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【结 构 式】 
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【分子编号】16993 【品名】methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 【CA登记号】79-22-1 |
【 分 子 式 】C2H3ClO2 【 分 子 量 】94.49732 【元素组成】C 25.42% H 3.2% Cl 37.52% O 33.86% |
合成路线1
该中间体在本合成路线中的序号：(II)1) By carboxylation of 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyctohepta[1,2-b]pyridine (I) with ethyl chloroformate (II) in refluxing benzene.
| 【1】 Magatti, C.V.; Villani, F.J.; Wong, J.; Poper, T.L.; Vashi, D.B.; N-substituted 11-(4-piperidylene)-5,6-dihydro-11H-. Arzneim-Forsch Drug Res 1986, 36, 9, 1311. |
| 【2】 Magatti, C.V.; Vashi, D.B.; Wong, J.; Poper, T.L.; Villani, F.J.; Derivatives of 10,11-dihydro-5H-dibenzola[a,d]cycl. J Med Chem 1972, 15, 7, 750. |
| 【3】 Villani, F.J. (Schering Corp.); Antihistaminic 11-(4-piperidylidene)-5H-benzo-[5,6. US 4282233 . |
| 【4】 Prous, J.; Castaner, J.; Loratadine. Drugs Fut 1987, 12, 6, 544. |
合成路线2
该中间体在本合成路线中的序号：(II)2) By reaction of 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (III) with the Grignard reagent (IV) to give the tertiary carbinol (V), which is dehydrated with 85% H2SO4 affording 8-chloro-11-piperidinylidene derivative (VI). Finally, cornpound (VI) is treated with ethyl chloroformate (II) in toluene.
| 【1】 Magatti, C.V.; Villani, F.J.; Wong, J.; Poper, T.L.; Vashi, D.B.; N-substituted 11-(4-piperidylene)-5,6-dihydro-11H-. Arzneim-Forsch Drug Res 1986, 36, 9, 1311. |
| 【2】 Magatti, C.V.; Vashi, D.B.; Wong, J.; Poper, T.L.; Villani, F.J.; Derivatives of 10,11-dihydro-5H-dibenzola[a,d]cycl. J Med Chem 1972, 15, 7, 750. |
| 【3】 Villani, F.J. (Schering Corp.); Antihistaminic 11-(4-piperidylidene)-5H-benzo-[5,6. US 4282233 . |
| 【4】 Prous, J.; Castaner, J.; Loratadine. Drugs Fut 1987, 12, 6, 544. |
| 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) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (III) | 16540 | (1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]-1-propanol | C34H36ClNO3 | 详情 | 详情 | |
| (IV) | 20645 | chloro(1-methyl-4-piperidinyl)magnesium | C6H12ClMgN | 详情 | 详情 | |
| (V) | 23553 | 8-chloro-11-(1-methyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol | C20H23ClN2O | 详情 | 详情 | |
| (VII) | 20647 | 8-chloro-11-(1-methyl-4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | 38092-89-6 | C20H21ClN2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The condensation of 1-(tert-butoxycarbonyl)piperidin-2-one (I) with methyl chloroformate (II) by means of LHMDS in THF gives 1-(tert-butoxycarbonyl)-2-oxopiperidine-3-carboxylic acid methyl ester (III), which is transesterified with the chiral auxiliary (IV) by means of DMAP in refluxing toluene to yield the shielded ester (V). The reaction of (V) with phenylselanyl chloride and NaH in THF/HMPA affords the selenide (VI), which is treated with H2O2 to produce an oxidative deselenation to afford the unsaturated ester (VII). The addition of lithium di(4-fluorophenyl)cuprate (VIII) to the asymmetric olefinic amidoester (VII) leads to the addition product (IX). Finally, the reductive cleavage of the chiral auxiliary by reduction with LiAlH4 in refluxing THF produces the simultaneous reduction of the tert-butoxycarbonyl group to afford the target intermediate, the (3S,4R)-4-(4-fluorophenyl-3-(hydroxymethyl)-1-methylpiperidine (X) (see scheme no. 10786004a, intermediate (V)).
| 【1】 Cossy, J.; et al.; A short formal synthesis of paroxetine. Diastereoselective cuprate addition to a chiral racemic olefinic amido ester. Tetrahedron Lett 2001, 42, 44, 7805. |
| 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) | 56469 | tert-butyl 2-oxo-1-piperidinecarboxylate | C10H17NO3 | 详情 | 详情 | |
| (II) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (III) | 56470 | 1-(tert-butyl) 3-methyl 2-oxo-1,3-piperidinedicarboxylate | C12H19NO5 | 详情 | 详情 | |
| (IV) | 56471 | N-(3,5-dimethylphenyl)-N-[(2S,3R)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]benzenesulfonamide | C24H31NO3S | 详情 | 详情 | |
| (V) | 56472 | 1-(tert-butyl) 3-{(2R,3S)-3-[3,5-dimethyl(phenylsulfonyl)anilino]-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl} 2-oxo-1,3-piperidinedicarboxylate | C35H46N2O7S | 详情 | 详情 | |
| (VI) | 56473 | 1-(tert-butyl) 3-{(2R,3S)-3-[3,5-dimethyl(phenylsulfonyl)anilino]-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl} 2-oxo-3-(phenylselanyl)-1,3-piperidinedicarboxylate | C41H50N2O7SSe | 详情 | 详情 | |
| (VII) | 56474 | 1-(tert-butyl) 3-{(2R,3S)-3-[3,5-dimethyl(phenylsulfonyl)anilino]-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl} 2-oxo-5,6-dihydro-1,3(2H)-pyridinedicarboxylate | C35H44N2O7S | 详情 | 详情 | |
| (VIII) | 56475 | C27H25CuF4Li | 详情 | 详情 | ||
| (IX) | 56476 | 1-(tert-butyl) 3-{(2R,3S)-3-[3,5-dimethyl(phenylsulfonyl)anilino]-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl} (3S,4R)-4-(4-fluorophenyl)-2-oxo-1,3-piperidinedicarboxylate | C41H49FN2O7S | 详情 | 详情 | |
| (X) | 56477 | (3R,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methyl-2-piperidinone | C13H16FNO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：The reaction of L-homophenylalanine (XXXIX) with methyl chloroformate, NaHCO3 and NaOH gives N-(methoxycarbonyl)-L-homophenylalanine (XXXI), which is treated with SOCl2 yielding the acyl chloride (XXXII). The cyclization of (XXXII) by means of AlCl3 in dichloromethane affords the chiral tetralone (XXXIII), which is condensed with the aryllithium (or arylmagnesium bromide) (XXXIV) to give the intermediate alcohol (XXXV). Elimination of the OH group of (XXXV) by means of Et3SiH and TFA yields the carbamate (XXXVI) as a 3.6:1 mixture of cis- and trans-isomers, which is reduced with LiAlH4 in refluxing THF providing the secondary amine (XXXVII). The alkylation of (XXXVII) with 2-bromoacetaldehyde dimethylacetal (XXV) by means of KF/Al2O3 in refluxing acetonitrile affords the tertiary amine (XXXVIII), also as a mixture of cis- and trans-isomers. The 1:3 trans/cis ratio of isomers in (XXXVIII) is improved up to 50:1 by treatment with t-BuOK in DMSO/DMF providing the desired trans(1R,2S)-isomer (XXVIII) already reported.
| 【1】 Draper, R.W.; et al.; Novel stereoselective syntheses of the fused benzazepine dopamine D1 antagonist (6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5-H-benzo[d]naphth[2,1-b]azepin-12-ol (Sch 39166): 2. L-homophenylalanine-based syntheses. Org Process Res Dev 1998, 2, 3, 186. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 | |
| (XXXIVb) | 36624 | bromo(4-chloro-3-methoxyphenyl)magnesium | C7H6BrClMgO | 详情 | 详情 | |
| (XXXIVa) | 36646 | (4-chloro-3-methoxyphenyl)lithium | C7H6ClLiO | 详情 | 详情 | |
| (XXV) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (XXVIII) | 63422 | (2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)-N-methylamine | C22H28ClNO3 | 详情 | 详情 | |
| (XXXI) | 36643 | (2S)-2-[(methoxycarbonyl)amino]-4-phenylbutyric acid | C12H15NO4 | 详情 | 详情 | |
| (XXXII) | 36644 | methyl (1S)-1-(chlorocarbonyl)-3-phenylpropylcarbamate | C12H14ClNO3 | 详情 | 详情 | |
| (XXXIII) | 36645 | methyl (2S)-1-oxo-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C12H13NO3 | 详情 | 详情 | |
| (XXXV) | 36647 | methyl (1R,2S)-1-(4-chloro-3-methoxyphenyl)-1-hydroxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C19H20ClNO4 | 详情 | 详情 | |
| (XXXVI) | 36648 | methyl (2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C19H20ClNO3 | 详情 | 详情 | |
| (XXXVII) | 36649 | (2S)-1-(4-chloro-3-methoxyphenyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-methylamine | C18H20ClNO | 详情 | 详情 | |
| (XXXVIII) | 36640 | N-[(1S,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)-N-methylamine; (1S,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine | C22H28ClNO3 | 详情 | 详情 | |
| (XXXIX) | 36642 | (2S)-2-amino-4-phenylbutyric acid | 943-73-7 | C10H13NO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The reaction of L-tyrosine (I) with methyl chloroformate (II) by means of NaOH in water gives the carbamate (III), which is methylated at the remaining phenol and carboxylic groups with dimethyl sulfate and K2CO3 in refluxing acetone to yield the 4-O-methyl tyrosine derivative (IV). The hydrolysis of the methyl ester of (IV) with NaOH in dioxane/water, followed by reaction with O-methylhydroxylamine by means of DCC and HOBT, affords the methyl hydroxamate (V). The cyclization of (V) by means of bis(trifluoroacetoxy)iodobenzene in dichloromethane/methanol provides the spirodienone (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to give the saturated ketone (VII). The protection of the ketonic group of (VII) with ethyleneglycol and PPTS yields the cyclic ketal (VIII), which is reduced with LiAlH4 in THF to afford the methoxyamine (IX). The protection of the N-methylamine of (IX) with benzyl chloroformate and TEA provides the carbamate (X), which is treated with Zn in acetic acid in order to cleave the N-methoxyamine group and yield the spiropyrrolidine (XI). The alkylation of the pyrrolidine NH with benzyl chloroformate (XII) and K2CO3 in warm acetonitrile affords the adduct (XIII), which is treated with H2 over Pd/C in methanol in order to remove the benzyl and benzyloxycarbonyl protecting groups, providing the amino acid (XIV). The cyclization of (XIV) by means of DPPA and NaHCO3 in DMF/dichloromethane gives the tetracyclic compound (XV), which is condensed with 4-(prenyloxy)benzaldehyde (XVI) by means of LDA in THF yielding the aldol condensation product (XVII).
