 g of intermediate A-2 was dissolved in 230 mL of chlorhydric acid 36%. The reaction mixture was cooled to 0C with an ice bath and 13.7 g of sodium nitrite was added portion-wise. The reaction was maintained at 0C during 1.5 hours, then mixed with 145 mL of a S02 saturated acetic acid solution, containing 10.5 mL of water and 9.3 g of CuC12. 2H20. After complete addition, the cooling bath was removed and the reaction mixture was stirred at room temperature during one hour, then poured onto ice. The solid was filtered off yielding 37.7 g of the intermediate B-2 3-fluoro-4-nitro- benzene sulfonyl chloride. To a solution of 53 g of intermediate C-1 (PG = Boc, R4 = isobutyl) in 500 mL of THF containing 42 mL of triethylamine was added portion-wise 37.7 g of intermediate B-2. The reaction mixture was stirred at room temperature overnight then evaporated. The residue was dissolved in ethylacetate and extracted with water, then with a solution of HCI 5% in water and with a K2CO3 solution in water. The organic layer was then dried over MgSO4 and evaporated. The crude compound was purified on silica gel yielding 53 g (65%) of the desired intermediate 2-a [(lS, 2R)-3-[[(3-fluoro-4-nitrophenyl)- sulfonyl] (2-methylpropyl) amino]-2-hydroxy-1-(phenylmethyl) propyl] carbamic acid, 1, 1-dimethylethyl ester. 2 g of intermediate 2-a were dissolved in 50 mL of DMF and 1.85 mL of isopropyl- amine were added. The reaction mixture was stirred at 60C overnight, then concentrated and the residue treated with a mixture of EtOAc and brine. The organic layer was then dried over MgS04 and evaporated to yield 2 g (91%) of the desired intermediate 2-b [ (IS, 2R)-2-hydroxy-3- [ (2-methylpropyl) [ [3- (2-methylpropyl) amino-4- nitrophenyl] sulfonyl] amino]-1-(phenylmethyl) propyl] carbamic acid, 1, 1-dimethylethyl ester, used without other purification in the next step. 2 g of intermediate 2-b were dissolved in 40 mL of methanol, then 1.5 g of ammonium formate and 0.2 g of palladium on charcoal (10%) were added. The reaction mixture was stirred overnight at 60C, then 0.5 g of ammonium formate and 0.2 g of palladium on charcoal were added. After three hours, the mixture was filtered on celite and evaporated. The residue was dissolved in 50 mL of DCM, washed with a solution of Na2CO3 in water, then brine, dried over MgS04 and evaporated to yield 1.3 g (68%) of intermediate 2-c [(1S, 2R)-3-[[4-amino-3-[(2-methylpropyl) amino] phenyl] sulfonyl]- (2-methylpropyl) amino]-2-hydroxy-1-(phenylmethyl) propyl] carbamic acid, 1, 1-dimethylethyl ester, used without other purification in the next step. 1. 3 g of intermediate 2-c was dissolved in 20 mL of ethyl orthoformate. The reaction mixture was stirred at 80C during 5 hours then concentrated. The residue was dissolved in ethyl acetate and washed with a solution of Na2C03 in water. The organic layer was dried over MgS04 and evaporated. The crude compound was purified on silica gel eluting with 0 to 2% methanol in DCM, yielding 0.8 g (70%) of the desired intermediate 2-d [ S, 2R)-2-hydroxy-3-[(2-methylpropyl) [[l-(2-methylpropyl)- benzimidazol-6-yl] sulfonyl] amino]-1-(phenylmethyl) propyl] carbamic acid, 1,1-dimethylethyl ester. 2.6 g of intermediate 2-d was dissolved in 100 mL of HCI 5N in isopropanol. The reaction mixture was stirred at room temperature during 2 hours, then concentrated to yield 2.5 g (94%) of the deprotected amine as an HCI salt, N-[(2R, 3S)-3-amino-2- hydroxy-4-phenylbutyl]-N-(2-methylpropyl)[1-(2-methylpropyl) benzimidazol-6-yl] - sulfonamide, hydrochloride (2-e). 2.5 g of 2-e and 1.5 mL of triethylamine were dissolved in 60 mL of DCM. 3.05 g of 1-[[(3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl] oxycarbonyloxy] -2,5- pyrrolidinedione were then added and the reaction mixture was stirred at room temperature during 4 hours. The reaction mixture was then washed with a solution of Na2CO3 in water, then brine, dried over MgS04 and evaporated. The crude compound was purifi...
N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)[1-(phenylmethyl)benzimidazol-6-yl]sulfonamide hydrochloride[ No CAS ]
[ 253265-97-3 ]
[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)[[1-(phenylmethyl)benzimidazol-6-yl]sulfonyl]amino]-1-(phenylmethyl)propyl]carbamic acid [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl] ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With triethylamine; In dichloromethane; at 20℃; for 4h;
Example 3; Preparation of Compound 1; Compound 1; 54 mg of intermediate D-2 (PG = Boc) were dissolved in 20 mL of THF and 11 mg of benzylamine were added. The reaction mixture was stirred at reflux during 4 hours, then concentrated. The crude compound was purified on silica gel eluting with 10% ethylacetate in hexane, yielding 60 mg of intermediate 3-a [(lS, 2R)-2-hydroxy-3-[(2- methylpropyl) [ [4-nitro-3- [ (phenylmethyl) amino] phenyl] sulfonyl] amino]-1-(phenyl- methyl) propyl] carbamic acid, 1, 1-dimethylethyl ester. 60 mg of intermediate 3-a was dissolved in 20 mL of methanol. The reaction mixture was then hydrogenated in the presence of 25 mg of palladium on charcoal (10%), at room temperature, overnight. After filtration of the catalyst, the reaction mixture was concentrated to give the intermediate 3-b [(1S,2R)-3-[[[4-amino-3-[(phenylmethyl)- amino] phenyl] sulfonyl] (2-methylpropyl) amino]-2-hydroxy-1-(phenylmethyl) propyl] - carbamic acid, 1,1-dimethylethyl ester which was used in the next step without further purification. 59 mg of intermediate 3-b was dissolved in 20 mL of methylorthoformate. The reaction mixture was stirred at 80C during 5 hours then concentrated. The residue was dissolved in ethyl acetate and washed with a solution of Na2C03 in water. The organic layer was dried over MgS04 and evaporated to give the intermediate 3-c [(1S, 2R)- 2-hydroxy-3- [ (2-methylpropyl) [ [ 1- (phenylmethyl) benzimidazol-6-yl] sulfonyl] amino] - l- (phenylmethyl) propyl] carbamic acid, 1, 1-dimethylethyl ester which was used in the next step without further purification. 500 mg of intermediate 3-c was reacted with 15 mL of HCI 5N in isopropanol at room temperature during 2 hours. The reaction mixture was then concentrated to give the intermediate 3-d as an HCI salt N- [ (2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl]-N- (2-methylpropyl) [l- (phenylmethyl) benzimidazol-6-yl] sulfonamide, hydrochloride which was used in the next step without further purification. 500 mg of the previous intermediate 3-d and 85 mg of triethylamine were dissolved in 10 mL of DCM. 271 mg of 1-[[(3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl] oxy- carbonyloxy]-2, 5-pyrrolidinedione were then added and the reaction mixture was stirred at room temperature during 4 hours. The reaction mixture was evaporated and the crude compound was purified on silica gel eluting with 5% methanol in DCM, yielding 236 mg (35%) of the desired final compound [(1S,2R)-2-hydroxy-3-[(2- methylpropyl) [ [1- (phenylmethyl) benzimidazol-6-yl] sulfonyl] amino]-1-(phenylmethyl)- propyl] carbamic acid, [(3R,3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl] ester (compound 1).
