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【结 构 式】

【分子编号】32812

【品名】1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione

【CA登记号】

【 分 子 式 】C11H13NO7

【 分 子 量 】271.22676

【元素组成】C 48.71% H 4.83% N 5.16% O 41.29%

与该中间体有关的原料药合成路线共 5 条

合成路线1

该中间体在本合成路线中的序号:(XI)

The Grignard reaction of vinyloxirane (I) with phenylmagnesium bromide and CuCN in THF gives 4-phenyl-2-buten-1-ol (II), which is submitted to a Sharpless epoxidation with t-BuOOH and Ti(Oi-Pr)4 in dichloromethane in the presence of (-)-diethyl tartrate [(-)-DET] yielding the chiral epoxide (III). The reaction of (III) with Ti(Oi-Pr)2(N3)2 in refluxing benzene affords the 3(S)-azido-4-phenylbutane-1,2(S)-diol (IV), which is epoxidized with 2-acetoxy-2-methylpropionyl chloride (A) and NaOMe in THF to give the chiral azidoepoxide (V). The reaction of (V) with isobutylamine (VI) in hot isopropanol yields the secondary amine (VII), which is condensed with 4-methoxyphenylsulfonyl chloride (VIII) in pyridine affording the sulfonamide (IX). The reduction of the azido group of (IX) with H2 over Pd/C in methanol provides (X) with a primary amino group that is finally condensed with the succinimidinyl carbonate (XI) by means of triethylamine in acetonitrile.

1 Ghosh, A.K.; Kincaid, J.F.; Cho, W.; Walters, D.E.; Krishnan, K.; Hussain, K.A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J.; Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998, 8, 6, 687.
2 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 .
3 Ghosh, A.K.; et al.; Potent HIV protease inhibitors: The development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands. J Med Chem 1993, 36, 16, 2300.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(A) 32808 2-chloro-1,1-dimethyl-2-oxoethyl acetate 40635-66-3 C6H9ClO3 详情 详情
(I) 32805 2-vinyloxirane 930-22-3 C4H6O 详情 详情
(II) 32806 (E)-4-phenyl-2-buten-1-ol C10H12O 详情 详情
(III) 32807 [(2R,3S)-3-benzyloxiranyl]methanol 116949-62-3 C10H12O2 详情 详情
(IV) 14544 (2S,3S)-3-azido-4-phenyl-1,2-butanediol C10H13N3O2 详情 详情
(V) 14547 (1S)-1-[(2S)oxiranyl]-2-phenylethyl azide; (2S)-2-[(1S)-1-azido-2-phenylethyl]oxirane C10H11N3O 详情 详情
(VI) 13306 2-Methyl-1-propanamine; Isobutylamine 78-81-9 C4H11N 详情 详情
(VII) 32809 (2R,3S)-3-azido-1-(isobutylamino)-4-phenyl-2-butanol C14H22N4O 详情 详情
(VIII) 15719 4-methoxybenzenesulfonyl chloride 98-68-0 C7H7ClO3S 详情 详情
(IX) 32810 N-[(2R,3S)-3-azido-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide C21H28N4O4S 详情 详情
(X) 32811 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide C21H30N2O4S 详情 详情
(XI) 32812 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione C11H13NO7 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XI)

The intermediate succinimidinyl carbonate (XI) has been obtained as follows: The reaction of 2,3-dihydrofuran (XII) with N-iodosuccinimide (NIS) and propargyl alcohol (XIII) in dichloromethane gives trans-3-iodo-2-(propargyloxy)tetrahydrofuran (XIV), which is cyclized by means of Bu3SnH and AIBN in hot toluene yielding the methylenic compound (XV). The ozonolysis of (XV) with O3, followed by reduction with NaBH4 in ethanol affords the racemic alcohol (XVI), which is submitted to an enantioselective acylation with Ac2O and lipase 30 to obtain the chiral alcohol (3R,3aS,6aR)-(XVI). Finally, this compound is treated with disuccinimidinyl carbonate and triethylamine in acetonitrile to provide the target intermediate (XI).

1 Ghosh, A.K.; Kincaid, J.F.; Cho, W.; Walters, D.E.; Krishnan, K.; Hussain, K.A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J.; Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998, 8, 6, 687.
2 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(rac)-(XVI) 32815 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol C6H10O3 详情 详情
3R,3aS,6aR-XVI) 32815 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol C6H10O3 详情 详情
(XI) 32812 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione C11H13NO7 详情 详情
(XII) 22766 2,3-dihydrofuran 1191-99-7 C4H6O 详情 详情
(XIII) 16664 Propargyl Alcohol; 2-propyn-1-ol 107-19-7 C3H4O 详情 详情
(XIV) 32813 (2R,3S)-3-iodo-2-(2-propynyloxy)tetrahydrofuran; (2R,3S)-3-iodotetrahydro-2-furanyl 2-propynyl ether C7H9IO2 详情 详情
(XV) 32814 (3aS,6aR)-3-methylenehexahydrofuro[2,3-b]furan C7H10O2 详情 详情

合成路线3

该中间体在本合成路线中的序号:(X)

The mixed carbonate ester intermediate (X) has been obtained as follows: The reaction of dihydrofuran (I) with propargyl alcohol (II) and N-iodosuccinimide (NIS) gives the propargyl ether (III), which is cyclized by means of tributyltin hydride and AIBN in refluxing toluene to yield the perhydrofuro[2,3-b]furan (IV). The oxidation of the methylene group of (IV) with ozone in methanol/dichloromethane affords the bicyclic ketone (V), which is reduced with NaBH4 in ethanol to provide racemic (VI). The digestion of (rac)-(VI) with immobilized lipase 30 and acetic anhydride in DME provides a mixture of the (3R)-alcohol (VII) and the (3S)-acetoxy derivative (VIII) that is separated by chromatography. Finally, the (3R)-(VII) alcohol is condensed with disuccinimidyl carbonate (IX) and TEA in acetonitrile to give the target mixed carbonate ester intermediate (X).