| 【1】 Basak, A.; Wardrop, D.J.; N-methoxy-N-acylnitrenium ions: Application to the formal synthesis of (-)-TAN1251A. Org Lett 2001, 3, 7, 1053. |
| 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) | 48794 | (S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine | 60-18-4 | C9H11NO3 | 详情 | 详情 |
| (II) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (III) | 48795 | (2S)-3-(4-hydroxyphenyl)-2-[(methoxycarbonyl)amino]propionic acid | C11H13NO5 | 详情 | 详情 | |
| (IV) | 48796 | methyl (2S)-2-[(methoxycarbonyl)amino]-3-(4-methoxyphenyl)propanoate | C13H17NO5 | 详情 | 详情 | |
| (V) | 48797 | methyl (1S)-2-(methoxyamino)-1-(4-methoxybenzyl)-2-oxoethylcarbamate | C13H18N2O5 | 详情 | 详情 | |
| (VI) | 48798 | methyl (3S)-1-methoxy-2,8-dioxo-1-azaspiro[4.5]deca-6,9-dien-3-ylcarbamate | C12H14N2O5 | 详情 | 详情 | |
| (VII) | 48799 | methyl (3S)-1-methoxy-2,8-dioxo-1-azaspiro[4.5]dec-3-ylcarbamate | C12H18N2O5 | 详情 | 详情 | |
| (VIII) | 48800 | methyl (11S)-9-methoxy-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-ylcarbamate | C14H22N2O6 | 详情 | 详情 | |
| (IX) | 48801 | (11S)-9-methoxy-N-methyl-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecan-11-amine; N-[(11S)-9-methoxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl]-N-methylamine | C13H24N2O3 | 详情 | 详情 | |
| (X) | 48802 | benzyl (11S)-9-methoxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl(methyl)carbamate | C21H30N2O5 | 详情 | 详情 | |
| (XI) | 48803 | benzyl (11S)-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl(methyl)carbamate | C20H28N2O4 | 详情 | 详情 | |
| (XII) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XIII) | 48804 | benzyl 2-[(11S)-11-[[(benzyloxy)carbonyl](methyl)amino]-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]acetate | C29H36N2O6 | 详情 | 详情 | |
| (XIV) | 48805 | 2-[(11S)-11-(methylamino)-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]acetic acid | C14H24N2O4 | 详情 | 详情 | |
| (XV) | 48806 | C14H22N2O3 | 详情 | 详情 | ||
| (XVI) | 19019 | 4-[(3-methyl-2-butenyl)oxy]benzaldehyde | C12H14O2 | 详情 | 详情 | |
| (XVII) | 19020 | (1R,4S)-4-[1-Hydroxy-1-[4-(3-methyl-2-butenyloxy)phenyl]methyl]-2-methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one | C26H36N2O5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)An improved synthesis of [14C]-peldesine has been reported: The reaction of S-methyl-[14C]-isothiourea (I) with methyl chloroformate (II) by means of tetrabutylammonium bromide in dichloromethane gives N,N'-bis(methoxycarbonyl)-S-methyl-[14C]-isothiourea (III). This compound is condensed with 3-amino-4-(3-pyridylmethyl)-1H-pyrrole-2-carboxylic acid methyl ester (IV) by means of acetic acid in methanol yielding the labeled guanidine (V). The cyclization of (V) by means of sodium methoxide in methanol affords the carbamate precursor (VI), which is finally deprotected with NaOH in hot water.
| 【1】 Elliott, A.J.; Kwong, C.D.; Montgomery, J.A.; An improved synthesis of 9-(3-pyridylmethyl)-[2-14C]-9-deazaguanine. J Label Compd Radiopharm 1998, 41, 10, 879. |
| 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) | 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 |
| (I) | 44636 | [[amino(imino)methyl]sulfanyl]methane | C2H6N2S | 详情 | 详情 | |
| (II) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (III) | 28696 | methyl (Z)-[(methoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate | C6H10N2O4S | 详情 | 详情 | |
| (III) | 45292 | methyl (Z)-[(methoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate | C6H10N2O4S | 详情 | 详情 | |
| (IV) | 16030 | methyl 3-amino-4-(3-pyridinylmethyl)-1H-pyrrole-2-carboxylate | C12H13N3O2 | 详情 | 详情 | |
| (V) | 28697 | methyl 3-([bis[(methoxycarbonyl)amino]methylene]amino)-4-(3-pyridinylmethyl)-1H-pyrrole-2-carboxylate | C17H19N5O6 | 详情 | 详情 | |
| (V) | 45293 | methyl 3-([bis[(methoxycarbonyl)amino]methylene]amino)-4-(3-pyridinylmethyl)-1H-pyrrole-2-carboxylate | C17H19N5O6 | 详情 | 详情 | |
| (VI) | 28698 | methyl 4-oxo-7-(3-pyridinylmethyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-ylcarbamate | C14H13N5O3 | 详情 | 详情 | |
| (VI) | 45294 | methyl 4-oxo-7-(3-pyridinylmethyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-ylcarbamate | C14H13N5O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：Reaction of tetrabutylammonium [11C]cyanide (I) with methyl chloroformate in a two phase system afforded labeled methyl cyanoformate (II), which was refluxed in ethanolic HCl to yield diethyl [1-11C]oxalate (III).
| 【1】 Thorell, J.O.; et al.; Synthesis of a C-11-labelled nitrated 1,4-dihydroquinoxaline-2,3-dione, the NMDA glycine receptor antagonist ACEA 1021 (Licostinel). J Label Compd Radiopharm 1998, 41, 4, 345-353. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 | |
| (II) | 18001 | methyl 2-nitriloacetate; carbonocyanic acid, methyl ester | 17640-15-2 | C3H3NO2 | 详情 | 详情 |
| (II) | 45300 | methyl 2-nitriloacetate | C3H3NO2 | 详情 | 详情 | |
| (III) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (III) | 45301 | ethyl 2-ethoxy-2-oxoacetate | C6H10O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IV)A new enantioselective synthesis of efavirenz starting from 2-[5-chloro-2-(4-methoxybenzylamino)phenyl]-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2(S)-ol (I), a previously described intermediate [see Drugs Fut 1998 23(2):133], has been reported: The oxidative cyclization of butynol (I) with dichlorodicyanobenzoquinone (DDQ) in toluene gives the benzoxazine (II) which, without isolation, is treated with NaOH and NaBH4 in methanol yielding the aminoalcohol (III). The acylation of (III) with methyl chloroformate (IV) and NaHCO3 in water affords the carbamate (V). Finally, this compound is cyclized by means of lithium tert-butoxide in tert-butyl methyl ether, or KOH in tert-butyl methyl ether/water.
| 【1】 Pierce, M.E.; et al.; Practical asymmetric synthesis of efavirenz (DMP 266), an HIV-1 reverse transcriptase inhibitor. J Org Chem 1998, 63, 23, 8536. |
| 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) | 16578 | (2S)-2-[5-chloro-2-[(4-methoxybenzyl)amino]phenyl]-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol | C21H19ClF3NO2 | 详情 | 详情 | |
| (II) | 21199 | (4S)-6-chloro-4-(2-cyclopropylethynyl)-2-(4-methoxyphenyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine; 4-[(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-yl]phenyl methyl ether | C21H17ClF3NO2 | 详情 | 详情 | |
| (III) | 21200 | (2S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol | 209414-27-7 | C13H11ClF3NO | 详情 | 详情 |
| (IV) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (V) | 21204 | methyl 4-chloro-2-[(1S)-3-cyclopropyl-1-hydroxy-1-(trifluoromethyl)-2-propynyl]phenylcarbamate | C15H13ClF3NO3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XXVIII)Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with HF and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in CH2Cl2 to yield the target thiazole intermediate (XXXIV).