N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)[2-methyl-1-(phenylmethyl)benzimidazol-6-yl]sulfonamide hydrochloride[ No CAS ]
[ 253265-97-3 ]
[(1S,2R)-2-hydroxy-3-[[[[2-methyl-1-(phenylmethyl)]benzimidazol-6-yl]sulfonyl](2-methylpropyl)amino]-1-(phenylmethyl)propyl]carbamic acid [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl] ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With triethylamine; In dichloromethane; at 20℃; for 2h;
Example 4; Preparation of Compound 2; Compound 2; 59 mg of intermediate F-2 (PG = Boc, R, 3 = benzyl) and 10 mg of acetic acid were stirred in 5 ml of dioxane/5 ml of 5N HC1 for the weekend at 110C. After cooling, EtOAc was added and the reaction was poured onto a mixture of ice, saturated NaHC03 solution and EtOAc. After extraction with EtOAc, the organic layer was dried and evaporated under reduced pressure to give the intermediate 4-a [ (lS, 2R)-2- hydroxy-3-[[[[2-methyl-1-(phenylmethyl)] benzimidazol-6-yl] sulfonyl] (2-methyl propyl) amino]-l-(phenylmethyl) propyl] carbamic acid, 1,1-dimethylethyl ester which was used in the next step without further purification. 500 mg of intermediate 4-a was reacted with 15 mL of HCI 5N in isopropanol at room temperature during 2 hours. The reaction mixture was then concentrated to give intermediate 4-b as an HC1 salt N-[(2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl]-N- (2-methylpropyl) [[2-methyl-1-(phenylmethyl)] benzimidazol-6-yl] sulfonamide, hydrochloride which was used in the next step without further purification. 510 mg of intermediate 4-b, 271 mg of 1-[[(3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3- yl] oxycarbonyloxy]-2, 5-pyrrolidinedione and 85 mg of triethylamine, were mixed in 30 mL of DCM. The reaction mixture was stirred during 2 hours at room temperature, washed with water then evaporated. The crude compound was purified on silica gel eluting with 5% methanol in DCM, yielding 165 mg (25%) of the final compound [ S, 2R)-2-hydroxy-3-[[[[2-methyl-1-(phenylmethyl)] benzimidazol-6-yl] sulfonyl]- (2-methylpropyl) amino]-1-(phenylmethyl) propyl] carbamic acid, [ (3R, 3aS, 6aR) - hexahydrofuro [2,3-b] furan-3-yl] ester (Compound 2).
N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)(1-methylbenzimidazol-5-yl)sulfonamide[ No CAS ]
[ 253265-97-3 ]
[(1S,2R)-3-[[(1-methylbenzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl] ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
With triethylamine; In dichloromethane; at 20℃; for 48h;
Example 6; Preparation of Compound 64; Compound 64; A mixture of 34.20 g of intermediate C-1 (PG = dibenzyl, R4 = isobutyl) and 12.48 g of triethylamine in 250 ml of dichloromethane was stirred at 0C. Then 25.16 g of intermediate A-4 was added and the reaction was stirred at room temperature. After 1 hour an extra 3 g of intermediate A-4 was added and the reaction was stirred during weekend. After washing with 5% HCI solution, saturated NaHC03 solution and brine, the organic layer was separated, dried and evaporated to give the intermediate 6-a N- [ (2R, 3S)-3- (dibenzylamino)-2-hydroxy-4-phenylbutyl]-N- (2-methylpropyl) (4-chloro-3-nitrophenyl) sulfonamide which was used in the next step without further purification. A mixture of 11.75 g of intermediate 6-a and 12 ml of methylamine (40 wt% in H2O) in 100 ml of methanol was stirred at room temperature for 24 hours. After evaporation under reduced pressure, the product was washed with H20 and extracted with EtOAc. The organic layer was dried and evaporated under reduced pressure to give the intermediate 6-b N-[(2R, 35)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N- (2-methylpropyl) (4-methylamino-3-nitrophenyl) sulfonamide which was used in the next step without further purification. A mixture of 11.5 g of intermediate 6-b, 2 ml of thiophene in diisopropylether (4%) and I g of palladium on charcoal (10%) in 100 ml of methanol was hydrogenated. After filtering over decalite, the filtrate was evaporated under reduced pressure to give the intermediate 6-c N- 3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N- (2-methylpropyl) (3-amino-4-methylaminophenyl) sulfonamide which was used in the next step without further purification. A mixture of 2 g of intermediate 6-c and 0.23 g of formic acid was stirred in 100 ml of dioxane/100 ml of 5N HCI for 48 hours at 110C. After cooling, EtOAc was added and the reaction was poured onto a mixture of ice, saturated NaHCO3 solution and EtOAc. After extraction with EtOAc, the organic layer was dried and evaporated under reduced pressure. The crude product was purified on silica gel eluting with 1% of methanol in dichloromethane to give 2.23 g of intermediate 6-d N-[(2R, 3S)-3-(dibenzylamino)-2- hydroxy-4-phenylbutyl]-N- (2-methylpropyl) (1, 2-dimethyl benzimidazol-5-yl)- sulfonamide. A mixture of 2.23 g of intermediate 6-d, 1.38 g of ammonium formate and 1.2 g of palladium on charcoal (10%) in 50 ml of ethanol was stirred at 80C for 1.5 hours. After filtering over decalite, the filtrate was evaporated under reduced pressure. The residue was purified by preparative HPLC to give 0.29 g of intermediate 6-e N- [ (2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl]-N- (2-methylpropyl) (1-methyl benzimidazol-5-yl) sulfonamide, with a yield of 18%. A mixture of 0.35 g of intermediate 6-e, 0.22 g of 1- [ [ (3R, 3aS, 6aR)-hexahydrofuro- [2,3-b] furan-3-yl] oxycarbonyloxy]-2, 5-pyrrolidinedione and 0.12 g of triethylamine in 20 ml of dichloromethane was stirred at room temperature for 48 hours. After washing with saturated NaHC03 solution, the organic layer was dried and evaporated under reduced pressure. The residue was purified by preparative HPLC to give 0.105 g of the final compound [ S, 2R)-3-[[(1-methylbenzimidazol-5-yl)sulfonyl] (2-methyl- propyl) amino]-2-hydroxy-1-(phenylmethyl) propyl] carbamic acid, [ (3R, 3aS, 6aR)- hexahydrofuro [2,3-b] furan-3-yl] ester, with a yield of 22% (compound 64).
