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【结 构 式】 
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【分子编号】16242 【品名】(2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate 【CA登记号】113826-06-5 |
【 分 子 式 】C10H12O4S 【 分 子 量 】228.26888 【元素组成】C 52.62% H 5.3% O 28.04% S 14.05% |
合成路线1
该中间体在本合成路线中的序号：(VIII)This compound can be prepared by two related ways: 1) The diazotation of L-serine methyl ester (I) with NaNO2 - HCl gives methyl (S)-glycerate (II), which by reaction with 2,2-dimethoxypropane and p-toluenesulfonic acid (or acetone and ZnCl2) is converted to methyl (S)-O-isopropylideneglycerate (III). The reduction of (III) with LiAlH4 in refluxing ether affords (S)-2,3-O-isopropylideneglycerol (IV), which by reaction with tosyl chloride in pyridine is converted to the corresponding tosylate (V). The partial hydrolysis of (V) with HCl in acetone affords (S)-glycerol-1-tosylate (VI), which is finally condensed with 1-phenylpiperazine (VII) in refluxing benzene. 2) The partial hydrolysis of (S)-2,3-epoxypropyl tosylate (VIII) with HCl as before gives the glycerol tosylate (VI), already obtained.
| 【1】 Borsa, M.; Tonon, G.; Malandrino, S. (Dompé Farm. SpA); Optically active compounds with antitussive and central sedative activity, a process for the preparation thereof and compositions containing the same. EP 0147847; US 4699911; US 4764515 . |
| 【2】 Giani, R.; Marione, E.; Melillo, G.; Borsa, M.; Tonon, G.C.; Synthesis and pharmacological screening of new phenylpiperazinepropane derivatives and their enantiomers. Arzneim-Forsch Drug Res 1988, 38, 8, 1139-41. |
| 【3】 Prous, J.; Castaner, J.; LEVDROPROPIZINE < Rec INN >. Drugs Fut 1989, 14, 6, 522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 | |
| (I) | 20915 | methyl (2S)-2-amino-3-hydroxypropanoate | 5680-80-8 | C4H9NO3 | 详情 | 详情 |
| (II) | 20916 | methyl (2R)-2,3-dihydroxypropanoate | C4H8O4 | 详情 | 详情 | |
| (III) | 20917 | methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate | 52373-72-5 | C7H12O4 | 详情 | 详情 |
| (IV) | 12709 | [(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 22323-82-6 | C6H12O3 | 详情 | 详情 |
| (V) | 20919 | [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate | 23788-74-1 | C13H18O5S | 详情 | 详情 |
| (VI) | 20920 | (2R)-2,3-dihydroxypropyl 4-methylbenzenesulfonate | C10H14O5S | 详情 | 详情 | |
| (VII) | 10756 | N-Phenylpiperazine; 1-Phenylpiperazine; Phenyl piperazine | 92-54-6 | C10H14N2 | 详情 | 详情 |
| (VIII) | 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Thermal cyclization of the azidocinnamate (II), obtained from O-benzylsalicylaldehyde (I) by methoxide condensation with ethyl azidoacetate, provides methyl 4-benzyloxyindol-2-carboxylate (III). Debenzylation by catalytic hydrogenolysis and alkylation of the phenol with (2S)-glycidyl tosylate gives the chiral oxirane (IV). Ring opening of (IV) followed by protection of the secondary amine by reaction with di-tert-butyldicarbonate and saponification of the methyl ester gives the key (S)-beta-blocker synthon (V). The required ACE inhibitor svnthon (VIII) is assembled from tert-butyl-N'-benzyloxycarbonyl-(S)-lysinate (VI). Alkylation of the alpha-amino group with the triflate of methyl (R)-lactate and saponification of the methyl ester gives N-[5-benzyloxycarbonylamino-1-(S)-tert-butyloxycarbonylpent-1-yl-(S)-alanine (VII). Condensation of (VII) with tert-butyl-(S)-prolinate. mediated by dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, followed by hydrogenolytic removal of the benzyloxycarbonyl group, provides tert-butyl-N-[5-amino-1-(S)-tert-butyloxycarbonylpent-1-yl]-(S)-alanyl-(S)-prolinate (VIII). Coupling of (V) with (VIII) using dicyclohexylcarbodiimide-1-hydroxybenzotriazole and removal of the tert-butyl protecting groups by acidolysis in trifluoroacetic acid, with ethyl methyl sulfide as a scavenger, gives crude BW-8385C as the bistrifluoroacetate salt. Purification is achieved by ion exchange chromatography on DE52 cellulose, followed by reverse-phase desalting to provide pure BW-B385C as the zwitterionic trihydrate.