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (XXII) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XXIII) | 44520 | (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile | C9H10N2OS | 详情 | 详情 | |
| (XXIV) | 44521 | ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C11H15NO3S | 详情 | 详情 | |
| (XXV) | 44522 | ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C17H29NO3SSi | 详情 | 详情 | |
| (XXVI) | 44523 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal | C15H25NO2SSi | 详情 | 详情 | |
| (XXVII) | 44524 | (4R,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol | C20H35NO2SSi2 | 详情 | 详情 | |
| (XXVIII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (XXIX) | 44525 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate | C22H37NO4SSi2 | 详情 | 详情 | |
| (XXX) | 44526 | 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether | C20H35NOSSi2 | 详情 | 详情 | |
| (XXXI) | 44527 | tert-butyl(dimethyl)silyl (1S,3Z)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butenyl ether; 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1,5-hexadienyl]-2-methyl-1,3-thiazole | C20H37NOSSi2 | 详情 | 详情 | |
| (XXXII) | 44491 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H28INOSSi | 详情 | 详情 | |
| (XXXIII) | 44492 | (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H14INOS | 详情 | 详情 | |
| (XXXIV) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XII)Tritium-labeled RS-25259-197 can be obtained by the reaction of methyl 4-bromophenylacetate (XI) with methyl chloroformate (XII) by means of lithium diisopropylamide (LDA) in THF, giving the malonic ester (XIII), which is condensed with methyl acrylate (XIV) by means of Na in methanol to yield the tricarboxylic ester (XV). The decarboxylative hydrolysis of (XV) first with NaOH and finally in acidic medium (HCl) affords 2-(4-bromophenyl)glutaric acid (XVI), which is cyclized with hot polyphosphoric acid (PPA) to give 6-bromo-4-oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (XVII). The reduction of (XVII) with NaBH4 in isopropanol yields the corresponding hydroxy acid (XVIII), which is dehydrated with p-toluenesulfonic acid to the lactone (XIX). Isomerization of (XIX) with H3PO4 in THF affords 6-bromo-1,2-dihydronaphthalene-1-carboxylic acid (XX), which is condensed with quinuclidin-3(S)-ylamine (III) by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in acetonitrile to give the corresponding amide as a mixture of diastereomers that is resolved by chromatography and crystallization in order to obtain the (S,S)-isomer (XXI). The hydrogenation of (XXI) with tritium (3H2) and Pd/C in ethyl acetate affords (S,S)-N-(3-quinuclidinyl)-3,4,7-tri-3H-1,2,3,4-tetrahydronaphthalene-1-carboxamide (XXII), which is reduced with the complex borane.dimethylsulfide to the corresponding amine (XXIII). Finally, this compound is cyclized with trichloromethyl chloroformate (diphosgene) in refluxing toluene.
| 【1】 Graul, A.; Castañer, J.; RS-25259-197. Drugs Fut 1996, 21, 9, 906. |
| 【2】 Gong, L.; Parnes, H.; Synthesis of the 3H-labelled 5-HT3 antagonist (RS-25259-197) at high specific activity. J Label Compd Radiopharm 1996, 38, 5, 425. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 16984 | (3S)-1-azabicyclo[2.2.2]octan-3-amine; 1-aza-Bicyclo[2.2.2]oct-3-ylamine; (3S)-1-azabicyclo[2.2.2]oct-3-ylamine | 120570-05-0 | C7H14N2 | 详情 | 详情 |
| (XI) | 16992 | methyl 2-(4-bromophenyl)acetate | 41841-16-1 | C9H9BrO2 | 详情 | 详情 |
| (XII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (XIII) | 16994 | dimethyl 2-(4-bromophenyl)malonate | C11H11BrO4 | 详情 | 详情 | |
| (XIV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (XV) | 16996 | trimethyl 1-(4-bromophenyl)-1,1,3-propanetricarboxylate | C15H17BrO6 | 详情 | 详情 | |
| (XVI) | 16997 | 2-(4-bromophenyl)pentanedioic acid | C11H11BrO4 | 详情 | 详情 | |
| (XVII) | 16998 | 6-bromo-4-oxo-1,2,3,4-tetrahydro-1-naphthalenecarboxylic acid | C11H9BrO3 | 详情 | 详情 | |
| (XVIII) | 16999 | 6-bromo-4-hydroxy-1,2,3,4-tetrahydro-1-naphthalenecarboxylic acid | C11H11BrO3 | 详情 | 详情 | |
| (XIX) | 17000 | 5-bromo-9-oxatricyclo[6.2.2.0(2,7)]dodeca-2,4,6-trien-10-one | C11H9BrO2 | 详情 | 详情 | |
| (XX) | 17001 | 6-bromo-1,2-dihydro-1-naphthalenecarboxylic acid | C11H9BrO2 | 详情 | 详情 | |
| (XXI) | 17002 | (1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-dihydro-1-naphthalenecarboxamide | C18H21BrN2O | 详情 | 详情 | |
| (XXII) | 17003 | (1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2,3,4-tetrahydro-1-naphthalenecarboxamide | C18H24N2O | 详情 | 详情 | |
| (XXII) | 45319 | (1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2,3,4-tetrahydro-1-naphthalenecarboxamide | C18H24N2O | 详情 | 详情 | |
| (XXIII) | 17004 | (3S)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]-1-azabicyclo[2.2.2]octan-3-amine; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]amine | C18H26N2 | 详情 | 详情 | |
| (XXIII) | 45320 | N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]amine; (3S)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]-1-azabicyclo[2.2.2]octan-3-amine | C18H26N2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(IV)Hemifumarate salt (I) was liberated by treatment with NaHCO3 and subsequently protected with trityl chloride to afford (II). Then, the methyl ester function of (II) was hydrolyzed with NaOH to furnish acid (III). Chlorination of methyl chloroformate (IV) with sulfuryl chloride in the presence of a catalytic amount of azobis(isobutyronitrile) (AIBN) yielded chloromethyl chloroformate (V), which was condensed with 3-pentanol (VI) in pyridine to provide carbonate (VII). The O-alkylation of acid (III) with 3-pentyloxycarbonyloxymethyl chloride (VII) in the presence of K2CO3 in DMF produced the pentyloxycarbonyloxymethyl ester (VIII). Finally, the trityl protecting group of (VIII) was removed with 85% formic acid at r.t., and the resulting product was converted to the hydrochloride salt by treatment with an ethanolic solution of HCl.
| 【1】 Sekine, Y.; Kawanishi, E.; Narita, H.; Hashimoto, Y.; Mizobe, M. (Tanabe Seiyaku Co., Ltd.); Imidazopyridine derivs. and process for preparing the same. CA 2146802; EP 0682023; JP 1996003162; US 5753672 . |
| 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) | 25230 | methyl 5-acetyl-2-propyl-3-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-4-carboxylate | C27H29N7O3 | 详情 | 详情 | |
| (II) | 25231 | methyl 5-acetyl-2-propyl-3-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-4-carboxylate | C46H43N7O3 | 详情 | 详情 | |
| (III) | 25232 | 5-acetyl-2-propyl-3-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-4-carboxylic acid | C45H41N7O3 | 详情 | 详情 | |
| (IV) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (V) | 19249 | Chloromethyl chloroformate; Chloro[(chlorocarbonyl)oxy]methane | 22128-62-7 | C2H2Cl2O2 | 详情 | 详情 |
| (VI) | 21970 | 3-pentanol | 584-02-1 | C5H12O | 详情 | 详情 |
| (VII) | 25234 | chloromethyl 1-ethylpropyl carbonate | C7H13ClO3 | 详情 | 详情 | |
| (VIII) | 25233 | [[(1-ethylpropoxy)carbonyl]oxy]methyl 5-acetyl-2-propyl-3-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-4-carboxylate | C52H53N7O6 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(XIII)The condensation of 4-aminobenzonitrile (I) with the chiral 2,3-epoxypropanol (II) in refluxing methanol gives 4-(2,3-dihydroxypropylamino)benzonitrile (III), which is cyclized with diethyl carbonate (IV) by means of tBu-OK at 100 C to yield the oxazolidinone (V). The reaction of the cyano group of (V) with hydroxylamine in methanol affords the N-hydroxyamidine (VI), which is cyclized with Ac2O at 120 C to provide the 1,2,4-oxadiazole (VII). The hydrolysis of the acetoxy group of (VII) with K2CO3 in refluxing methanol gives the primary alcohol (VIII), which is treated with Ms-Cl and pyridine to yield the corresponding mesylate (IX). The condensation of (IX) with 2-(1-piperazinyl)acetic acid ethyl ester (X) in refluxing acetonitrile affords the adduct (XI), which is hydrogenated with H2 over Pd/C and hydrolyzed with HOAc to obtain the benzamidine derivative (XII). Finally, this compound is acylated with methyl chloroformate (XIII) and NaOH in dichloromethane/water.