N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)(2-methylbenzimidazol-5-yl)sulfonamide[ No CAS ]
[ 253265-97-3 ]
[(1S,2R)-2-hydroxy-3-[[(2-methylbenzimidazol-5-yl)sulfonyl](2-methylpropyl)amino]-1-(phenylmethyl)propyl]carbamic acid [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl] ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With triethylamine; In dichloromethane; at 20℃; for 17h;
Example 7; Preparation of Compound 24; Compound 24; 20 g of intermediate D-4 (PG = dibenzyl, R4 = isobutyl) in 400 ml of ammonia in isopropanol was stirred at 120C overnight. After evaporation under reduced pressure, the product was washed with H2O and extracted with dichloromethane. The organic layer was dried and evaporated under reduced pressure to give the intermediate 7-a N- [(2R, 3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl) (4-amino-3-nitrophenyl) sulfonamide which was used in the next step without further purification. A mixture of 20 g of intermediate 7-a, 3 ml of thiophene in diisopropylether (4%) and 2 g of palladium on charcoal (10%) in 150 ml of methanol was hydrogenated. After filtering over decalite, the filtrate was evaporated under reduced pressure to give the intermediate 7-b N-[(2R, 3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N- (2-methylpropyl) (3,4-diaminophenyl) sulfonamide which was used in the next step without further purification. A mixture of 1 g of intermediate 7-b and 0.13 g of acetic acid was stirred in 40 ml of dioxane/40 ml of 5N HCl for 48 hours at 110C. After cooling, EtOAc was added and the reaction was poured onto a mixture of ice, saturated NaHCO3 solution and EtOAc. After extraction with EtOAc, the organic layer was dried and evaporated under reduced pressure to give the intermediate 7-c N-[(2R, 3S)-3-(dibenzylamino)-2-hydroxy-4- phenylbutyl]-N- (2-methylpropyl) (2-methylbenzimidazol-5-yl) sulfonamide which was used in the next step without further purification. A mixture of 1.55 g of intermediate 7-c and 0.4 g of palladium on charcoal (10%) in 20 ml of methanol was hydrogenated. After filtering over decalite, the filtrate was evaporated under reduced pressure. The crude compound was purified on silica gel eluting with 4% of methanol in dichloromethane to give 0.18 g of intermediate 7-d N-[(2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl) (2-methyl- benzimidazol-5-yl) sulfonamide. A mixture of 0.18 g of intermediate 7-d, 0.11 g of 1- [ [ (3R, 3aS, 6aR)-hexahydrofuro- [2,3-b] furan-3-yl] oxycarbonyloxy] -2, 5-pyrrolidinedione and 46 mg oftriethylamine in 20 ml of dichloromethane was stirred at room temperature for 17 hours. After washing with saturated NaHC03 solution, the organic layer was dried and evaporated under reduced pressure. The residue was purified on silica gel eluting with 2% of methanol in dichloromethane to give 0.22 g of the final compound [(lS, 2R)-2-hydroxy-3-[[(2- methylbenzimidazol-5-yl) sulfonyl] (2-methylpropyl) amino]-1-(phenylmethyl) propyl] - carbamic acid, [ (3R, 3aS, 6aR)-hexahydrofuro [2,3-b] furan-3-yl] ester with a yield of 89% (compound 24).
N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)[1-[2-(pyrrolidin-1-yl)ethyl]benzimidazol-6-yl]sulfonamide[ No CAS ]
[ 253265-97-3 ]
[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[[(1-[2-(pyrrolidin-1-yl)ethyl]benzimidazol-6-yl)sulfonyl](2-methylpropyl)amino]propyl]carbamic acid [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl] ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
With triethylamine; In dichloromethane; at 20℃; for 4h;
Example 8; Preparation of compound 20; Intermediate F-5; 37 g of intermediate F-5 (PG = dibenzyl, PG'= boc, R4 = isobutyl) and 6.5 g of triethylamine were mixed in 100 mL of DCM. 26.2 g of Boc2O were then added at 0C, then the reaction mixture was heated at 50C during 2 days and evaporated to give 49 g of the desired intermediate 8-a [4-[[[(2R, 359-3-(dibenzylamino)-2-hydroxy-4- phenylbutyl] (2-methylpropyl) amino] sulfonyl]-2-nitrophenyl] carbamic acid, 1,1-dimethylethyl ester, used without further purification in the next step. 42 g of 8-a were dissolved in 500 mL of methanol and hydrogenated in the presence of palladium on charcoal (10%) and thiophene. The reaction mixture was then evaporated and purified on silica gel eluting with DCM, yielding 30 g (75%) of intermediate 8-b [2-amino-4-[[[(2R,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl] (2-methylpropyl) - amino] sulfonyl] phenyl] carbamic acid, 1,1-dimethylethyl ester. Compound 20 1.44 g of intermediate 8-b, 284 mg of chloroacetyl chloride and 262 mg of triethyl- amine were mixed in 20 mL of DCM at 0C. The reaction mixture was then stirred at room temperature overnight, then washed with water, dried over MgSO4 and evaporated to yield 1.5 g of intermediate 8-c [2-(chloroacetylamino)-4-[[[(2R,3S)-3- (dibenzylamino) -2-hydroxy-4-phenylbutyl] (2-methylpropyl) amino] sulfonyl] phenyl] carbamic acid, 1,1-dimethylethyl ester, used without further purification in the next step. 800 mg of 8-c and 298 mg of pyrrolidine were mixed in 10 mL of THF. The reaction mixture was stirred at room temperature overnight and evaporated. The residue was treated with a mixture of water and DCM. The organic phase was dried over MgS04 and evaporated to yield 920 mg of intermediate 8-d [4-[[[(2R,3S)-3-(dibenzylamino)-2- hydroxy-4-phenylbutyl] (2-methylpropyl) amino] sulfonyl]-2-[[(pyrrolidin-1-yl) acetyl]- amino] phenyl] carbamic acid, 1,1-dimethylethyl ester, used without further purification in the next step. 920 mg of the previous intermediate 8-d and 1.3 g of acid trifluoroacetic were mixed in 10 mL of DCM. The reaction mixture was stirred at room temperature overnight, then a saturated solution of NaHC03 in water was added. The organic layer was separated and evaporated to yield 790 mg of intermediate 8-e [2-amino-5-[[[(2R,3S)-3-(dibenzyl- amino) -2-hydroxy-4-phenylbutyl] (2-methylpropyl) amino] sulfonyl] phenyl]-(pyrrolidin- 1-yl) acetamide, used without further purification in the next step. 790 mg of the previous intermediate 8-e was dissolved in 10 mL of THF. 129 mg of LiAIH4 was then added and the reaction mixture was stirred at reflux during 3 hours. 