| 【1】 Allan, G.; Hardy, G.W.; BW-B385C. Drugs Fut 1988, 13, 3, 203. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 | |
| 19832 | tert-butyl (2S)-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | ||
| 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 | |
| 32916 | ethyl 2-azidoacetate | 637-81-0 | C4H7N3O2 | 详情 | 详情 | |
| 63428 | 3-methyl-1H-indole | C9H9N | 详情 | 详情 | ||
| (I) | 21874 | 2-(benzyloxy)benzaldehyde | 5896-17-3 | C14H12O2 | 详情 | 详情 |
| (II) | 21875 | methyl (Z)-2-azido-3-[2-(benzyloxy)phenyl]-2-propenoate | C17H15N3O3 | 详情 | 详情 | |
| (III) | 21876 | methyl 4-(benzyloxy)-1H-indole-2-carboxylate | C17H15NO3 | 详情 | 详情 | |
| (IV) | 21877 | methyl 4-[(2R)oxiranylmethoxy]-1H-indole-2-carboxylate | C13H13NO4 | 详情 | 详情 | |
| (V) | 21878 | 4-([(2S)-3-[(tert-butoxycarbonyl)(isopropyl)amino]-2-hydroxypropyl]oxy)-1H-indole-2-carboxylic acid | C20H28N2O6 | 详情 | 详情 | |
| (VI) | 21879 | tert-butyl (2S)-2-amino-6-[[(benzyloxy)carbonyl]amino]hexanoate | C18H28N2O4 | 详情 | 详情 | |
| (VII) | 21880 | (2S)-2-[[(1S)-5-[[(benzyloxy)carbonyl]amino]-1-(tert-butoxycarbonyl)pentyl]amino]propionic acid | C21H32N2O6 | 详情 | 详情 | |
| (VIII) | 21881 | tert-butyl (2S)-1-((2S)-2-[[(1S)-5-amino-1-(tert-butoxycarbonyl)pentyl]amino]propanoyl)-2-pyrrolidinecarboxylate | C22H41N3O5 | 详情 | 详情 | |
| (IX) | 21882 | tert-butyl (2S)-1-((2S)-2-[[(1S)-1-(tert-butoxycarbonyl)-5-([[4-([(2S)-3-[(tert-butoxycarbonyl)(isopropyl)amino]-2-hydroxypropyl]oxy)-1H-indol-2-yl]carbonyl]amino)pentyl]amino]propanoyl)-2-pyrrolidinecarboxylate | C42H67N5O10 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)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4
该中间体在本合成路线中的序号：(XI)Condensation of dibenzosuberenone (I) with sodium 2-chloro-2,2-difluoroacetate (II) in diglyme at 165 C gives 10,11-(difluoromethano)benzosuberone (III), which is reduced with NaBH4 in THF/methanol to yield the corresponding syn-alcohol (IV). Reaction of alcohol (IV) with hot SOCl2 affords a mixture of the syn- and anti-chloro derivatives (V). This mixture (V) is treated with 1-for-mylpiperazine (VI) in refluxing acetonitrile to provide a mixture of syn- and anti-4-[10,11-(difluoromethano)dibenzosuber-5-yl]piperazine-1-carbaldehyde (VI), which is separated by chromatography. The desired anti-isomer (VII) is then treated with KOH in refluxing ethanol/water to give the piperazine derivative (VIII), which is finally condensed with 5-[2(R),3-epoxypropoxy]quinoline (IX) in refluxing isopranol. 5-[2(R),3-Epoxypropoxy]quinoline (IX) is obtained by reaction of 5-hydroxyquinoline (X) with (R)-glycidyl tosylate (XI) by means of NaH in DMF.