| 【1】 Gante, J.; et al.; New antithrombotic RGD-mimetics with bioavailability. Bioorg Med Chem Lett 1996, 6, 20, 2425. |
| 【2】 Gante, J.; Juraszyk, H.; Raddatz, P.; Wurziger, H.; Bernotat-Danielowski, S.; Melzer, G. (Merck Patent GmbH); Adhesion receptor antagonists. CA 2175767; DE 19516483; EP 0741133; JP 1996301857; US 6455529 . |
| 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) | 15361 | 4-Aminobenzonitrile | 873-74-5 | C7H6N2 | 详情 | 详情 |
| (II) | 19241 | (2S)oxiranylmethanol | 60456-23-7 | C3H6O2 | 详情 | 详情 |
| (III) | 54669 | 4-{[(2S)-2,3-dihydroxypropyl]amino}benzonitrile | C10H12N2O2 | 详情 | 详情 | |
| (IV) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (V) | 54670 | 4-[(5S)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]benzonitrile | C11H10N2O3 | 详情 | 详情 | |
| (VI) | 54671 | N'-hydroxy-4-[(5S)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]benzenecarboximidamide | C11H13N3O4 | 详情 | 详情 | |
| (VII) | 54672 | {(5S)-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl acetate | C15H15N3O5 | 详情 | 详情 | |
| (VIII) | 54673 | (5S)-5-(hydroxymethyl)-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-1,3-oxazolidin-2-one | C13H13N3O4 | 详情 | 详情 | |
| (IX) | 54674 | {(5S)-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl methanesulfonate | C14H15N3O6S | 详情 | 详情 | |
| (X) | 54675 | 1-(Ethoxycarbonylmethyl)piperazine; N-(Carboethoxymethyl)piperazine; (1-Piperazino)acetic acid ethyl ester | 40004-08-8 | C8H16N2O2 | 详情 | 详情 |
| (XI) | 54676 | ethyl 2-[4-({(5R)-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-1-piperazinyl]acetate | C21H27N5O5 | 详情 | 详情 | |
| (XII) | 54677 | ethyl 2-{4-[((5R)-3-{4-[amino(imino)methyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-1-piperazinyl}acetate | C19H27N5O4 | 详情 | 详情 | |
| (XIII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(VIII)The asymmetric dihydroxylation of styrene (I) by means of K3Fe(CN)6 and OsO4, catalyzed by 1,4-bis(dihydroquinin-9-O-yl)phthalazine ((DHQ)2PHAL)in tert-butanol/water gives the 1(R)-phenylethane-1,2-diol (II), which is treated with Ts-Cl and pyridine in dichloromethane to yield the monotosylate (III). The reaction of (III) with NaCN in Et-OH/water affords 3(R)-hydroxy-3-phenylpropionitrile (IV), which is reduced by means of BH3/Me2S in refluxing THF to provide the corresponding amine (V). The O-alkylation of (V) with 4-(trifluoromethyl)chlorobenzene (VI) by means of NaH in hot DMSO gives 3(R)-phenyl-3-[4(trifluoromethyl)phenoxy]propylamine (VII), which is treated with methyl chloroformate (VIII) and K2CO3 in dichloromethane to yield the carbamate (IX) Finally, this compound is reduced by means of LiAlH4 in THF to provide the target (R)-fluoxetine.
| 【1】 Pandey, R.K.; et al.; An asymmetric dihydroxylation route to enantiomerically pure norfluoxetine and fluoxetine. Tetrahedron Lett 2002, 43, 25, 4425. |
| 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) | 19649 | 1-vinylbenzene | 100-42-5 | C8H8 | 详情 | 详情 |
| (II) | 57175 | R(-)-1-Phenyl-1,2-ethanediol R(-)-Phenylethylene glycol | C8H10O2 | 详情 | 详情 | |
| (III) | 57176 | (2S)-2-hydroxy-2-phenylethyl 4-methylbenzenesulfonate | C15H16O4S | 详情 | 详情 | |
| (IV) | 57177 | (3R)-3-hydroxy-3-phenylpropanenitrile | C9H9NO | 详情 | 详情 | |
| (V) | 57178 | (1R)-3-amino-1-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
| (VI) | 11973 | 1-Chloro-4-(trifluoromethyl)benzene; 4-Chlorobenzotrifluoride | 98-56-6 | C7H4ClF3 | 详情 | 详情 |
| (VII) | 57179 | (3R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine; (3R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine | C16H16F3NO | 详情 | 详情 | |
| (VIII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (IX) | 57180 | methyl (3R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylcarbamate | C18H18F3NO3 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：Orcinol (I) was acetylated with Ac2O in pyridine to give diacetate (II), which was submitted to a Fries rearrangement in the presence of AlCl3 in chlorobenzene at 90 C to afford acetophenone (III). Subsequent condensation of (III) with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (IV) was effected either in the presence of CdCO3 in boiling toluene or K2CO3 and tributyl benzylammonium chloride in CH2Cl2 at r.t. The resulting (glucopyranosyloxy)acetophenone (V) was condensed with 5-formylbenzofuran (VI) in the presence of KOH to give chalcone (VII). Hydrogenation of (VII) over Pt/C then yielded the (benzofuranyl)propiophenone (VIII). After protection of the 6'-hydroxyl group of (VIII) as the allyl ether (X) with allyl bromide (IX) and K2CO3, the primary alcohol of (X) was acylated with ClCOOMe to furnish carbonate ester (XI). Finally, the O-allyl group of (XI) was cleaved with palladium catalyst and ammonium formate.
| 【1】 Doggrell, S.A.; Castañer, J.; T-1095. Drugs Fut 2001, 26, 8, 750. |
| 【2】 Tsujihara, K.; et al.; Na+-glucose contransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives substituted on the B ring. J Med Chem 1999, 42, 26, 5311. |
| 【3】 Hongu, M.; Matsumoto, M.; Oku, A.; Saito, K.; Tsujihara, K. (Tanabe Seiyaku Co., Ltd.); Propiophenone derivs. and process for preparing the same. EP 0850948; JP 1998237089; US 6048842 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 | |
| (I) | 27257 | 5-Methyl-1,3-benzenediol; Orcinol | 505-15-4 | C7H8O2 | 详情 | 详情 |
| (II) | 27258 | 3-(acetoxy)-5-methylphenyl acetate | C11H12O4 | 详情 | 详情 | |
| (III) | 27259 | 1-(2,6-dihydroxy-4-methylphenyl)-1-ethanone | C9H10O3 | 详情 | 详情 | |
| (IV) | 27260 | (2R,3R,4S,5S,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl acetate | 572-09-8 | C14H19BrO9 | 详情 | 详情 |
| (V) | 27261 | (2R,3R,4S,5R,6S)-6-(2-acetyl-3-hydroxy-5-methylphenoxy)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-2H-pyran-3-yl acetate | C23H28O12 | 详情 | 详情 | |
| (VI) | 27262 | 1-benzofuran-5-carbaldehyde | C9H6O2 | 详情 | 详情 | |
| (VII) | 27263 | (E)-3-(1-benzofuran-5-yl)-1-(2-hydroxy-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-2-propen-1-one | C24H24O9 | 详情 | 详情 | |
| (VIII) | 27264 | 3-(1-benzofuran-5-yl)-1-(2-hydroxy-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-1-propanone | C24H26O9 | 详情 | 详情 | |
| (IX) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (X) | 27265 | 1-(2-(allyloxy)-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-3-(1-benzofuran-5-yl)-1-propanone | C27H30O9 | 详情 | 详情 | |
| (XI) | 27266 | ((2R,3S,4S,5R,6S)-6-[3-(allyloxy)-2-[3-(1-benzofuran-5-yl)propanoyl]-5-methylphenoxy]-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl methyl carbonate | C29H32O11 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(LII)The condensation of carbaldehyde (XLVII) with the intermediate Pmb-protected phenyl sulfone (XXIII) by means of BuLi, Ac2O and Na/Hg gives the linear adduct (XLVIII), which is protected at its free OH group by means of DHP and PPTS, and selectively deprotected with TBAF yielding the primary alcohol (XLIX). The oxidation of (XLIX) with DMP affords the acetaldehyde derivative (L), which is condensed with CBr4 and PPh3 to provide the dibromovinyl derivative (LI). The condensation of (LI) with methyl chloroformate (LII) by means of BuLi gives the acetylenic ester (LIII), which is treated with CSA to eliminate the THP protecting group and yield the hydroxy ester (LIV). The hydrolysis of the ester (LIV) with LiOH in THF/water affords the hydroxyacid (LV).