2 mL of water and 2 mL of a 20% solution of NaOH in water were then added to the reaction mixture, which was filtered over decalite and evaporated to yield 780 mg of intermediate 8-f N-[(2R, 3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N- (2-methylpropyl) [4-amino-3- [2- (pyrrolidin-1-yl) ethylamino] phenyl] sulfonamide, used without further purification in the next step. 780 mg of the previous intermediate 8-f and 30 mL of HCI 5N in isopropanol were mixed in 30 mL of dioxane. 2 mL of formic acid were then added and the reaction mixture stirred at 100C during 4 hours. After cooling to room temperature, EtOAc was added and, while maintaining a vigourous stirring, solid K2C03 was added to neutralize the reaction mixture. The organic layer was then separated and evaporated to yield 850 mg of intermediate 8- N- [ (2, 3)-3- (dibenzylamino)-2-hydroxy-4-phenylbutyl]-N- (2- methylpropyl) [1-[2-(pyrrolidin-1-yl) ethyl] benzimidazol-6-yl] sulfonamide, used without further purification in the next step. 850 mg of the previous intermediate 8-g, ammonium formate and palladium on charcoal (10%) were mixed in 10 mL of ethanol. The reaction mixture was heated at 80C and stirred during 2 hours, then filtered on decalite and purified on silica gel, yielding 320 mg of the deprotected compound 8-h N-[(2R, 3S)-3-amino-2-hydroxy-4- phenylbutyl]-N-(2-methylpropyl) [l-[2-(pyrrolidin-1-yl) ethyl] benzimidazol-6-yl]- sulfonamide. 320 mg of the previous intermediate 8-h, 169 mg of 1-[[(3R,3aS,6aR)-hexahydrofuro- [2,3-b] furan-3-yl] oxycarbonyloxy] -2, 5-pyrrolidinedione and 70 mg of triethylamine were mixed in 10 mL of DCM. The reaction mixture was stirred at room temperature for 4 hours, evaporated and purified on silica gel eluting with 8% ammonia in DCM, yielding 112 mg (27%) of the desired final compound [(lS, 2R)-2-hydroxy-1-(phenyl- methyl)-3-[[[1-[2-(pyrrolidin-1-yl) ethyl] benzimidazol-6-yl] sulfonyl] (2-methylpropyl)- amino] propyl] carbamic acid, [ (3R, 3aS, 6aR)-hexahydro furo [2,3-b] furan-3-yl] ester (compound 25).
With triethylamine; In dichloromethane; at 20℃; for 2h;
Example 9; Preparation of compound 40; To 1.5 g of intermediate F-5 (PG, PG'= Boc, R4 = isobutyl) dissolved in 25 mL of DCM, were added 321 p. L of phenylacetaldehyde and 1.06 g of sodium triacetoxyboro- hydride. The mixture was stirred at room temperature overnight, then washed with a saturated solution of Na2CO3 in water, then brine, dried over MgS04 and evaporated to give 2.1 g (100%) of intermediate H-5' (= H-5 wherein PG, PG'= boc, R4 = isobutyl, R13 is phenylethyl) as an orange oil. 2.1 g of intermediate H-5'were dissolved in 50 mL of dioxane and reacted with 100 mL of HCI 7N in isopropanol, at room temperature, for 16 hours. The reaction mixture was then evaporated and treated with a mixture of DCM and a saturated solution of Na2CO3 in water, dried over MgS04 and evaporated to give 1.4 g of crude intermediate which was used directly in the next step. 1.4 g of the previous intermediate, 677 mg of 1-[[(3R,3aS,6aR)-hexahydrofuro- [2,3-b] furan-3-yl] oxycarbonyloxy] -2, 5-pyrrolidinedione and 250 mg of triethylamine were mixed in 25 mL of DCM. The reaction mixture was stirred at room temperature for 2 hours, evaporated and purified on silica gel eluting with 5% methanol in DCM, yielding 900 mg (56%) of the desired compound 1-7' (= I-7 wherein Ri3 is phenyl- ethyl, R1-L is 1-[[(3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl] oxycarbonyl], R4 is isobutyl). 800 mg of intermediate 1-7"and 428 mg of thiocarbonyl diimidazole were dissolved in 10 mL of THF. After stirring at room temperature for 16 hours, 215 mg of thiocarbonyl diimidazole were added to the mixture. After 16 hours, the reaction mixture was evaporated and purified on silica gel eluting with 5% methanol in DCM, yielding 350 mg (41%) of the desired compound J-7' (= J-7 wherein wherein R 13 is phenylethyl, RI-L is 1-[[(3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl] oxycarbonyl], R4 is isobutyl) To 350 mg of intermediate J-7'were added 31 uL of MeI and 69 mg of K2CO3 in 5 mL of DMF. The mixture was stirred at room temperature for 1 hour, then evaporated, dissolved in DCM and washed with brine, dried over MgS04 and evaporated to yield 360 mg (100%) of intermediate K-7' (= K-7 wherein Rl3 is phenylethyl, Rs-L is 1- [ [ (3R, 3aS, 6aR)-hexahydrofuro [2,3-b] furan-3-yl] oxycarbonyl], R4 is isobutyl, R is methyl) which was used without further purification in the next step. 360 mg of intermediate K-7'and 122 mg of mCPBA were dissolved in 5 mL of DCM and stirred at room temperature for 2 hours. 100 mg of mCPBA were then added to the mixture which was stirred for another hour, then washed with a saturated solution of Na2CO3 in water, then brine, dried over MgS04 and purified on silica gel eluting with 1% methanol in DCM, yielding 140 mg (38%) of the desired intermediate L-7' (= L-7 wherein wherein R, 3 is phenylethyl, R1-L is 1-[[(3R,3aS,6aR)-hexahydrofuro [2,3-b]- furan-3-yl] oxycarbonyl], R4 is isobutyl). To 140 mg of intermediate L-7'dissolved in 10 mL of acetonitrile were added 1 mL of 1-(2-Aminoethyl) pyrrolidine. The reaction mixture was stirred 48 hours under reflux, then evaporated and purified by preparative HPLC, yielding 60 mg (40%) of the desired final compound 40 [(1S,2R)-2-hydroxy-3-[[[[1-(phenethyl)-2-[2-(pyrrolidin-1- yl) ethylamino]] benzimidazol-6-yl] sulfonyl] (2-methylpropyl) amino]-1-(phenylmethyl) propyl] carbamic acid, [ (3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl] ester. Mass spectral data: m/z = 789 (M+H).