| 【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; Bayes, M.; Zosuquidar Trihydrochloride.. Drugs Fut 2003, 28, 2, 125-136. |
| 【2】 Knaus, E.E.; Vo, D.; Wolowyk, M.W.; Synthesis and cardioselective beta-adrenergic antagonist activity of quinolyloxypropanolamines. Drug Des Discov 1992, 9, 1, 69. |
| 【3】 Bruno, N.A.; Nelson, J.T.; Wu, H.; Muehldorf, A.V.; Makra, F.; Cheung, P.; Slate, D.L.; Zutshi, N.; Casey, S.M.; Pfister, J.R.; Methanodibenzosuberylpiperazines as potent multidrug resistance reversal agents. Bioorg Med Chem Lett 1995, 5, 21, 2473. |
| 【4】 Pfister, J.R.; Slate, D.L. (Syntex (USA) LLC); 10,11-Methanodibenzosuberane derivs. used as chemosensitizing agents. EP 0695293; EP 0866063; JP 1996509223; WO 9424107 . |
| 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) | 29151 | 5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone | 2222-33-5 | C15H10O | 详情 | 详情 |
| (II) | 59522 | sodium 2-chloro-2,2-difluoroacetate | C2ClF2NaO2 | 详情 | 详情 | |
| (III) | 56203 | 1,1-difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]cyclohepten-6(1H)-one | C16H10F2O | 详情 | 详情 | |
| (IV) | 56204 | (1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-ol | C16H12F2O | 详情 | 详情 | |
| (V) | 56205 | 6-chloro-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene | C16H11ClF2 | 详情 | 详情 | |
| (VI) | 23801 | 1-piperazinecarbaldehyde; N-Formylpiperazine | 7755-92-2 | C5H10N2O | 详情 | 详情 |
| (VII) | 56206 | 4-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]-1-piperazinecarbaldehyde | C21H20F2N2O | 详情 | 详情 | |
| (VIII) | 56207 | 1-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]piperazine | C20H20F2N2 | 详情 | 详情 | |
| (IX) | 56211 | (2R)oxiranylmethyl 5-quinolinyl ether; 5-[(2R)oxiranylmethoxy]quinoline | C12H11NO2 | 详情 | 详情 | |
| (X) | 23805 | 5-quinolinol | 578-67-6 | C9H7NO | 详情 | 详情 |
| (XI) | 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Alkylation of the sodium salt of 5-nitroguaiacol (I) with allyl bromide (II) gave the allyl ether (III). The methoxy group of (III) was then displaced by NaOH in hot DMSO to produce 2-(allyloxy)-4-nitrophenol (IV), which was further alkylated with (R)-glycidyl tosylate (V), yielding the chiral oxirane (VI). Claisen rearrangement of the allyl ether function of (VI), followed by intramolecular cyclization between the phenol and epoxide groups in hot mesitylene furnished the benzodioxane derivative (VII). Treatment of (VII) with p-toluenesulfonyl chloride afforded tosylate (VIII). Oxidative cleavage of the allyl group of (VIII) with KMnO4 under phase-transfer conditions gave rise to the carboxylic acid (IX). Catalytic hydrogenation of the nitro group of (IX), followed by lactamization of the resultant aminoacid (X) under acidic conditions produced the dioxinoindolone system (XI). Then, nucleophilic displacement of the tosylate group of (XI) with benzylamine (XII) yielded the desired amine, which was finally converted to the corresponding fumarate salt.
| 【1】 Stack, G.P.; Mewshaw, R.E.; Bravo, B.A.; Kang, Y.H. (Wyeth); Dioxino derivs. and their use as dopamine agonists. EP 0771800; JP 1997249671; US 5756532 . |
| 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) | 56181 | sodium 2-methoxy-5-nitrobenzenolate | C7H6NNaO4 | 详情 | 详情 | |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 56182 | allyl 2-methoxy-5-nitrophenyl ether; 2-(allyloxy)-1-methoxy-4-nitrobenzene | C10H11NO4 | 详情 | 详情 | |
| (IV) | 56183 | 2-(allyloxy)-4-nitrophenol | C9H9NO4 | 详情 | 详情 | |
| (V) | 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 |
| (VI) | 56184 | (2R)-2-{[2-(allyloxy)-4-nitrophenoxy]methyl}oxirane; allyl 5-nitro-2-[(2R)oxiranylmethoxy]phenyl ether | C12H13NO5 | 详情 | 详情 | |
| (VII) | 56185 | [(2S)-8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol | C12H13NO5 | 详情 | 详情 | |
| (VIII) | 56186 | [(2R)-8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate | C19H19NO7S | 详情 | 详情 | |
| (IX) | 56187 | 2-[(3R)-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl]acetic acid | C18H17NO9S | 详情 | 详情 | |
| (X) | 56188 | 2-[(3R)-6-amino-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2,3-dihydro-1,4-benzodioxin-5-yl]acetic acid | C18H19NO7S | 详情 | 详情 | |
| (XI) | 56189 | [(2R)-8-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate | C18H17NO6S | 详情 | 详情 | |
| (XII) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The reaction of 5-chloro-2-hydroxybenzaldehyde (I) with the chiral glycidyl tosylate (II) by means of K2CO3 in DMF gives the condensation product (III), which is oxidized with m-chloroperbenzoic acid to formyl ester (IV). The cyclization of (IV) with sodium methoxide in methanol affords the hydroxymethyl benzodioxane (V), which is tosylated with tosyl chloride in pyridine to the tosylate (VI). Finally, this compound is condensed with 1-(2-methoxyphenyl)piperidin-4-ylmethylamine (VII) by means of K2CO3 in refluxing acetonitrile.
