|
【结 构 式】 
|
【分子编号】16239 【品名】(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol 【CA登记号】126456-43-7 |
【 分 子 式 】C9H11NO 【 分 子 量 】149.19248 【元素组成】C 72.46% H 7.43% N 9.39% O 10.72% |
合成路线1
该中间体在本合成路线中的序号：(II)1) The reaction of cis-(1S,2R)-indanediol (I) with acetonitrile and concentrated H2SO4 gives cis-(1S,2R)-1-aminoindan-2-ol (II), which is cyclocondensed with 3-phenylpropionyl chloride (III), isopropenyl methyl ether and triethylamine to yield the acetonide amide (IV). The condensation of amide (IV) with (S)-(+)-glycidyl p-toluenesulfonate (V) in the presence of lithium hexamethyldisylazide (LHS) affords the chiral epoxide (VI), which is condensed with 4-(tert-butoxycarbonyl)-N-tert-butylpiperazine-2(S)-carboxamide (VII) in refluxing isopropyl acetate and deprotected with aqueous HCl to give the dihydroxy-diamide (VIII). Finally, this compound is condensed with 3-(chloromethyl)pyridine (IX) by means of triethylamine in DMF. 2) The amide (IV) can also be alkylated with allyl bromide and butyllithium to the pentenyl amide (X), which is diastereoselectively converted to the chiral iodohydrine (XI) by means of N-iodosuccinimide (NIS). Finally, this compound is cyclized in basic medium, yielding the epoxide (VI), already obtained.
| 【1】 Maligres, P.E.; Upadhyay, V.; Rossen, K.; Cianciosi, S.J.; Purick, R.M.; Eng, K.K.; Reamer, R.A.; Askin, D.; Volante, R.P.; Reider, P.J.; Diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides: Synthesis of the Merck HIV-1 protease inhibitor epoxide intermediate. Tetrahedron Lett 1995, 36, 13, 2195-8. |
| 【2】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600. |
| 【3】 Askin, D.; Volante, R.P.; Eng, K.K. (Merck & Co., Inc.); Process for making HIV protease inhibitors. WO 9502584 . |
| 【4】 Verhoeven, T.R.; Roberts, E.F.; Senanayake, C.H.; Ryan, K.M. (Merck & Co., Inc.); Regiospecific processes to make cis-1-amino-2-alkanol from diol or halohydrin. US 5449830 . |
| 【5】 Askin, D.; Eng, K.K.; Rossen, K.; Purick, R.M.; Wells, K.M.; Volante, R.P.; Reider, P.J.; Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524. Tetrahedron Lett 1994, 35, 5, 673-6. |
| 【6】 Dorsey, B.D.; Levin, R.B.; McDaniel, S.L.; et al.; L-735,524: The design of a potent and orally bioavailable HIV protease inhibitor. J Med Chem 1994, 37, 21, 3443-51. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 | |
| 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 | |
| (I) | 16238 | (1S,2R)-2,3-dihydro-1H-indene-1,2-diol | 67528-22-7 | C9H10O2 | 详情 | 详情 |
| (II) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
| (III) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
| (IV) | 16241 | 1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone | C21H23NO2 | 详情 | 详情 | |
| (V) | 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 |
| (VI) | 16243 | (2R)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone | C24H27NO3 | 详情 | 详情 | |
| (VII) | 16244 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | 150323-35-6 | C14H27N3O3 | 详情 | 详情 |
| (VIII) | 16245 | (2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide | C30H42N4O4 | 详情 | 详情 | |
| (IX) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (X) | 16247 | (2S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-penten-1-one | C24H27NO2 | 详情 | 详情 | |
| (XI) | 16248 | (2R,4S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-hydroxy-5-iodo-1-pentanone | C24H28INO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)3) The alkylation of 5(S)-(tert-butyldimethylsilyloxymethyl)tetrahydrofuran-2-one (XII) by means of benzyl bromide (XIII) and lithium diisopropylamide (LDA) gives the corresponding 3(R)-benzyl derivative (XIV), which is deprotected with aqueous HF, yielding the hydroxymethyl compound (XV). The esterification of (XV) with trifluoromethanesulfonic anhydride affords the corresponding triflate (XVI), which is condensed with the chiral piperazine (VII) by means of diisopropylethylamine in isopropanol, giving the substituted furanone (XVII). Ring opening of the furanone (XVII) with LiOH, DME and imidazole yields the substituted hydroxypentanamide (XVIII), which is protected with tert-butyldimethylsilyl chloride to afford the protected amide (XIX). The trans-amidation of (XIX) with 2-hydroxyindan-1-amine (II) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) in DMF gives the protected dihydroxy diamide (XX), which is deprotected with trimethylsilyl triflate, affording the dihydroxy diamide (VII), already obtained. This compound is then alkylated with 3-(chloromethyl)pyridine (IX) as before.