| 【1】 Ghosh, A.K.; Wang, Y.; Kim, J.T.; Total synthesis of microtubule-stabilizing agent (-)-laulimalide. J Org Chem 2001, 66, 26, 8973. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIII) | 63121 | (3S,4S,5E)-4-[(4-methoxybenzyl)oxy]-6-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1-(phenylsulfonyl)-5-hexen-3-ol | C26H32O6S | 详情 | 详情 | |
| (XLVII) | 63142 | (2S)-4-{(2S)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-2-(methoxymethoxy)-4-pentenal | C24H44O5Si | 详情 | 详情 | |
| (XLVIII) | 63143 | (1E,3S,4S,6E,8S)-10-{(2S)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-3-[(4-methoxybenzyl)oxy]-8-(methoxymethoxy)-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1,6,10-undecatrien-4-ol | C44H70O8Si | 详情 | 详情 | |
| (XLIX) | 63144 | 2-{(2R,6R)-6-[(2S,6S,7E,10S,11S,12E)-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-10-(tetrahydro-2H-pyran-2-yloxy)-7,12-tridecadienyl]-5,6-dihydro-2H-pyran-2-yl}-1-ethanol | C43H64O9 | 详情 | 详情 | |
| (L) | 63145 | 2-{(2R,6R)-6-[(2S,6S,7E,10S,11S,12E)-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-10-(tetrahydro-2H-pyran-2-yloxy)-7,12-tridecadienyl]-5,6-dihydro-2H-pyran-2-yl}acetaldehyde | C43H62O9 | 详情 | 详情 | |
| (LI) | 63146 | (1S,3E,5S)-7-{(2S)-3-[(2R,6R)-6-(3,3-dibromo-2-propenyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-1-{(1S,2E)-1-[(4-methoxybenzyl)oxy]-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-5-(methoxymethoxy)-3,7-octadienyl tetrahydro-2H-pyran-2-yl ether 2-{[(1S,3E,5S)-7-{(2S)-3-[(2R,6R)-6-(3,3-dibromo-2-propenyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-1-{(1S,2E)-1-[(4-methoxybenzyl)oxy]-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-5-(methoxymethoxy)-3,7-octadienyl]oxy}tetrahydro-2H-pyran | C44H62Br2O8 | 详情 | 详情 | |
| (LII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (LIII) | 63147 | methyl 4-{(2R,6R)-6-[(2S,6S,7E,10S,11S,12E)-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-10-(tetrahydro-2H-pyran-2-yloxy)-7,12-tridecadienyl]-5,6-dihydro-2H-pyran-2-yl}-2-butynoate | C46H64O10 | 详情 | 详情 | |
| (LIV) | 63148 | methyl 4-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-10-hydroxy-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynoate | C41H56O9 | 详情 | 详情 | |
| (LV) | 63149 | 4-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-10-hydroxy-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynoic acid | C40H54O9 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：6-Methoxytryptamine (I) was condensed with methyl chloroformate to give carbamate (II), and further alkylation with benzyl bromide yielded the N-benzyl indole (III). Oxidation of the indole ring of (III) with DMSO/HCl gave oxindole (IV). Phase-transfer methylation using iodomethane and benzyltrimethylammonium bromide afforded the racemic methyl derivative (Va-b). Subsequent reduction and cyclization of (Va-b) by means of Red-Al furnished the tricyclic compound (VIa-b), which was resolved with dibenzoyl D-tartaric acid to provide the (3aS)-enantiomer (VII). Conversion of (VII) to the N,N'-dibenzyl analogue (XI) was achieved via quaternization to the ammonium salt (VIII) with iodomethane in Et2O. Ring-opening of (VIII) under basic conditions produced the hydroxy tryptamine (IX), which was again quaternized to (X) with iodomethane and then cyclized with benzylamine to provide directly the dibenzyl compound (XI). Ether cleavage of (XI) with boron tribromide gave the phenolic derivative (XII). This was coupled with 4-isopropylphenyl isocyanate in the presence of a catalytic amount of Na to yield carbamate (XIV). Finally, hydrogenolytic cleavage of the benzyl groups of (XIV) over Pd(OH)2 furnished the title compound.
| 【1】 Yu, Q.-S.; et al.; Total syntheses and anticholinesterase activities of (3aS)-N(8)-norphysostigmine, (3aS)-N(8)-norphenserine, their antipodal isomers and other N(8)-substituted analogues. J Med Chem 1997, 40, 18, 2895-2901. |
| 【2】 Yu, Q.-S.; et al.; Syntheses and anticholinesterase activities of (3aS)-N1,N8-bisnorphenserine, (3aS)-N1,N8-bisnorphysostigmine. Their antipodal isomers and other potential metabolites of phenserine. J Med Chem 1998, 41, 13, 2371-79. |
| 【3】 Holloway, H.W.; Yu, Q.-S.; Greig, N.H.; Utsuki, T.; Brossi, A.; Synthesis of novel phenserine-based-selective inhibitors of butyrylcholinesterase for Alzheimer's disease. J Med Chem 1999, 42, 10, 1855. |
| 【4】 Soncrant, T.T.; Brossi, A.; Greig, N.H.; Hausman, M.; Yu, Q.-S. (Axonyx Inc.; National Institutes of Health); Highly selective butyrylcholinesterase inhibitors for the treatment and diagnosis of Alzheimer's disease and dementias. CA 2264750; EP 0949920; WO 9902154 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 | |
| (Va) | 36829 | methyl 2-[(3S)-1-benzyl-5-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]ethylcarbamate | C21H24N2O4 | 详情 | 详情 | |
| (VIa),(VII) | 36830 | (3aS)-8-benzyl-5-methoxy-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole; (3aS)-8-benzyl-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether | C20H24N2O | 详情 | 详情 | |
| (Vb) | 36837 | methyl 2-[(3R)-1-benzyl-5-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]ethylcarbamate | C21H24N2O4 | 详情 | 详情 | |
| (VIb) | 36838 | (3aR)-8-benzyl-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether; (3aR)-8-benzyl-5-methoxy-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole | C20H24N2O | 详情 | 详情 | |
| (I) | 36825 | O-Methylserotonin; 3-(2-Aminoethyl)-5-methoxyindole; 2-(5-Methoxy-1H-indol-3-yl)ethylamine; 2-(5-Methoxy-1H-indol-3-yl)-1-ethanamine; 5-Methoxytryptamine | 608-07-1 | C11H14N2O | 详情 | 详情 |
| (II) | 36826 | methyl 2-(5-methoxy-1H-indol-3-yl)ethylcarbamate | C13H16N2O3 | 详情 | 详情 | |
| (III) | 36827 | methyl 2-(1-benzyl-5-methoxy-1H-indol-3-yl)ethylcarbamate | C20H22N2O3 | 详情 | 详情 | |
| (IV) | 36828 | methyl 2-(1-benzyl-5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl)ethylcarbamate | C20H22N2O4 | 详情 | 详情 | |
| (VIII) | 36831 | (3aS)-8-benzyl-5-methoxy-1,1,3a-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-1-ium iodide | C21H27IN2O | 详情 | 详情 | |
| (IX) | 36832 | (3S)-1-benzyl-3-[2-(dimethylamino)ethyl]-5-methoxy-3-methyl-2,3-dihydro-1H-indol-2-ol | C21H28N2O2 | 详情 | 详情 | |
| (X) | 36833 | 2-[(3S)-1-benzyl-2-hydroxy-5-methoxy-3-methyl-2,3-dihydro-1H-indol-3-yl]-N,N,N-trimethyl-1-ethanaminium iodide | C22H31IN2O2 | 详情 | 详情 | |
| (XI) | 36834 | (3aS,8aR)-1,8-dibenzyl-5-methoxy-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole; (3aS,8aR)-1,8-dibenzyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether | C26H28N2O | 详情 | 详情 | |
| (XII) | 36835 | (3aS,8aR)-1,8-dibenzyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ol | C25H26N2O | 详情 | 详情 | |
| (XIII) | 34537 | 4-isopropylphenyl isocyanate; 1-isocyanato-4-isopropylbenzene | 31027-31-3 | C10H11NO | 详情 | 详情 |
| (XIV) | 36836 | (3aS,8aR)-1,8-dibenzyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl 4-isopropylphenylcarbamate | C35H37N3O2 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：The reaction of 1-[2-(diethylamino)ethylamino]-9-oxothioxanthene-4-carbaldehyde (I) with formic acid and formamide at 160 C gives N-[1-[2-(diethylamino)ethylamino]-9-oxothioxanthen-4-ylmethyl]formamide (II), which is hydrolyzed with hot aqueous HCl yielding the corresponding amine (III). Finally, this compound is acylated with methyl chloroformate and TEA in dichloromethane.
| 【1】 Brown, S.; Sandhu, G.S. (Sanofi-Synthelabo); Lyophilized thioxanthenone antitumor agents. WO 9710809 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 | |
| (I) | 27504 | 1-[[2-(diethylamino)ethyl]amino]-9-oxo-9H-thioxanthene-4-carbaldehyde | C20H22N2O2S | 详情 | 详情 | |
| (II) | 27505 | (1-[[2-(diethylamino)ethyl]amino]-9-oxo-9H-thioxanthen-4-yl)methylformamide | C21H25N3O2S | 详情 | 详情 | |
| (III) | 27506 | 4-(aminomethyl)-1-[[2-(diethylamino)ethyl]amino]-9H-thioxanthen-9-one | C20H25N3OS | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(VI)The alcoholysis of 1-benzyl-2-pyrrolidinone (I) with HCl in ethanol gives 4-(benzylamino)butyric acid ethyl ester (II), which is condensed with ethyl 2-bromoacetate (III) to yield the tertiary amine (IV). The cyclization of (IV) by means of NaOEt affords 1-benzyl-3-hydroxy-1,2,5,6-tetrahydropyridine-4-carboxylic acid ethyl ester (V), which by hydrogenolytic debenzylation, followed by reaction with methyl chloroformate (VI), affords the 1,4-dicarboxylate (VII). The reduction of (VII) with H2 over Ni gives the cis-3-hydroxy-1,4-dicarboxylate (VIII), which is hydrolyzed and selectively decarboxylated with HCl, yielding cis-3-hydroxypiperidine-4-carboxylic acid (IX). Finally, this compound is dehydrated by means of HBr and TEA.