1-benzyl-3-(benzyloxycarbonyl-isobutyl-amino)-2-hydroxy-propyl-amine[ No CAS ]
[ 253265-97-3 ]
[ 865105-52-8 ]
Yield
Reaction Conditions
Operation in experiment
96.4%
With triethylamine; In dichloromethane; at 20℃; for 24h;
[1 -Benzyl-3-(benzyloxycarbonyl-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester (5); A solution of 1-benzyl-3-(benzyloxycarbonyl-isobutyl-amino)-2-hydroxy-propyl- ammonium chloride (4) (29.70 g, 72.90 mmol, 1 equiv), triethylamine (22.00 g, 220 mmol, 3 equiv) and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro- furo[2,3-b]furan-3-yl ester (19.80 g, 73.00 mmol, 1 equiv) in 120 imL of dichlomethane were stirred at ambient temperature. Due to the incompleteness of the reaction, carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester (5.00 g, 18.43 mmol) was added to the solution. The solution was stirred at room temperature for 24 h. The solution was washed twice with 300 mL of water and once with 300 mL of saturated NaHCO3 solution. The organic layer was dried on MgSO4, <n="21"/>filtered, and evaporated to dryness to obtain the desired product as a white solid. (37.04 g, 70.34 mmol, 96.4%). LRMS(ES+): m/z 527 [M+H]+.
With N-ethyl-N,N-diisopropylamine; In dichloromethane;
(3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-isobutyl-carbamic acid benzyl ester 16 (7.54 g, 15 mmol) and 35 ml of 4M HCl in dioxane were stirred 30 min under an argon atmosphere. The mixture was concentrated in vacuo, and co-evaporated twice with dichloromethane. The residue was dissolved in dichloromethane (50 ml) and N,N-diisopropylethylamine (6.1 ml, 35 mmol), and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester 17 (4.88 g, 18 mmol) was added. The reaction mixture was stirred overnight, and then concentrated in vacuo. The residue was diluted with dichloromethane, and sequentially washed with brine, 10% KHSO4, brine, saturated NaHCO3, and brine, then dried over MgSO4, and concentrated in vacuo. The oily residue was purified by flash chromatography using 70:30 ethyl acetate hexane as eluant, to give [3-(Hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-2-hydroxy-4-phenyl-butyl]-isobutyl-carbamic acid benzyl ester 18 (5.8 g, 73%) as a white solid. TLC: Rf 0.56 (7:3 ethyl acetate:hexane). MS 527 (MH)+. Related procedure: Ghosh, et al. BMCL 687 (1998).
5.8 g
With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 0.5h;Inert atmosphere;
[(2R,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl](2-methylpropyl)-carbamic acid, phenylmethyl ester 2 (7.54 g, 15 mmol) and 35 ml of 4M HCl in dioxane were stirred 30 min under an argon atmosphere. The mixture was concentrated in vacuo, and co-evaporated twice with CH2Cl2. The residue [MS m/z 371.4 (MH)+] was dissolved in CH2Cl2 (50 ml) and DIPEA (6.1 ml, 35 mmol), and carbonic acid 2,5-dioxo-1-pyrrolidinyl-carbonic acid, [(3R,3aS,6aR)- hexahydrofuro[2,3-b]furan-3-yl] ester 3 (CAS 253265-97-3)2,iv (4.88 g, 18 mmol) was added. The reaction mixture was stirred overnight, and then concentrated in vacuo. The residue was diluted with CH2Cl2, and sequentially washed with brine, 10% KHSO4, brine, sat. NaHCO3, and brine, then dried over MgSO4, and concentrated in vacuo. The oily residue was purified by flash chromatography using 70:30 EtOAc/ hexane as eluant, to give [(2R,3S)-3-[[[[(3R,3aS,6aR)-hexahydrofuro [2,3-b]furan-3-yl]oxy]carbonyl]amino]-2-hydroxy-4-phenylbutyl](2-methylpropyl)-carbamic acid, phenylmethyl ester 4 (5.8 g, 73%) as a white solid.12 MS m/z 527.4 (MH)+.
{1-benzyl-2-hydroxy-3-[isobutyl-(3-methyl-1H-indazole-5-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dichloromethane;
{1-Benzyl-2-hydroxy-3-[isobutyl-(3-methyl-1H-indazole-5-sulfonyl)-amino]-propyl}-carbamic acid tert-butyl ester (25 mg, 0.047 mmol) was added to a solution of 4N HCl in dioxane (0.25 mL). Material precipitated out so 800 uL conc. HCl was added and the reaction heated at reflux for 2 h. The resulting solution was concentrated under vacuum and concentrated 2 additional times from 1 mL methylene chloride. This crude amine was dissolved in 0.5 mL methylene chloride and diisopropylethylamine (80 uL, 0.46 mmol) was then added. To this solution was added carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester (16 mg, 0.055 mmol) and the reaction stirred overnight. The reaction was concentrated under vacuum and purified by preparative HPLC. MS 587 (MH+).
{(1S,2R)-3-[(3-amino-benzo[d]isoxazole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid (3R,3aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With triethylamine; In dichloromethane; at 20℃;
500mg of d-2 was stirred at RT in 50 ml dichloromethane and 0. 18 ml (1.30 mmol) triethylamine. Then d-1 was added and the mixture was stirred overnight at RT. The mixture was washed with a sodium bicarbonate solution, the organic layer was separated, dried with magnesiumsulfate, filtered and the solvent evaporated. Purification on silica (Dichloromethane/Methanol 98/2) yielded 300 mg of compound 1 (45% yield)
1-benzyl-3-(benzyloxycarbonyl-isobutyl-amino)-2-hydroxy-propyl-ammonium chloride[ No CAS ]
[ 253265-97-3 ]
[ 865105-52-8 ]
Yield
Reaction Conditions
Operation in experiment
96.4%
A solution of 1-benzyl-3-(benzyloxycarbonyl-isobutyl-amino)-2-hydroxy-propyl- ammonium chloride (4) (29.70 g, 72.90 mmol, 1 equiv), triethylamine (22.00 g, 220 mmol, 3 equiv) and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo- [2,3 b]furan-3-yl ester (19.80 g, 73.00 mmol, 1 equiv) in 120 ml. of dichlomethane were stirred at ambient temperature. Due to the incompleteness of the reaction, carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester (5.00 g, 18.43 mmol) was added to the solution. The solution was stirred at room temperature for 24 h. The solution was washed twice with 300 ml. of water and once with 300 ml. of saturated NaHCtheta3 solution. The organic layer was dried on MgSO4, filtered, and evaporated to dryness to obtain the desired product as a white solid. (37.04 g, 70.34 mmol, 96.4%). LRMS(ES+): m/z 527 [M+H]+.
