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【结 构 式】 
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【分子编号】13953 【品名】(3S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid; (S)-(-)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid 【CA登记号】74163-81-8 |
【 分 子 式 】C10H11NO2 【 分 子 量 】177.20288 【元素组成】C 67.78% H 6.26% N 7.9% O 18.06% |
合成路线1
该中间体在本合成路线中的序号：(VI)The condensation of alanine tert-butyl ester (I) with ethyl 2-bromo-4-phenylbutanoate (II) by means of triethylamine in hot DMF gives ethyl 2-[[1-(tert-butoxycarbonyl)ethyl]amino]-4-phenylbutanoate (III), which is partially hydrolyzed with trifluoroacetic acid yielding ethyl 2-[[1-carboxyethyl]amino]-4-phenylbutanoate (IV). The condensation of (IV) with benzyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (V) [prepared from the corresponding acid (VI) and benzyl alcohol (A) by means of polyphosphoric acid] by means of triethylamine and 1-hydroxybenzotriazole affords benzyl 2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (VII), which is finally debenzylated by hydrogenolysis with H2 over Pd/C in THF.
| 【1】 Hoefle, M.L.; Klutchko, S. (Pfizer Inc.); Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids. DD 201787; EP 0049605; EP 0096157; US 4344949 . |
| 【2】 Castaner, J.; Serradell, M.N.; Blancafort, P.; CI-906. Drugs Fut 1983, 8, 12, 1014. |
| 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) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
| (I) | 29385 | tert-butyl (2S)-2-aminopropanoate | C7H15NO2 | 详情 | 详情 | |
| (II) | 20810 | ethyl 2-bromo-4-phenylbutanoate | C12H15BrO2 | 详情 | 详情 | |
| (III) | 31121 | ethyl 2-[[(1S)-2-(tert-butoxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C19H29NO4 | 详情 | 详情 | |
| (IV) | 31124 | (2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid | C15H21NO4 | 详情 | 详情 | |
| (V) | 31122 | benzyl 1,2,3,4-tetrahydro-3-isoquinolinecarboxylate | C17H17NO2 | 详情 | 详情 | |
| (VI) | 13953 | (3S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid; (S)-(-)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid | 74163-81-8 | C10H11NO2 | 详情 | 详情 |
| (VII) | 31123 | benzyl 2-((2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate | C32H36N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The condensation of alanine tert-butyl ester (I) with ethyl 2-bromo-4-phenylbutanoate (II) by means of triethylamine in hot DMF gives ethyl 2-[[1-(tert-butoxycarbonyl)ethyl]amino]-4-phenylbutanoate (III), which is partially hydrolyzed with trifluoroacetic acid yielding ethyl 2-[[1-carboxyethyl]amino]-4-phenylbutanoate (IV). The condensation of (IV) with tert-butyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (VIII) [prepared from the corresponding acid (VI) and isobutylene (B) by means of H2SO4] as before gives tert-butyl-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (IX), which is finally hydrolyzed partially by treatment with trifluoroacetic acid.