| 【1】 Christensen, V.; Krogsgaard-Larsen, P.; Falch, E.; Chemistry and pharmacology of the GABA agonists THIP (Gabodaxol) and isoguvacine. Drugs Fut 1984, 9, 8, 597. |
| 【2】 Johnston, G.A.R.; Krogsgaard-Larsen, P.; Structure-activity studies on the inhibition of GABA binding to rat brain membranes by muscinol and related compounds. J Neurochem 1978, 30, 1377-1382. |
| 【3】 Krogsgaard-Larsen, P.; Christensen, T.R.; GABA agonists. Synthesis and structure-activity studies on analogues of isoguvacine and THIP. Eur J Med Chem 1979, 14, 157-164. |
| 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) | 43664 | 1-benzyl-2-pyrrolidinone | 5291-77-0 | C11H13NO | 详情 | 详情 |
| (II) | 43665 | ethyl 4-(benzylamino)butanoate | C13H19NO2 | 详情 | 详情 | |
| (III) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (IV) | 43666 | ethyl 4-[benzyl(2-ethoxy-2-oxoethyl)amino]butanoate | C17H25NO4 | 详情 | 详情 | |
| (V) | 43667 | ethyl 1-benzyl-5-hydroxy-1,2,3,6-tetrahydro-4-pyridinecarboxylate | C15H19NO3 | 详情 | 详情 | |
| (VI) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (VII) | 43668 | 4-ethyl 1-methyl 5-hydroxy-3,6-dihydro-1,4(2H)-pyridinedicarboxylate | C10H15NO5 | 详情 | 详情 | |
| (VIII) | 43669 | 4-ethyl 1-methyl (3S,4S)-3-hydroxy-1,4-piperidinedicarboxylate | C10H17NO5 | 详情 | 详情 | |
| (IX) | 43670 | (3S,4S)-3-hydroxy-4-piperidinecarboxylic acid | C6H11NO3 | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：(VI)The ethanolysis of 1-benzylpyrrolidin-2-one (I) with HCl in ethanol gives 4-(benzylamino)butyric acid ethyl ester (II), which is alkylated with ethyl bromoacetate (III), yielding the tertiary amine (IV). The cyclization of (IV) by means of sodium ethoxide affords 1-benzyl-3-hydroxy-1,2,5,6-tetrahydropyridine-4-carboxylic acid ethyl ester (V), which by hydrogenolytic debenzylation, followed by reaction with methyl chloroformate (VI), affords the 1,4-dicarboxylate (VII). The reaction of (VII) with ethyleneglycol (VIII) and TsOH gives the cyclic ketal (IX), which is treated with hydroxylamine and NaOMe to yield the carbohydroxamic acid (X). The cyclization of (X) by means of H2SO4 affords 3-hydroxy-4,5,6,7-tetrahydropyrido[4,3-d]oxazole-6-carboxylic acid methyl ester (XI), which is finally decarboxylated by means of HBr and TEA.
| 【1】 Krogsgaard-Larsen, P.; Muscimol analogues. II. Synthesis of some bicylic 3-isoxazol zwitterions. Acta Chem Scand 1977, B31, 584-588. |
| 【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Paton, D.M.; THIP. Drugs Fut 1980, 5, 5, 257. |
| 【3】 Christensen, V.; Krogsgaard-Larsen, P.; Falch, E.; Chemistry and pharmacology of the GABA agonists THIP (Gabodaxol) and isoguvacine. Drugs Fut 1984, 9, 8, 597. |
| 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) | 43664 | 1-benzyl-2-pyrrolidinone | 5291-77-0 | C11H13NO | 详情 | 详情 |
| (II) | 43665 | ethyl 4-(benzylamino)butanoate | C13H19NO2 | 详情 | 详情 | |
| (III) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (IV) | 43666 | ethyl 4-[benzyl(2-ethoxy-2-oxoethyl)amino]butanoate | C17H25NO4 | 详情 | 详情 | |
| (V) | 43667 | ethyl 1-benzyl-5-hydroxy-1,2,3,6-tetrahydro-4-pyridinecarboxylate | C15H19NO3 | 详情 | 详情 | |
| (VI) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (VII) | 43668 | 4-ethyl 1-methyl 5-hydroxy-3,6-dihydro-1,4(2H)-pyridinedicarboxylate | C10H15NO5 | 详情 | 详情 | |
| (VIII) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (IX) | 43675 | 10-ethyl 7-methyl 1,4-dioxa-7-azaspiro[4.5]decane-7,10-dicarboxylate | C12H19NO6 | 详情 | 详情 | |
| (X) | 43676 | methyl 10-[(hydroxyamino)carbonyl]-1,4-dioxa-7-azaspiro[4.5]decane-7-carboxylate | C10H16N2O6 | 详情 | 详情 | |
| (XI) | 43677 | methyl 3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate | C8H10N2O4 | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：(III)The deprotection of 1-benzyl-2-oxopiperidine-3-carboxylic acid ethyl ester (I) by hydrogenation with H2 over Pd/C in aq. ethanol gives 2-oxopiperidine-3-carboxylic acid ethyl ester (II), which is condensed with methyl chloroformate (III) and K2CO3 in water to yield 1-(methoxycarbonyl)-2-oxopiperidine-3-carboxylic acid ethyl ester (IV). The reaction of (IV) with ethyleneglycol (V) and Ts-OH in refluxing benzene affords the ethylene ketal (VI), which is treated with hydroxylamine and KOH in methanol to provide the carbohydroxamic acid (VII). The cyclization of (VII) by means of hot conc. HCl or HClO4 gives 3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylic acid methyl ester (VIII), which is finally treated with HBr in refluxing acetic acid and neutralized with TEA to yield the target isoxazolo-pyridine derivative.
| 【1】 Krogsgaard-Larsen, P. (H. Lundbeck A/S); Heterocyclic cpds.. EP 0000167; EP 0000338; EP 0027279; EP 0028017; US 4278676; US 4301287 . |
| 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) | 57371 | ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate | C15H19NO3 | 详情 | 详情 | |
| (II) | 57372 | ethyl 3-oxo-4-piperidinecarboxylate | C8H13NO3 | 详情 | 详情 | |
| (III) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (IV) | 57373 | 4-ethyl 1-methyl 3-oxo-1,4-piperidinedicarboxylate | C10H15NO5 | 详情 | 详情 | |
| (V) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (VI) | 43675 | 10-ethyl 7-methyl 1,4-dioxa-7-azaspiro[4.5]decane-7,10-dicarboxylate | C12H19NO6 | 详情 | 详情 | |
| (VII) | 43676 | methyl 10-[(hydroxyamino)carbonyl]-1,4-dioxa-7-azaspiro[4.5]decane-7-carboxylate | C10H16N2O6 | 详情 | 详情 | |
| (VIII) | 43677 | methyl 3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate | C8H10N2O4 | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：(XXVIII)Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with FH and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in dichloromethane to yield the target thiazole intermediate (XXXIV).