A solution of above amine 4 (74 mg, 0.151 mmol) in a mixture of 30% trifluoroacetic acid in CH2Cl2 (10 mL) was stirred 23 0C for 40 min. After this period, the reaction mixture was concentrated under reduced pressure and the residue was redissolved in CH2Cl2 (1O mL). To this solution were added(3i?,3aS',6ai?)-3-Hydroxyhexahydrofuro[2,3-b]furanyl succinimidyl carbonate 71> 2 (45 mg, 0.17 mmol) and triethylamine (155 muL, 1.51 mmol). The resulting mixture was stirred at 23 0C for 3 h. The reaction mixture was then concentratated reduced pressure and the residue was purified by column chromatography over silica gel (2% MeOH in CHCl3 as the eluent) to provide compound 6b (75 mg, 89%) as a white amorphous solid. 1H-NMR (500 MHz, CDCl3) delta 0.81 (d, 3H, J = 6.6 Hz), 0.90 (d, 3H, J = 6.6 Hz), 1.42-1.46 (M, IH), 1.57-1.65 (m, IH), 1.79-1.85 (m, IH), 2.75-2.81 (m, 2H), 2.87-2.98 (m, 3H), 3.05-3.16 (m, 2H), 3.64-3.71 (m, 2H), 3.82-3.88 (m, 3H), 3.92-3.96 (m, IH), 4.97-5.01 (m, 2H), 5.63 (d, IH, J = 5.14 Hz), 6.67 (d, 2H, J = 8.6 Hz), 7.18-7.28 (m, 5H), 7.53 (d, 2H, J = 8.6 Hz).
With triethylamine; In dichloromethane; at 20℃; for 6h;
Amine 70 (48 mg, 0.12 mmol), 7 (39 mg, 0.14 mmol),Et3N (2 equiv.), in methylene chloride (1 mL), were allowed to stirr for 6 hours at room temperature. Then the reaction mixture was diluted with methylene chloride (10 mL) and the organic layer washed with brine (2x20 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated. Purification of the resulting crude by flash silica gel chromatography provided the title compound 74 (44 mg) as solid. 1H-NMR (CDC13,4OO MHz): delta 7.4 (m, IH), 7.25 (m, 8H), 5.63 (d IH, J=5.16 Hz), 5.46 (m, IH), 5.05 (m, IH), 4.88 (m, IH), 3.8 (m, 6H), 3.61 (m, 2H), 3.2, 3.06, and 2.86 (three m, 6H), 2, 1.8, 1.54-1.78 (three m, 10 H), 0.92 and 0,88 (ABq 6H, J=6.5 Hz)
A solution of above amine 3 (75 mg) in a mixture of 30% trifluoroacetic acid in CH2Cl2 (10 mL) was stirred 23 0C for 40 min. After this period, the reaction mixture was concentrated under reduced pressure and the residue was redissolved in CH2Cl2 (10 mL). To this solution were added (3i?,3aS,6aR)-3- hydroxyhexahydrofuro[2,3-b]furanyl succinimidyl carbonate 7 (45 mg, 0.17 mmol) and triethylamine (155 muL, 1.51 mmol). The resulting mixture was stirred at 23 0C for 3 h. The reaction mixture was then concentrated reduced pressure and the residue was purified by column chromatography over silica gel (2% MeOH in CHCl3 as the eluent) to provide compound 6a (78 mg, 90%) as a white amorphous solid. 1 H-NMR (CDCI3, 400 MHz): deltadelta 7.71 (d, 2H, J=8.5 Hz), 7.29-7.20 (m, 5H), 6.98 (d, 2H, J=7.0 Hz), 5.65 (d, IH, J=5.2 Hz), 5.01 (m, 2H), 3.95-3.82 (m, 7H), 3.69 (m, 2H), 3.0-2.7 (m, 6H), 1.85 (m, IH), 1.64-1.45 (m, 3H), 0.92 (d, 3H, J=6.5Hz), 0.89 (d, 3 H, J=6.6 Hz).
Starting material B (52.5 mg, 0.08 mmol, 1.0 eq) and 1 mL of hydrogen chloride (4M in 1,4-dioxane) were stirred for 20 min. at room temperature under argon. The mixture was concentrated in vacuum, and then co-evaporated twice with CH2Cl2. The residue was dissolved in CH2Cl2 and DIPEA was added until basic. Then C (27 mg, 0.1 mmol, 1.2 eq) and DIPEA (17 mul, 0.1 mmol, 1.2 eq) were added and reaction was stirred over night. The reaction mixture was concentrated in vacuum, diluted with CH2Cl2, washed with 10% aqueous KHSO4, brine, saturated NaHCO3, brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by crystallization from ethyl acetate/hexanes (67% yield).TLC Rf=0.42 (ethyl acetate)MS m/z 700 (M+H)HPLC conditions:Waters column YMC ODS-AQ S-3 120A 3.0×100 mmMobile phase A-water, 0.1% TFAMobile phase B-methanol, 0.1% TFAFlow 0.75 mL/minGradient:0-3 min-20% B3-16 min-20-85% B16-20 min-85% BDetection by UV at 222 nm
With triethylamine; In dichloromethane; at 20℃; for 3.5h;
[108] Synthesis of (3R,3aS,6a/?)-Hexahydrofuro[2,3-Z>]furan-3-yl (2S,3R)-4-(4- amino-N-(isobutyI-d9)-phenylsulfonamido)-3-hydroxy-l-phenylbutan-2- ylcarbamate (109). According to the general methods of Ghosh, AK et al., J Org Chem, 2004, 69:7822-7829, a solution of 14 (0.70 g, 1.75 mmol) and known 2,5- dioxopyrrolidin-l-yl-(3i?,3a5',6a/?)-hexahydrofuro[2,3-]furan-3-yl carbonate (15; see Ghosh, AK et al., J Org Chem, 2004, 69:7822-7829; and Canoy, WL; et al., Org. Lett., 2008, 10(6):l 103-1106) (0.42 g, 1.57 mmol, 0.9 equiv) in dichloromethane (20 mL) is stirred under nitrogen at rt. Triethylamine (0.36 g, 3.5 mmol, 2 equiv) is added and stirring is continued for 3.5 h. The reaction mixture is diluted with dichloromethane (80 mL) and the solution is washed with water (80 mL), brine (80 mL), dried over sodium sulfate and filtered. The solvent is removed under reduced pressure and the crude product is purified by chromatography on silica gel, eluting with 0.8% methanol in dichloromethane to afford Compound 109.