| 【1】 Hoefle, M.L.; Klutchko, S. (Pfizer Inc.); Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids. DD 201787; EP 0049605; EP 0096157; US 4344949 . |
| 【2】 Castaner, J.; Serradell, M.N.; Blancafort, P.; CI-906. Drugs Fut 1983, 8, 12, 1014. |
| 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) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
| (I) | 29385 | tert-butyl (2S)-2-aminopropanoate | C7H15NO2 | 详情 | 详情 | |
| (II) | 20810 | ethyl 2-bromo-4-phenylbutanoate | C12H15BrO2 | 详情 | 详情 | |
| (III) | 31121 | ethyl 2-[[(1S)-2-(tert-butoxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C19H29NO4 | 详情 | 详情 | |
| (IV) | 31124 | (2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid | C15H21NO4 | 详情 | 详情 | |
| (VI) | 13953 | (3S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid; (S)-(-)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid | 74163-81-8 | C10H11NO2 | 详情 | 详情 |
| (VIII) | 31125 | tert-butyl 1,2,3,4-tetrahydro-3-isoquinolinecarboxylate | C14H19NO2 | 详情 | 详情 | |
| (IX) | 31126 | tert-butyl 2-((2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate | C29H38N2O5 | 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 synthesis of Ro-31-8959/003 (X) was carried out as follows: Condensation of L-phenylalanine (I) with formaldehyde in concentrated hydrochloric acid gave the tetrahydroisoquinoline (II), which was hydrogenated in 90% acetic acid over rhodium on carbon to yield the decahydroisoquinoline (III) as a mixture of diastereoisomers. Treatment of (III) with benzyl chloroformate in aqueous sodium hydroxide solution gave a mixture of N-protected amino acids which was separated by fractional crystallization of the cyclohexylamine salts to give the (S,S,S)-isomer. Reaction with dicyclohexylcarbodiimide and N-hydroxysuccinimide in dimethoxyethane, followed by treatment of the activated ester with tert-butylamine in dichloromethane and subsequent hydrogenolysis of the benzyloxycarbonyl protecting group gave the decahydroisoquinoline (IV). In the other branch of the synthesis L-phenylalanine was treated with benzyl chloroformate in aqueous sodium hydroxide solution to give the N-protected amino acid. This was converted to the corresponding mixed anhydride with isobutyl chloroformate and N-ethylmorpholine in tetrahydrofuran and immediately reacted with diazomethane in diethyl ether to give the diazomethyl ketone (V). Treatment of (V) with ethereal hydrogen chloride gave the chloromethyl ketone (VI), which on reduction with sodium borohydride in aqueous tetrahydrofuran gave a mixture of diastereoisomeric chlorohydrins. Solvent extraction with boiling n-hexane followed by recrystallization of the less soluble isomer from isopropanol gave pure chlorohydrin (VII), which on treatment with ethanolic potassium hydroxide gave the epoxide (VIII). Condensation of (VIII) with (IV) in ethanol gave the hydroxyethylamine (IX). Hydrogenolysis of (IX) was followed by condensation with N-benzyloxycarbonyl-L-asparagine in tetrahydrofuran in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide. Hydrogenolysis in ethanol over palladium on charcoal, followed by condensation with quinoline-2-carboxylic acid in tetrahydrofuran in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, gave the free base, Ro-31-8959/000. Treatment with methanesulfonic acid in aqueous ethanol then afforded the mesylate salt (X), Ro-31-8959/003.
| 【1】 Martin, J.A.; Ro-31-8959/003. Drugs Fut 1991, 16, 3, 210. |
| 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) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 13953 | (3S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid; (S)-(-)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid | 74163-81-8 | C10H11NO2 | 详情 | 详情 |
| (III) | 13954 | (3S)Decahydro-3-isoquinolinecarboxylic acid | C10H17NO2 | 详情 | 详情 | |
| (IV) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (V) | 13956 | (3S)-1-Imino-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]-2-butanone | C18H18N2O3 | 详情 | 详情 | |
| (VI) | 13957 | (3S)-1-Chloro-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]-2-butanone | C18H18ClNO3 | 详情 | 详情 | |
| (VII) | 13958 | (2S,3S)-1-Chloro-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]-2-butanol | C18H20ClNO3 | 详情 | 详情 | |
| (VIII) | 13959 | N-[(1S)-1-[(2S)Oxiranyl]-2-phenylethyl]-N-[(2-phenylacetyl)oxy]amine; (1S)-1-[(2S)Oxiranyl]-2-phenyl-N-[(2-phenylacetyl)oxy]-1-ethanamine | C18H19NO3 | 详情 | 详情 | |
| (IX) | 13960 | (3S,4aS,8aS)-N-(tert-Butyl)-2-((2R,3S)-2-hydroxy-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]butyl)decahydro-3-isoquinolinecarboxamide | C32H45N3O4 | 详情 | 详情 |