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (XXII) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XXIII) | 44520 | (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile | C9H10N2OS | 详情 | 详情 | |
| (XXIV) | 44521 | ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C11H15NO3S | 详情 | 详情 | |
| (XXV) | 44522 | ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C17H29NO3SSi | 详情 | 详情 | |
| (XXVI) | 44523 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal | C15H25NO2SSi | 详情 | 详情 | |
| (XXVII) | 44524 | (4R,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol | C20H35NO2SSi2 | 详情 | 详情 | |
| (XXVIII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (XXIX) | 44525 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate | C22H37NO4SSi2 | 详情 | 详情 | |
| (XXX) | 44526 | 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether | C20H35NOSSi2 | 详情 | 详情 | |
| (XXXI) | 44527 | tert-butyl(dimethyl)silyl (1S,3Z)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butenyl ether; 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1,5-hexadienyl]-2-methyl-1,3-thiazole | C20H37NOSSi2 | 详情 | 详情 | |
| (XXXII) | 44491 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H28INOSSi | 详情 | 详情 | |
| (XXXIII) | 44492 | (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H14INOS | 详情 | 详情 | |
| (XXXIV) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：(B)The reaction of 4-chloro-2-amino-1-nitrobenzene (I) with sodium phenylmercaptide (A) in DMF gives 2-amino-4-phenylthio-1-nitrobenzene (II), which is treated with acetic anhydride to yield 2-acetamido-4-phenylthio-1-nitrobenzene (III). This product is oxidized with peracetic acid in methanol giving 2-amino-4-phenylsulfinyl-1-nitrobenzene (V). Then the nitro group is reduced with H2 over Pd/C in methanol yielding 1,2-diamino-4-phenylsulfinylbenzene (VI). This product is finally condensed with N,N'-bis(methoxycarbonyl)-S-methylisothiourea (VII) in ethanol - water - acetic acid. The isothiourea (VII) is obtained by reaction of S-methylisothiouronium sulfate (VIII) with methyl chloroformate (B) by means of KOH in water
| 【1】 Beard, C.C.; et al. (Syntex, Inc.); DE 2363351 . |
| 【2】 Castaner, J.; Bogan, J.A.; Oxfendazole. Drugs Fut 1976, 1, 9, 438. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (A) | 60753 | sodium benzenethiolate | C6H5NaS | 详情 | 详情 | |
| (I) | 15709 | 5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline | 1635-61-6 | C6H5ClN2O2 | 详情 | 详情 |
| (II) | 60754 | 2-nitro-5-(phenylsulfanyl)aniline; 2-nitro-5-(phenylsulfanyl)phenylamine | C12H10N2O2S | 详情 | 详情 | |
| (III) | 60755 | N-[2-nitro-5-(phenylsulfanyl)phenyl]acetamide | C14H12N2O3S | 详情 | 详情 | |
| (IV) | 60756 | N-[2-nitro-5-(phenylsulfinyl)phenyl]acetamide | C14H12N2O4S | 详情 | 详情 | |
| (V) | 60757 | 2-nitro-5-(phenylsulfinyl)aniline; 2-nitro-5-(phenylsulfinyl)phenylamine | C12H10N2O3S | 详情 | 详情 | |
| (VI) | 60758 | 4-(phenylsulfinyl)-1,2-benzenediamine; 2-amino-4-(phenylsulfinyl)phenylamine | C12H12N2OS | 详情 | 详情 | |
| (VII) | 28696 | methyl (Z)-[(methoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate | C6H10N2O4S | 详情 | 详情 | |
| (VIII) | 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 |
合成路线23
该中间体在本合成路线中的序号：(II)The reaction of 2-(tert-butoxycarbonylamino)hexadecanoic acid (I) with ethyl chloroformate (II) and NMM in THF gives the mixed anhydride (III), which is reduced by means of NaBH4 in methanol to yield the corresponding hexadecanol (IV). The reaction of (IV) with MsCl and TEA affords the mesylate (V), which is treated with sodium azide in DMF to provide the azido derivative (VI). The reduction of (VI) with H2 over Pd/C in chloroform gives the corresponding amine (VII), which is finally alkylated with ethyl bromide and TEA in DMF to yield the target tertiary amine.
| 【1】 del Olmo, E.; Alves, M.; Lopez, J.L.; Inchaustti, A.; Yaluff, G.; Rojas de Arias, A.; San Feliciano, A.; Leishmanicidal activity of some aliphatic diamines and amino-alcohols. Bioorg Med Chem Lett 2002, 12, 4, 659. |
| 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) | 51342 | 2-[(tert-butoxycarbonyl)amino]hexadecanoic acid | C21H41NO4 | 详情 | 详情 | |
| (II) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (III) | 51343 | C24H45NO6 | 详情 | 详情 | ||
| (IV) | 51344 | tert-butyl 1-(hydroxymethyl)pentadecylcarbamate | C21H43NO3 | 详情 | 详情 | |
| (V) | 63167 | 2-[(tert-butoxycarbonyl)amino]hexadecyl methanesulfonate | C22H45NO5S | 详情 | 详情 | |
| (VI) | 63168 | tert-butyl 1-(azidomethyl)pentadecylcarbamate | C21H42N4O2 | 详情 | 详情 | |
| (VII) | 63169 | tert-butyl 1-(aminomethyl)pentadecylcarbamate | C21H44N2O2 | 详情 | 详情 |
合成路线24
该中间体在本合成路线中的序号：(III)The reduction of 6-nitro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (I) with H2 over Pd/C in ethanol gives the corresponding 6-amino derivative (II), which is condensed with methyl chloroformate (III) and pyridine to afford the target carbamate.
| 【1】 Yerxa, B.R.; Peterson, W.M.; Pintor, J.J.; Peral, M.A.; Plourde, R. Jr.; Brown, E.G. (Inspire Pharmaceuticals, Inc.; Universidad Complutense de Madrid); Method for reducing intraocular pressure using indole derivs.. WO 0209702 . |
| 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) | 57858 | 6-Nitro-2,3,4,9-tetrahydro-beta-carbolin-1-one | C11H9N3O3 | 详情 | 详情 | |
| (II) | 57859 | 6-amino-2,3,4,9-tetrahydro-1H-beta-carbolin-1-one | C11H11N3O | 详情 | 详情 | |
| (III) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
合成路线25
该中间体在本合成路线中的序号：(XV)Treatment of 2-fluorobenzyl bromide (I) with hydrazine hydrate in refluxing EtOH gives 2-fluorobenzyl hydrazine (II) (1), which by cyclocondensation with the sodium salt of ethyl cyanopyruvate (III) — prepared by reaction of diethyl oxalate (IV) with acetonitrile mediated by NaOEt (2) — by means of TFA in refluxing dioxane yields the 5-aminopyrazole derivative (V). Condensation of intermediate (V) with 3-dimethylaminoacrolein (VI) in the presence of TFA in refluxing dioxane provides the pyrazolo[3,4-b]pyridine derivative (VII), which is amidated with methanolic ammonia, affording amide (VIII). Treatment of amide (VIII) with pyridine and trifluoroacetic anhydride in THF followed by methanolysis of the resulting nitrile (IX) by means of NaOMe in MeOH generates the methyl imidoate (X), which, without isolation, undergoes amination with NH4Cl in the presence of glacial acetic acid in refluxing MeOH to give the carboxamidine (XI). Coupling of amidine (XI) with phenylazomalononitrile (XII) by means of NaOMe in DMF at 110 °C affords diamine (XIII), which upon reduction with H2 over Raney-Ni in H2O/DMF at 62 °C provides triamine (XIV). Acylation of amine (XIV) with methyl chloroformate (XV) in pyridine affords carbamate (XVI), which is finally N-methylated by means of MeI and NaH in DMF (3) or LiHMDS in THF (4). Scheme 1.
| 【1】 Kelley, J.L., Davis, R.G., McLean, E.W., Glen, R.C., Soroko, F.E., Cooper, B.R. Synthesis and anticonvulsant activity of N-benzylpyrrolo[2,3-d]-, -pyrazolo[3,4-d]-, and -triazolo[4,5-d]pyrimidines: Imidazole ring-modified analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine. J Med Chem 1995, 38(19): 3884-8. |
| 【2】 Von Borsche, W., Manteuffel, R. Substituted pyrazole derivatives condensed with six-membered heterocyclic rings. Justus Liebigs Ann Chem 1934, 512: 97. |
| 【3】 Alonso-Alija, C., Bischoff, E., Muenter, K., Feurer, A., Stahl, E., Weigand, S., Stasch, J.-P. (Bayer Healthcare AG). Carbamate-substituted pyrazolopyridines. CA 2485143, DE 10220570, EP 1506193, JP 2005531553, US 2006052397, US 7173037, WO 2003095451. |
| 【4】 Mittendorf, J., Weigand, S., Alonso-Alija, C. et al. Discovery of riociguat (BAY 63-2521): A potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem 2009, 4(5): 853-65. |
| 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) | 38775 | 1-(bromomethyl)-2-fluorobenzene | 446-48-0 | C7H6BrF | 详情 | 详情 |
| (II) | 50471 | 1-(2-fluorobenzyl)hydrazine | 51859-98-4 | C7H9FN2 | 详情 | 详情 |
| (III) | 52079 | sodium (Z)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate | 627076-29-3 | C6H6NNaO3 | 详情 | 详情 |
| (IV) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (V) | 50472 | ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate | 256504-39-9 | C13H14FN3O2 | 详情 | 详情 |
| (VI) | 11789 | (E)-3-(Dimethylamino)-2-propenal | 692-32-0 | C5H9NO | 详情 | 详情 |
| (VII) | 50473 | ethyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate | 256376-59-7 | C16H14FN3O2 | 详情 | 详情 |
| (VIII) | 50474 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide | 256376-62-2 | C14H11FN4O | 详情 | 详情 |
| (IX) | 50475 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile | 256376-65-5 | C14H9FN4 | 详情 | 详情 |
| (X) | 50476 | methyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidoate | 304874-06-4 | C15H13FN4O | 详情 | 详情 |
| (XI) | 50477 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide | 256376-68-8 | C14H12FN5 | 详情 | 详情 |
| (XII) | 63162 | 2-[(E)-2-phenyldiazenyl]malononitrile | 6017-21-6 | C9H6N4 | 详情 | 详情 |
| (XIII) | 63163 | 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4,6-pyrimidinediamine; 6-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4-pyrimidinylamine | 428854-23-3 | C23H18FN9 | 详情 | 详情 |
| (XIV) | 63164 | 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylamine; 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine | 428854-24-4 | C17H15FN8 | 详情 | 详情 |
| (XV) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (XVI) | 65980 | Methyl (4,6-diamino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)carbamate | 625115-52-8 | C19H17FN8O2 | 详情 | 详情 |
合成路线26
该中间体在本合成路线中的序号：(II)O-Protection of 2,4-di-tert-butylphenol (I) with methyl chloroformate (II) in the presence of Et3N and DMAP in CH2Cl2 gives 2,4-ditert-butylphenyl methyl carbonate (III), which by nitration with HNO3 and H2SO4 provides a mixture of the 5- and 6-nitrophenyl carbonates (IVa) and (IVb), respectively. Hydrolysis of the mixture of carbonates (IVa) and (IVb) by means of KOH in MeOH followed by chromatographic separation of the resulting mixture of nitrophenols affords 2,4-di-tert-butyl-5-nitrophenol (V), which is reduced by transfer hydrogenation with HCOONH4 in the presence of Pd/C in refluxing EtOH to the amine (VI). Finally, amine (VI) is condensed with 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (VII) by means of HBTU and Et3N in DMF or CH2Cl2 .