| 【1】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600. |
| 【2】 Vacca, J.P.; Holloway, M.K.; Dorsey, B.D.; Hungate, R.W.; Guare, J.P. (Merck & Co., Inc.); HIV protease inhibitors useful for the treatment of AIDS. EP 0541168; JP 1993279337; WO 9309096 . |
| 【3】 Vacca, J.P.; Guare, J.P.; Dorsey, B.D.; Holloway, M.K.; Hungate, R.W. (Merck & Co., Inc.); HIV protease inhibitors in pharmaceutical combinations for the treatment of AIDS. EP 0617968; JP 1996508496; WO 9422480 . |
| 【4】 Vacca, J.P.; Dorsey, B.D.; Guare, J.P.; Holloway, M.K.; Hungate, R.W.; Levin, R.B. (Merck & Co., Inc.); HIV protease inhibitors useful for the treatment of AIDS. EP 0696277; JP 1996509980; US 5413999; WO 9426717 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
| (VII) | 16244 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | 150323-35-6 | C14H27N3O3 | 详情 | 详情 |
| (VIII) | 16245 | (2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide | C30H42N4O4 | 详情 | 详情 | |
| (IX) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (XII) | 16249 | (5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)dihydro-2(3H)-furanone | C11H22O3Si | 详情 | 详情 | |
| (XIII) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (XIV) | 16251 | (3R,5S)-3-benzyl-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)dihydro-2(3H)-furanone | C18H28O3Si | 详情 | 详情 | |
| (XV) | 16252 | (3R,5S)-3-benzyl-5-(hydroxymethyl)dihydro-2(3H)-furanone | C12H14O3 | 详情 | 详情 | |
| (XVI) | 16253 | [(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]methyl trifluoromethanesulfonate | C13H13F3O5S | 详情 | 详情 | |
| (XVII) | 16254 | tert-butyl (3S)-4-[[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]methyl]-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | C26H39N3O5 | 详情 | 详情 | |
| (XVIII) | 16255 | tert-butyl (3S)-4-[(2S,4R)-5-amino-4-benzyl-2-hydroxy-5-oxopentyl]-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | C26H42N4O5 | 详情 | 详情 | |
| (XIX) | 16256 | tert-butyl (3S)-4-((2S,4R)-5-amino-4-benzyl-2-[[tert-butyl(dimethyl)silyl]oxy]-5-oxopentyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C32H56N4O5Si | 详情 | 详情 | |
| (XX) | 16257 | tert-butyl (3S)-4-((2S,4R)-4-benzyl-2-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C41H64N4O6Si | 详情 | 详情 | |
| (XXI) | 16258 | tert-butyl (3S)-4-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C35H50N4O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Treatment of [U-ring-14C] acetophenone (I) with O-methylhydroxylamine hydrochloride in pyridine/EtOH and catalytic MgSO4 yields labeled acetophenone oxime methyl ether (II), which is then subjected to Didier's enantioselective reduction with BH3·THF and 1S,2R-1-amino-indan-2-ol (III) to provide labeled (S)-(IV). Finally, phenylethylamine (S)-(IV) is coupled to chiral acid (V) with 1-hydroxybenzotriazole hydrate (HOBt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-methylmorpholine (NMM).
| 【1】 Zhang, Y.S.; Synthesis of 14C-labeled S-(-)-1-phenylethylamine and its application to the synthesis of [14C] CI-1021, a potential antiemetic agent(1). J Label Compd Radiopharm 2000, 43, 11, 1087. |
| 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) | 10317 | Acetophenone | 98-86-2 | C8H8O | 详情 | 详情 |
| (I) | 45337 | C8H8O | 详情 | 详情 | ||
| (II) | 44172 | 1-phenyl-1-ethanone O-methyloxime | C9H11NO | 详情 | 详情 | |
| (II) | 45338 | C9H11NO | 详情 | 详情 | ||
| (III) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
| (IV) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (IV) | 45339 | C8H11N | 详情 | 详情 | ||
| (V) | 44173 | (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid | C22H20N2O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Oxidation of L-mannonic gamma-lactone (I) with aqueous nitric acid provided bislactone (II). Subsequent treatment of bislactone (II) with benzyl trichloroacetimidate (III) and trifluoromethanesulfonic acid furnished dibenzyl ether (IV). Then, nucleophilic opening of both lactone groups of (IV) with (1S,2R)-1-amino-2-indanol (V) in refluxing dichloromethane yielded the title bisamide.