With triethylamine; In N,N-dimethyl-formamide; at 15 - 18℃; for 5h;pH 7 - ~ 8;Industry scale;
5) Preparation of compound (5); Compound (4) retained in the reactor from the previous stage was dissolved in 20.4 kg of dimethylformamide, 3.9 kg triethylamine was added to provide a pH of 7~8, then 3.3 kg of l-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5- pyrrolidinedione was added to the mixture which was then stirred at 150C- 180C for about 5 hours. Water was slowly added and precipitation was observed. The precipitate was filtered off and the cake was dissolved in 71 kg of chloroform. The aqueous phase was separated off. Chloroform was removed from the organic phase under reduced pressure (<30C/0.085 MPa). Compound (5) was obtained as a white glassy solid (purity: 96.4% by HPLC area, mobile phase:MeCN/l 5mmol/L KH2P(VO.1 %W/VTEA (60/40); retention time: 18.322 min.) and retained in the reactor for the next stage of the process.
Example 35: Synthesis of Compound 7935-1 Compound 79; Amine 35-1 was prepared using the procedures as exemplified for the preparation of Intermediate 28-3. A solution of Intermediate 35-1 (250 mg, 0.39 mmol, 1.0 eq.) and Precursor 24 (150 mg, 0.55 mmol, 1.4 eq.) in DMF (4 mL) was stirred for one hour at room temperature. Water and a saturated aqueous Na2C03 solution were added to the reaction mixture, the precipitate was filtered off and washed with water. The crude product was suspended in boiling acetonitrile and subsequently allowed to cool to room temperature, 236 mg (73%) of Compound 79 was obtained as a white powder.
(S)-3-amino-(S)-2-hydroxy-4-phenyl-1-chlorobutane hydrochloride[ No CAS ]
[ 253265-97-3 ]
[ 1318641-60-9 ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 20℃; for 3h;Inert atmosphere;
2. Compound III from above (125 mg) was added into a pre-dried 25 ml round bottom flask under nitrogen. (2S,3S)-3-amino-l-chloro-2-hydroxy-4-phenylbutane hydrochloride (94 mg), Et3N (0.4 ml), and CH2C12 (20 ml) were added and stirred at ambient temperature for 3 hours, under TLC control. The solvent was then filtered, the organic layer was washed with 5% NaH2P04 (5 ml) and with water (15 ml), then dried over Na2S04, filtered and concentrated to give 120 mg of compound 5 as a white solid. NMR spectrum corresponded to structure.
((2S,3R)-4-(1-acetyl-N-isobutylindoline-5-sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamate[ No CAS ]
[ 253265-97-3 ]
[ 1393348-47-4 ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile;
To tert-butyl ((2S,3R)-4-(1-acetyl-N-isobutylindoline-5-sulfonamido)-3-hydroxy-1- phenylbutan-2-yl)carbamate 13 (24 mg, 0.043 mmol) in dioxane (0.20 ml) was added concentrated HCl (0.15 ml). This mixture was heated at reflux for 1.5 h, concentrated in vacuo, and reconcentrated twice with CH3CN to remove residual HCl. The crude residue was dissolved in CH3CN (0.50 ml) and DIPEA (0.035 ml, 0.20 mmol), and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester (14 mg, 0.052 mmol), stirred overnight, and then concentrated in vacuo. The residue was diluted with CH2Cl2, and sequentially washed with brine, H2O, sat. NaHCO3, and brine again, then dried over Na2SO4, and concentrated in vacuo to 34 mg oil which was chromatographed on silica gel using 70:30 EtOAc/hexane as eluant, to provide (3R,3aS,6aR)-hexahydro-furo[2,3-b]furan-3-yl ((2S,3R)-3-hydroxy-4-(N- isobutylindoline-5-sulfonamido)-1-phenylbutan-2-yl)carbamate 11 MS m/z 574.3 (MH)+, HPLC 95% pure. 1H NMR (CDCl3) 7.44 (m, 2H), 7.26 (m, 5H), 6.56 (d, J = 6.8, 1H), 5.64 (d, J = 5.2, 1H), 5.00 (m, 3H), 3.65 - 3.94 (m, 10H), 2.75 - 3.15 (m, 8H), 1.80 (m, 1H), 1.67 (m, 1H), 1.47 (m, 1H), 0.95 (d, J = 6.4, 3H), 0.89 (d, J = 6.4, 3H).
[(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.2 g
With triethylamine; In dichloromethane; for 3h;
Triethylamine (0.85 mL) was added to a stirred solution of 4-amino-N-(2R,3S)-(3- amino-2-hydroxy-4-phenyl butyl)-N-isobutylbenzenesulfonamide (0.2 g, 5.1 1 mmol) and dichloromethane (5 mL). Stirring was continued for further 10 minutes at 20C to 25C. (3R,3aS,6aR)-3-Hydroxyhexahydrofuro-[2,3-b]furanylsuccinimyl carbonate (0.42 g, 1.5 mmol) was added to the reaction mixture and the mixture was stirred for 3 hours. The reaction mixture was washed with water (2 x 15 mL), dried over sodium sulfate and concentrated to obtain a residue. The residue was purified by column chromatography using silica gel as stationary phase and dichloromethane-methanol as eluent to obtain the title compound.Yield: 0.2 g
To the mixture of Diamino alcohol monohydrochloride (5 g), methylene chloride (50 ml), DM water (15 ml), 10% w/w aqueous sodium hydroxide solution (5 ml) was added to adjust the pH to 10 at 20-30 C. The organic layer was separated and washed with DM water (10 ml). Methylene chloride extract was dried over anhydrous sodium sulphate and 1 [[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione (3.17 g) was added and cooled to 5-10 C. Thereafter, triethylamine (1.18 g) was added and the temperature of reaction mass was raised to 25-30 C. and stirred at this temperature for 3 h. The reaction mass was washed with 7% w/w aqueous sodium bicarbonate solution (20 ml), followed by DM water (2×15 ml) and then concentrated under reduced pressure at 30-40 C. to obtain Darunavir as viscous oily mass. [0112] Yield: 8 g (Viscous oily mass)
(3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol[ No CAS ]
[ 253265-97-3 ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In acetonitrile; at 24 - 45℃; for 1h;