4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (VII) is prepared by coupling of diethyl 2-(ethoxymethylene)malonate (VIII) with aniline (IX) by heating at 140-150 °C to afford diethyl 2-(anilinomethylene) malonate (X), which by cyclization by means of PPA and POCl3 at 70 °C yields ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (XI). Finally, ethyl ester derivative (XI) is saponified with NaOH at reflux, followed by acidification with HCl .
| 【1】 Hadida Ruah, S.S., Hazlewood, A.R., Grootenhuis, P.D.J., Van Goor, F.F., Singh, A.K., Zhou, J., McCartney, J. (Vertex Pharmaceuticals, Inc.).Modulators of ATP-binding cassette transporters. CN 10193301, EP 1773816, JP 2008504291, US 2006074075, US 7495013, US 8101767, WO 2006002421. |
| 【2】 Hurter, P. (Vertex Pharmaceuticals, Inc.). Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. EP 1993360, JP 200952278, US 011064811, WO 2007079139. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 68207 | 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate | 873055-55-1 | C16H23NO5 | 详情 | 详情 |
| (IVb) | 68208 | 2,4-di-tert-butyl-6-nitrophenyl methyl carbonate | 详情 | 详情 | ||
| (I) | 68205 | 2,4-di-tert-butylphenol;2,4-Bis(1,1-dimethylethyl)-phenol | 96-76-4 | C14H22O | 详情 | 详情 |
| (II) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (III) | 68206 | 2,4-ditert-butylphenyl methyl carbonate | C16H24O3 | 详情 | 详情 | |
| (V) | 68209 | 2,4-di-tert-butyl-5-nitrophenol | C14H21NO3 | 详情 | 详情 | |
| (VI) | 68210 | 5-amino-2,4-di-tert-butylphenol | C14H23NO | 详情 | 详情 | |
| (VII) | 68211 | 4-oxo-1,4-dihydroquinoline-3-carboxylic acid | 13721-01-2 | C10H7NO3 | 详情 | 详情 |
| (VIII) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (IX) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (X) | 35953 | diethyl 2-(anilinomethylene)malonate | C14H17NO4 | 详情 | 详情 | |
| (XI) | 68212 | ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate | C12H11NO3 | 详情 | 详情 |
合成路线27
该中间体在本合成路线中的序号：(X)Protection of 1,5,6,7-tetrahydroindol-4-one (I) with Boc2O by means of t-BuOK in refluxing THF gives the corresponding N-Boc-indolone (II), which is then reduced with H2 over Pt/C in MeOH to yield (3aR*, 4S*,7aR*)-cis-N-Boc-4-hydroxyoctahydroindole (III). Swern oxidation of alcohol (III) using (COCl)2, DMSO and Et3N in THF affords the racemic perhydroindolone (IV), which is resolved using chiral chromatography to the (3aR,7aR)-enantiomer (V). Alternatively, enantioselective acetylation of racemic alcohol (III) with vinyl acetate in the presence of immobilized Candida antarctica lipase (Novozyme 435), followed by flash chromatographic separation of the undesired (3aS,4R,7aS)-acetate provides unreacted (3aR,4S,7aR)-alcohol (VI), which is then oxidized to ketone (V) under Swern conditions. Treatment of 1-ethynyl-3-methylbenzene (VII) with BuLi in THF at –20 °C and subsequent enantioselective condensation with ketone (V) leads to propargylic alcohol (VIII), which is then N-deprotected with HCl in EtOAc to produce the amine (IX). Finally, amine (IX) is acylated with methyl chloroformate (X) in the presence of Et3N in CH2Cl2 .
Alternatively, Michael addition of aziridine (XI) to 2-cyclohexenone (XII) in toluene gives 3-(1-aziridinyl)cyclohexanone (XIII), which is submitted to aziridine ring opening by treatment with methyl chloroformate in toluene to provide methyl N-2-chloroethyl-N-(3-oxocyclohexyl)carba-mate (XIV). Intramolecular cyclization of carbamate (XIV) in the presence of pyrrolidine and Et3N in CH2Cl2 affords racemic methyl 4-oxooctahydroindole-1-carboxylate (XV), which is then subjected to chiral chromatographic separation, resulting in the (3aR,7aR)-enantiomer (XVI). Finally, 1-ethynyl-3-methylbenzene (VII) is stereospecifically added to ketone (XVI) in the presence of n-Hex-Li in THF .
| 【1】 Auberson, Y., Ofner, S., Gasparini, F. (Novartis AG; Novartis Pharma GmbH). Acetylene derivatives having mGluR5 antagonistic activity. EP 1453512, JP 2005514381, JP 200830326, US 200506591, US 7348353, US 2008146647, US 2008303226, WO 2003047581. |
| 【2】 Kuesters, E., Acemoglu, M., Lustenberger, P., Sedelmeier, G., Schmidt, B.,Penn, G. (Novartis AG). Processes for the preparation of 4-oxo-octahydroindole-1-carbocylic acid methyl ester and derivatives thereof. CN 102119151, EP 2315748, JP 2011530566, KR 2011042222, US 2011144352, US 8084487, WO 2010018154. |
| 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) | 68376 | 6,7-dihydro-1H-indol-4(5H)-one;1,5,6,7-tetrahydro-4h-indol-4-one;4-0xo-4,5,6,7-tetrahydroindole;4-Oxo-1,5,6,7-tetrahydroindole | 13754-86-4 | C8H9NO | 详情 | 详情 |
| (II) | 68377 | tert-butyl 4-oxo-4,5,6,7-tetrahydro-1H-indole-1-carboxylate | C13H17NO3 | 详情 | 详情 | |
| (III) | 68378 | racemic N-Boc-4-hydroxyoctahydroindole;racemic tert-butyl 4-hydroxyoctahydro-1H-indole-1-carboxylate | C13H23NO3 | 详情 | 详情 | |
| (IV) | 68379 | racemic tert-butyl 4-oxooctahydro-1H-indole-1-carboxylate | C13H21NO3 | 详情 | 详情 | |
| (V) | 68380 | (3aR,7aR)-tert-butyl 4-oxooctahydro- 1H-indole-1-carboxylate | C13H21NO3 | 详情 | 详情 | |
| (VI) | 68381 | (3aR,4S,7aR)-cis-N-Boc-4- hydroxyoctahydroindole;(3aR,4S,7aR)-tert-butyl 4- hydroxyoctahydro-1H-indole-1-carboxylate | C13H23NO3 | 详情 | 详情 | |
| (VII) | 68382 | 1-ethynyl-3-methylbenzene;3-Ethynyltoluene;3-Methylphenylacetylene;3'-Methylphenylacetylene | 766-82-5 | C9H8 | 详情 | 详情 |
| (VIII) | 68384 | (3aR,4S,7aR)-tert-butyl 4-hydroxy-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate | C22H29NO3 | 详情 | 详情 | |
| (IX) | 68383 | (3aR,4S,7aR)-4-(m-tolylethynyl)octahydro-1H-indol-4-ol hydrochloride | C17H21NO.HCl | 详情 | 详情 | |
| (X) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (XI) | 10151 | Ethyleneimine; Aziridine; Azirane | 151-56-4 | C2H5N | 详情 | 详情 |
| (XII) | 26253 | 2-cyclohexen-1-one；Cyclohex-2-enone；2-cyclohexenone | 930-68-7 | C6H8O | 详情 | 详情 |
| (XIII) | 68385 | 3-(1-aziridinyl)cyclohexanone;3-(aziridin-1-yl)cyclohexanone | C8H13NO | 详情 | 详情 | |
| (XIV) | 68386 | methyl N-2-chloroethyl-N-(3-oxocyclohexyl) carbamate;methyl (2-chloroethyl)(3-oxocyclohexyl)carbamate | C10H16ClNO3 | 详情 | 详情 | |
| (XV) | 68387 | racemic methyl 4-oxooctahydroindole-1-carboxylate | C10H15NO3 | 详情 | 详情 | |
| (XVI) | 68388 | (3aR,7aR)-methyl 4-oxooctahydro-1H-indole-1-carboxylate | C10H15NO3 | 详情 | 详情 |