| 【1】 Bjorsne, M.; Alterman, M.; Muhlman, A.; et al.; Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors. Use of L-mannaric acid as a peptidomimetic scaffold. J Med Chem 1998, 41, 20, 3782. |
| 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) | 25665 | (3R,4S,5S)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxydihydro-2(3H)-furanone | C6H10O6 | 详情 | 详情 | |
| (II) | 25666 | (3R,3aS,6R,6aS)-3,6-dihydroxytetrahydrofuro[3,2-b]furan-2,5-dione | C6H6O6 | 详情 | 详情 | |
| (III) | 25667 | ethyl 2,2,2-trichloroethanimidoate | 23213-96-9 | C4H6Cl3NO | 详情 | 详情 |
| (IV) | 25668 | (3R,3aS,6R,6aS)-3,6-bis(benzyloxy)tetrahydrofuro[3,2-b]furan-2,5-dione | C20H18O6 | 详情 | 详情 | |
| (V) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(X)The oxidation of the chiral 2(R)-(benzyloxymethyl-4-phenyl-1-butanol (I) with (COCl)2 and TEA in DMSO/dichloromethane gives the corresponding aldehyde (II) , which by a pinacol coupling promoted by VCl3, Zn and 1,3-dimethylimidazolidin-2-one (DMI) in dichloromethane yields the glycol (III) as a mixture of all the possible enantiomers. The protection of the glycol function of (III) by means of 2,2-dimethoxypropane (IV), 2-methoxypropene and CSA in acetone affords the isopropylidene ketal (V), which is debenzylated by hydrogenation with H2 over Pd/C in aq. NaHCO3/EtOAc to provide the hexane-1,6-diol (VI). The oxidation of diol (VI) with RuCl3 and NaIO4 in acetonitrile/water/dichloromethane gives the adipic acid derivative (VII), which is treated with disuccinimidyl carbonate (VIII) to yield the corresponding enantiomeric mixture of activated esters, which is resolved by column chromatography to isolate the (R,R)-activated ester (IX). The reaction of (IX) with (1S,2R)-1-amino-2-indanol (X) in hot dichloroethane (DCE) affords the diamide (XI), which is finally deprotected (elimination of the isopropylidene group) by means of FeCl3.6H2O in dichloromethane to provide the target (R,R,R,R)-dihydroxydiamide.
| 【1】 Muhlman, A.; et al.; Synthesis of novel potent, diol-based HIV-1 protease inhibitors via intermolecular pinacol homocoupling of (2S)-2-benzyloxymethyl-4-phenylbutanal. J Med Chem 2001, 44, 21, 3407. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (R,R)-(III) | 52454 | 1,8-diphenyl-3,6-bis{[(phenylmethyl)oxy]methyl}-4,5-octanediol | C36H42O4 | 详情 | 详情 | |
| (R,S)-(III) | 52455 | 1,8-diphenyl-3,6-bis{[(phenylmethyl)oxy]methyl}-4,5-octanediol | C36H42O4 | 详情 | 详情 | |
| (S,S)-(III) | 52456 | 1,8-diphenyl-3,6-bis{[(phenylmethyl)oxy]methyl}-4,5-octanediol | C36H42O4 | 详情 | 详情 | |
| (I) | 52452 | 4-phenyl-2-{[(phenylmethyl)oxy]methyl}-1-butanol | C18H22O2 | 详情 | 详情 | |
| (II) | 52453 | 4-phenyl-2-{[(phenylmethyl)oxy]methyl}butanal | C18H20O2 | 详情 | 详情 | |
| (IV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (V) | 52457 | 2,2-dimethyl-4,5-bis(3-phenyl-1-{[(phenylmethyl)oxy]methyl}propyl)-1,3-dioxolane; 2-[2,2-dimethyl-5-(3-phenyl-1-{[(phenylmethyl)oxy]methyl}propyl)-1,3-dioxolan-4-yl]-4-phenylbutyl phenylmethyl ether | C39H46O4 | 详情 | 详情 | |
| (VI) | 52458 | C25H34O4 | 详情 | 详情 | ||
| (VII) | 52459 | C25H30O6 | 详情 | 详情 | ||
| (VIII) | 20417 | 1-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]oxy)-2,5-pyrrolidinedione | 74124-79-1 | C9H8N2O7 | 详情 | 详情 |
| (IX) | 52460 | 1-({2-[5-(1-{[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}-3-phenylpropyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-phenylbutanoyl}oxy)-2,5-pyrrolidinedione | C33H36N2O10 | 详情 | 详情 | |
| (X) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
| (XI) | 52461 | C43H48N2O6 | 详情 | 详情 |