Example 13 1-[[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl] oxy]carbonyl]oxy]pyrrolidine-2,5-dione Di(N-succinimidyl) carbonate (14.5 g, 0.057 mol) and the oily product (5.0 g, 0.038 mol) obtained in Example 11 were suspended in acetonitrile (61.4 g). To this suspension, triethylamine (6.49 g, 0.064 mol) was added dropwise at 24C. The reaction mixture was heated to 45C and stirred for one hour, and then the solvent was distilled off. To the residue, ethyl acetate (125 mL) and a 20% salt solution (20 mL) were added. After insoluble solids were filtered out, the filtrate was subjected to liquid-liquid extraction. Furthermore, a 20% salt solution (20 mL) was added to the organic layer for phase separation. The organic layer was dried over anhydrous sodium sulfate (15.0 g) and the solvent was distilled off. To the residue thus obtained, tetrahydrofuran and heptane were added to undergo crystallization, providing 6.0 g of the title compound in a pale brownish white crystal (56% yield). The diastereomer ratio ((3R,3aS,6aR) form/(3S,3aS,6aR) form) determined by NMR analysis was 97/3, and the result of the enantiomer excess determined by HPLC was 99.5%ee. HPLC conditions (enantiomer excess): Column: CHIRALPAK IA (250 * 4.6 mm, 5 mum), Mobile phase A: hexane, Mobile phase B: tetrahydrofuran, Flow rate: 0.5 ml/min, Detector: UV 225 nm. 1H-NMR(CDCl3,400MHz)deltappm: 1.93-2.04(m, 1H), 2.12-2.18(m, 1H), 2.84(s, 4H), 3.08-3.16(m, 1H), 3.91-3.97(m, 2H), 4.04(dt, 1H, J=2.4, 8.4 Hz), 4.12(dd, 1H, J=6.0, 9. 6 Hz), 5.25(td, 1H, J=8.4, 5.6 Hz), 5.75(d, 1H, J=4.8 Hz)
A. To a round-bottom flask containing compound 3 (0.327 g, 0.543 mmol) was added 15 mL of 4.0 M HC1 in dioxane. After stirring for 4 h, the reaction mixture was purged with N2(g) to remove excess HCl(g). Once the evolution of HCl(g) ceased, the reaction mixture was concentrated under reduced pressure and dried overnight under high vacuum. The residue was then dissolved in 10 mL of DCM and placed under an inert atmosphere. Triethylamine (0.38 mL, 2.7 mmol) and compound 7 (synthesized as described previously, [1] 0.147 g, 0.543 mmol) were then added, and the reaction mixture was stirred at room temperature overnight. After reacting for 16 h, the reaction was concentrated under reduced pressure, and the product was purified by column chromatography (silica, 5% v/v MeOH in DCM), yielding 8 as a white solid (0.293 g, 82%). 1H NMR (400 MHz, CDC13) delta = 7.94 (d, J = 7.6 Hz, 2H), 7.75 (d, J = 7.6 Hz, 2H), 7.30- 7.26 (m, 2H), 7.22-7.20 (m, 3H), 5.65 (d, J = 5.1 Hz, 1H), 5.04-4.99 (m, 1H), 4.95-4.92 (m, 1H), 3.96 (t, J = 8.2 Hz, 1H), 3.88-3.83 (m, 3H), 3.72-3.68 (m, 2H), 3.63-3.59 (1H), 3.20- 3.14 (m, 1H), 3.09-3.05 (m, 1H), 3.02-2.97 (m, 2H), 2.93-2.87 (m, 1H), 2.83-2.78 (m, 2H), 1.87-1.79 (m, 1H), 1.49-1.43 (m, 1H), 1.36 (s, 12H), 1.26-1.24 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDC13) delta = 155.4, 140.1, 137.5, 135.4, 129.3, 128.6, 126.6, 126.3, 109.3, 84.5, 73.4, 72.7, 70.7, 69.6, 58.0, 55.1, 53.7, 45.3, 35.6, 27.3, 25.8, 24.9, 24.8, 20.1, 19.8; HRMS (ESI) calculated for [C33H5iBN309S]+ (M + NH4+) requires mlz = 676.3431, found 676.3440.
N-((2R,3S)-4-(adamantan-1-yl)-3-amino-2-hydroxybutyl)-N-isobutyl-4-methoxybenzenesulfonamide[ No CAS ]
[ 253265-97-3 ]
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-1-(adamantan-1-yl)-3-hydroxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-butan-2-yl)carbamate[ No CAS ]
N-((2R,3S)-4-(adamantan-1-yl)-3-amino-2-hydroxybutyl)-N-isobutyl-4-aminobenzenesulfonamide[ No CAS ]
[ 253265-97-3 ]
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-1-(adamantan-1-yl)-4-((4-amino-N-isobutylphenyl)-sulfonamido)-3-hydroxybutan-2-yl)carbamate[ No CAS ]
N-((2R,3S)-4-(adamantan-1-yl)-3-amino-2-hydroxybutyl)-N-benzyl-4-methoxybenzenesulfonamide[ No CAS ]
[ 253265-97-3 ]
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-1-(adamantan-1-yl)-4-((N-benzyl-4-methoxyphenyl)-sulfonamido)-3-hydroxybutan-2-yl)carbamate[ No CAS ]
N-((2R,3S)-4-(adamantan-1-yl)-3-amino-2-hydroxybutyl)-4-methoxy-N-phenylbenzenesulfonamide[ No CAS ]
[ 253265-97-3 ]
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-1-(adamantan-1-yl)-3-hydroxy-4-((4-methoxy-N-phenylphenyl)sulfonamido)butan-2-yl)carbamate[ No CAS ]
With triethylamine; In tetrahydrofuran; for 2h;Reflux;
The compounds of formula 1 obtained in Example 3 (3.8g, 0.02mol) was dissolved in 30ml of tetrahydrofuran, was added dropwise to N- hydroxyalkylSuccinimide (2.3g, 0.02mol) in 45ml of tetrahydrofuran was added triethylamine (2.02g, 0.02mol), the addition was complete, reflux, 2 hours reaction, TLC detection material disappeared, water was added to brine and extracted , take the upper concentrated to give 5.4g compound of formula 6-1 in a yield of 99.6%.
Example 3 Preparation of darunavir propionate solvate A 2 L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was charged <strong>[253265-97-3]1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]-carbonyl]oxy)-2,5-pyrrolidinedione</strong> of Formula V (65.6 gms), ethyl acetate (1000 ml) and water (200 ml) at 25 C. to 30 C. To the reaction mass Formula II (100 gms; obtained from Example 1) was added at 25 C. to 30 C. and stirred for about 90-120 minutes at same temperature and the reaction completion was monitored by HPLC. After completion of the reaction, the organic layer and the aqueous layers were separated and the organic layer was washed with 5% aqueous sodium bisulfate solution (2*300 ml; 15 gms of sodium bisulfate+285 ml water) followed by with 10% aqueous potassium carbonate solution (300 ml) and then with water (300 ml) and aqueous sodium chloride solution (300 ml). Aqueous and organic layers were separated and the organic layer was distilled off completely under vacuum at below 40 C. to obtain residue. To the residue, ethyl acetate (25 ml) and propionic acid (1000 ml) was added at temperature 15-20 C. and stirred for about 30 mins at same temperature. The reaction mass was allowed to cool to 0-5 C. and stirred for about 90 mins. Precipitated solid was filtered and washed with chilled propionic acid (50 ml). The wet product was dried at about 45 C. to about 50 C. under reduced pressure to provide the title compound. Yield: 135 gms. HPLC purity: 99.3% Formula II: 0.05% The XRPD is set forth in FIG. 01
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