| 【1】 Birch, A.M.; Needham, P.L.; Kerrigan, F.; Gill, J.C.; Bradley, P.A.; N-substituted (2,3-dihydro-1,4-benzodioxin-2-yl)methylamine derivatives as D2 antagonists/5HT1A partial agonists with potential as atypical antipsychotic agents. J Med Chem 1999, 42, 17, 3342. |
| 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) | 26408 | 5-chlorosalicylaldehyde; 5-chloro-2-hydroxybenzaldehyde | 635-93-8 | C7H5ClO2 | 详情 | 详情 |
| (II) | 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 |
| (III) | 26409 | 5-chloro-2-[(2R)oxiranylmethoxy]benzaldehyde | C10H9ClO3 | 详情 | 详情 | |
| (IV) | 26410 | 5-chloro-2-[(2R)oxiranylmethoxy]phenyl formate | C10H9ClO4 | 详情 | 详情 | |
| (V) | 26411 | [(2S)-7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol | C9H9ClO3 | 详情 | 详情 | |
| (VI) | 26412 | [(2R)-7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate | C16H15ClO5S | 详情 | 详情 | |
| (VII) | 25196 | [1-(2-methoxyphenyl)-4-piperidinyl]methylamine; [1-(2-methoxyphenyl)-4-piperidinyl]methanamine | C13H20N2O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The protected azidoglycoside derivative (I) is condensed with (R)-glycidol tosylate (II) to produce the glycidyl ether (III). Epoxide opening in (III) with N,N'-dimethyl-1,4-butanediamine (IV) furnishes the diamine-linked bis azidoglycoside (V). The title compound is then obtained by simultaneous reduction of the azido groups and O benzyl groups cleavage in (V) upon catalytic hydrogenation over Pearlman's catalyst.
| 【1】 Liang, C.; Duffield, J.J.; Marby, K.A.; Rabuka, D.; Romero, A.; Sgarbi, P.W.M.; Shue, Y.-K.; Sucheck, J.; Yao, S.; Zhang, Z.; Cheng, M.; Chan, F.K.; Hu, C.; Ng, S.P.; Hwang, S.-B.; The synthesis and biological activity of multivalent aminoglycoside analogues of OPT-11. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1687. |
| 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) | 62185 | (1R,2R,3S,5R,6S)-3,5-diazido-2-{[(2S,3R,4R,5S,6R)-3-azido-6-(azidomethyl)-4,5-bis(benzyloxy)tetrahydro-2H-pyran-2-yl]oxy}-6-(benzyloxy)cyclohexanol | C33H36N12O6 | 详情 | 详情 | |
| (II) | 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 |
| (III) | 62187 | (2R,3R,4R,5S,6R)-3-azido-6-(azidomethyl)-4,5-bis(benzyloxy)-2-({(1R,2R,3S,4R,6S)-4,6-diazido-3-(benzyloxy)-2-[(2R)oxiranylmethoxy]cyclohexyl}oxy)tetrahydro-2H-pyran; (2R,3R,4R,5S,6R)-3-azido-6-(azidomethyl)-5-(benzyloxy)-2-({(1R,2R,3S,4R,6S)-4,6-diazido-3-(benzyloxy)-2-[(2R)oxiranylmethoxy]cyclohexyl}oxy)tetrahydro-2H-pyran-4-yl benzyl ether | C36H40N12O7 | 详情 | 详情 | |
| (IV) | 62188 | N-methyl-N-[4-(methylamino)butyl]amine; N~1~,N~4~-dimethyl-1,4-butanediamine | C6H16N2 | 详情 | 详情 | |
| (V) | 62189 | (1S)-2-{[(1R,2R,3S,5R,6S)-3,5-diazido-2-{[(2R,3R,4R,5S,6R)-3-azido-6-(azidomethyl)-4,5-bis(benzyloxy)tetrahydro-2H-pyran-2-yl]oxy}-6-(benzyloxy)cyclohexyl]oxy}-1-[{4-[((1S)-2-{[(1R,2R,3S,5R,6S)-3,5-diazido-2-{[(2R,3R,4R,5S,6R)-3-azido-6-(azidomethyl | C76H92N26O14 | 详情 | 详情 |