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【结 构 式】

【分子编号】32815

【品名】(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol

【CA登记号】

【 分 子 式 】C6H10O3

【 分 子 量 】130.1436

【元素组成】C 55.37% H 7.74% O 36.88%
与该中间体有关的原料药合成路线共 10 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10

合成路线1

该中间体在本合成路线中的序号：(rac)-(XVI)

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).

参考文献 中间体
合成目标
【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2

该中间体在本合成路线中的序号：3R,3aS,6aR-XVI)

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).

参考文献 中间体
合成目标
【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：(VI),(VII)

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).

参考文献 中间体
合成目标
【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：(I)

　

参考文献 中间体
合成目标
【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

合成路线5

该中间体在本合成路线中的序号：(IV)

　

参考文献 中间体
合成目标
【1】 Ghosh AK, ChenY.1995. Synthesis and optical resolution of high affinity P2-Iigands for HIV-1 protease inhibitors Tetrahedron Lett, 36: 505～508
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(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) 32814 (3aS,6aR)-3-methylenehexahydrofuro[2,3-b]furan C7H10O2 详情 详情
(IV) 32815 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol C6H10O3 详情 详情
(XI) 32815 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol C6H10O3 详情 详情

合成路线6

该中间体在本合成路线中的序号：(XI)

　

参考文献 中间体
合成目标
【1】 Ghosh AK, ChenY.1995. Synthesis and optical resolution of high affinity P2-Iigands for HIV-1 protease inhibitors Tetrahedron Lett, 36: 505～508
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(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) 32814 (3aS,6aR)-3-methylenehexahydrofuro[2,3-b]furan C7H10O2 详情 详情
(IV) 32815 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol C6H10O3 详情 详情
(XI) 32815 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol C6H10O3 详情 详情

合成路线7

该中间体在本合成路线中的序号：(VII)

　

参考文献 中间体
合成目标
【1】 Gbosh AK, Kincaid JF. 1996. Nonpeptidal P2 tigands for HIV protease inlubitors: structurebased design,synthesis, and biological evaluationJ Med Chem, 39: 3278-3290
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） 66223 (3S,4R)-4-allyl-5-methoxytetrahydrofuran-3-ol 　 C8H14O3 详情 详情
(I) 66219 (S)-diethyl 2-hydroxysuccinate 　 C8H14O5 详情 详情
(II) 66220 （2R,3S）-diethyl 2-allyl-3-hydroxysuccinate 　 C11H18O5 详情 详情
(III) 66221 (S)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)pent-4-en-1-ol 　 C10H18O3 详情 详情
(IV) 66222 (S)-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)hex-5-en-2-one 　 C11H18O3 详情 详情
(VI) 66224 (3S,4R)-4-(2-hydroxyethyl)-5-methoxytetrahydrofuran-3-ol 　 C7H14O4 详情 详情
(VII) 32815 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol C6H10O3 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XI)

　

参考文献 中间体
合成目标
【1】 Ghosh AK.Leshchenko S,et aL 2004. Stereoselective photOchemical l,3-dioxolane addition to 5-alkoxym-ethyl-2 (5H)-furanome: synthesis of bis-tetrahydrofuranyl ligand for HIV protease inhibitor UIG94017(TMG114).J Org Chem, 69: 7822～7829
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） 66228 (R)-1-(benzyloxy)but-3-en-2-yl acrylate 　 C14H16O3 详情 详情
(I) 17346 Benzyloxyacetaldehyde; 2-(Benzyloxy)acetaldehyde 60656-87-3 C9H10O2 详情 详情
(II) 66225 1-(benzyloxy)but-3-en-2-ol 　 C11H14O2 详情 详情
(III) 66226 (R)-1-(benzyloxy)but-3-en-2-ol 　 C11H14O2 详情 详情
(IV) 66227 (S)-1-(benzyloxy)but-3-en-2-yl acetate 　 C13H16O3 详情 详情
(VI) 66229 (R)-5-((benzyloxy)methyl)furan-2(5H)-one 　 C12H12O3 详情 详情
(VII) 66230 (4R,5R)-5-((benzyloxy)methyl)-4-(1,3-dioxolan-2-yl)dihydrofuran-2(3H)-one 　 C15H18O5 详情 详情
(VIII) 66231 (4R,5R)-4-(1,3-dioxolan-2-yl)-5-(hydroxymethyl)dihydrofuran-2(3H)-one 　 C8H12O5 详情 详情
(IX) 66232 (4R,5R)-4-(1,3-dioxolan-2-yl)-5-(hydroxymethyl)tetrahydrofuran-2-ol 　 C8H14O5 详情 详情
(X) 66233 (3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol 　 C6H10O3 详情 详情
(XI) 32815 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol C6H10O3 详情 详情

合成路线9

该中间体在本合成路线中的序号：(VII)

　

参考文献 中间体
合成目标
【1】 Kesteleyn BRR.Surlenux DLNG.2003.Pmcess for the preparation hexahydro-furo[2,3-b] .furan-3-oL W0 2003022853 。
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） 66237 3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol 　 C9H17NO5 详情 详情
(I) 36759 (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde 15186-48-8 C6H10O3 详情 详情
(II) 66234 (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde 15186-48-8 C6H10O3 详情 详情
(III) 66235 (S,E)-ethyl 3-(2,2-dimethyl-1,3-dioxolan-4-yl)acrylate 64520-58-7 C10H16O4 详情 详情
(IV) 66236 ethyl 3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutanoate 　 C11H19NO6 详情 详情
(VI) 66238 (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol 　 C6H10O3 详情 详情
(VII) 32815 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol C6H10O3 详情 详情

合成路线10

该中间体在本合成路线中的序号：(VI)

　

参考文献 中间体
合成目标
【1】 Kesteleyn BRR, Surleraux DLNG. 2003. Process for the preparation of hexahydro-furo [2,3-b] funrr3-oL. W0 2003022853
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） 66242 (3aR,6aS)-4-methoxytetrahydrofuro[3,4-b]furan-2(3H)-one 　 C7H10O4 详情 详情
(I) 66234 (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde 15186-48-8 C6H10O3 详情 详情
(II) 66239 (S)-dimethyl 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methylene)malonate 　 C11H16O6 详情 详情
(III) 66240 dimethyl 2-(1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-nitroethyl)malonate 　 C12H19NO8 详情 详情
(IV) 66241 (3R,6aS)-methyl 4-methoxy-2-oxohexahydrofuro[3,4-b]furan-3-carboxylate 　 C9H12O6 详情 详情
(VI) 32815 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol C6H10O3 详情 详情
Extended Information