1 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI),(VII) 32815 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol C6H10O3 详情 详情
(I) 22766 2,3-dihydrofuran 1191-99-7 C4H6O 详情 详情
(II) 16664 Propargyl Alcohol; 2-propyn-1-ol 107-19-7 C3H4O 详情 详情
(III) 32813 (2R,3S)-3-iodo-2-(2-propynyloxy)tetrahydrofuran; (2R,3S)-3-iodotetrahydro-2-furanyl 2-propynyl ether C7H9IO2 详情 详情
(IV) 32814 (3aS,6aR)-3-methylenehexahydrofuro[2,3-b]furan C7H10O2 详情 详情
(V) 53547 (3aR,6aR)tetrahydrofuro[2,3-b]furan-3(2H)-one n/a C6H8O3 详情 详情
(VIII) 53548 (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl acetate n/a C8H12O4 详情 详情
(IX) 20417 1-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]oxy)-2,5-pyrrolidinedione 74124-79-1 C9H8N2O7 详情 详情
(X) 32812 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione C11H13NO7 详情 详情

合成路线4

该中间体在本合成路线中的序号:(X)

The reaction of butadiene monooxide (XI) with phenylmagnesium bromide (XII) and CuCN in THF gives trans-4-phenyl-2-buten-1-ol (XIII), which is enantioselectively epoxidated with Ti(O-iPr)4, diethyl D-tartrate and tBu-OOH to yield the (2R,3R)-epoxide (XIV). The reaction of (XIV) with Ti(O-iPr)4 and N3-SiMe3 in refluxing benzene affords the chiral azidodiol (XV), which is epoxidated by means of 2-acetoxyisobutyryl chloride (AcBCl) and NaOMe in THF to provide the chiral azidoepoxide (XVI) (1). Opening of the epoxide ring of (XVI) with isobutylamine (XVII) in hot isopropanol gives the secondary amine (XVIII), which is acylated with 4-aminophenylsulfonyl chloride (XIX) and pyridine in dichloromethane to yield the corresponding sulfonamide (XX). The reduction of the azido group of (XX) with H2 over Pd/C in THF/methanol/HOAc affords the expected primary amine (XXI), which is finally condensed with the already reported intermediate (X) in dichloromethane to provide the target carbamate.

1 Ghosh, A.K.; Kincaid, J.F.; Cho, W.; Walters, D.E.; Krishnan, K.; Hussain, K.A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J.; Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998, 8, 6, 687.
2 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 32812 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione C11H13NO7 详情 详情
(XI) 32805 2-vinyloxirane 930-22-3 C4H6O 详情 详情
(XII) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(XIII) 32806 (E)-4-phenyl-2-buten-1-ol C10H12O 详情 详情
(XIV) 53549 [(2R,3R)-3-benzyloxiranyl]methanol n/a C10H12O2 详情 详情
(XV) 14544 (2S,3S)-3-azido-4-phenyl-1,2-butanediol C10H13N3O2 详情 详情
(XVI) 14547 (1S)-1-[(2S)oxiranyl]-2-phenylethyl azide; (2S)-2-[(1S)-1-azido-2-phenylethyl]oxirane C10H11N3O 详情 详情
(XVII) 13306 2-Methyl-1-propanamine; Isobutylamine 78-81-9 C4H11N 详情 详情
(XVIII) 32809 (2R,3S)-3-azido-1-(isobutylamino)-4-phenyl-2-butanol C14H22N4O 详情 详情
(XIX) 53550 4-aminobenzenesulfonyl chloride 98-62-4 C6H6ClNO2S 详情 详情
(XX) 53551 4-amino-N-[(2R,3S)-3-azido-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide n/a C20H27N5O3S 详情 详情
(XXI) 45533 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide C20H29N3O3S 详情 详情

合成路线5

该中间体在本合成路线中的序号:(II)

 

1 Goyvaerts NMF, Wigerinck PTBP, et al.2005. Process for the preparation of (3R,3aS,6aR)-hexahydrofuro [2,3-b] funur-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl) amino}l-benzyl-2-hydroxy-propylcarbamate from l-oxirayl-2-phenylethylcarbamates. W0 2005063770
2 Surleraux DLNG, Tahri A.et aL 2005. Discovery and selection ofTMC114,a next genention HIV-1 protease inhibitor.JMed Chem, 48. 1813~1822
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 44938 tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate C25H35N3O7S 详情 详情
(I) 32815 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol C6H10O3 详情 详情
(II) 32812 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione C11H13NO7 详情 详情
(III) 66218 Carbamic acid,[(1R)-1-(2R)-oxiranyl-2-phenylethyl]-, 1,1-dimethylethyl ester, rel- ;Carbamicacid, (1-oxiranyl-2-phenylethyl)-, 1,1-dimethylethyl ester, (R*,R*)-(à)-;Carbamic acid,(1-oxiranyl-2-phenylethyl)-, 1,1-dimethylethyl ester, (R*,R*)- 98818-34-9 C15H21NO3 详情 详情
(IV) 44417 tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate 160232-08-6 C19H32N2O3 详情 详情
(VI) 45533 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide C20H29N3O3S 详情 详情
Extended Information