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【结 构 式】 
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【分子编号】26012 【品名】ethyl (1S)-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate 【CA登记号】 |
【 分 子 式 】C18H19NO2 【 分 子 量 】281.3544 【元素组成】C 76.84% H 6.81% N 4.98% O 11.37% |
合成路线1
该中间体在本合成路线中的序号：(X)YM-905 has been obtained by two related ways: 1) The benzoylation of 2-phenylethylamine (I) with benzoyl chloride (II) and triethylamine in chloroform, or with benzoic acid (III), DPPA and triethylamine in DMF, gives the corresponding benzamide (IV), which is cyclized by means of POCl3 and P2O5 in refluxing xylene and reduced with NaBH4 in ethanol, yielding racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V). The reaction of (V) with ethyl chloroformate by means of K2CO3 in chloroform affords racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethyl ester (VI), which is transesterified with quinuclidine-3(R)-ol (VII) by means of NaH in refluxing toluene to provide the quinuclidinyl ester (VIII) as a diastereomeric mixture. This mixture is resolved by chiral HPLC, giving the target compound as a pure enantiomer. 2) The racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V) can also be submitted to optical resolution with (+)-tartaric acid to give 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (IX), which is condensed with ethyl chloroformate by means of K2CO3 in chloroform to afford 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethyl ester (VI). This compound is transesterified with quinuclidine-3(R)-ol (VII) by means of NaH in refluxing toluene to directly provide the pure enantiomer.
| 【1】 Mealy, N.; Castañer, J.; YM-905. Drugs Fut 1999, 24, 8, 871. |
| 【2】 Takeuchi, M.; Naito, R.; Hayakawa, M.; Okamoto, Y.; Yonetoku, Y.; Ikeda, K.; Isomura, Y. (Yamanouchi Pharmaceutical Co., Ltd.); Novel quinuclidine derivs. and medicinal compsn. thereof. EP 0801067; US 6017927; WO 9620194 . |
| 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) | 18333 | Phenethylamine; 2-Phenyl-1-ethanamine | 64-04-0 | C8H11N | 详情 | 详情 |
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (III) | 10202 | Benzoic acid | 65-85-0 | C7H6O2 | 详情 | 详情 |
| (IV) | 26007 | N-phenethylbenzamide | C15H15NO | 详情 | 详情 | |
| (V) | 26008 | 1-phenyl-1,2,3,4-tetrahydroisoquinoline | C15H15N | 详情 | 详情 | |
| (VI) | 26009 | ethyl 1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C18H19NO2 | 详情 | 详情 | |
| (VII) | 16152 | (3R)-1-azabicyclo[2.2.2]octan-3-ol; (R)-(-)-Quinuclidinol | 42437-96-7 | C7H13NO | 详情 | 详情 |
| (VIII) | 26010 | (3R)-1-azabicyclo[2.2.2]oct-3-yl 1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C23H26N2O2 | 详情 | 详情 | |
| (IX) | 26011 | (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline | C15H15N | 详情 | 详情 | |
| (X) | 26012 | ethyl (1S)-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C18H19NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)
| 【1】 Naito R. Yonetoku Y, Okamoto Y, et aL. 2005. Synthesis and antimuscarinic properties of quinuclidin-3-yl 1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives as novel muscarinic receptor antagonists. J Med Chem, 48(21):6597～6606 |
| 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) | 26007 | N-phenethylbenzamide | C15H15NO | 详情 | 详情 | |
| (II) | 66735 | 1-phenyl-3,4-dihydroisoquinoline | 52250-50-7 | C15H13N | 详情 | 详情 |
| (III) | 66736 | 1-phenyl-1,2,3,4-tetrahydroisoquinoline | C15H15N | 详情 | 详情 | |
| (IV) | 66737 | C15H15N.C4H6O6 | 详情 | 详情 | ||
| (V) | 26011 | (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline | C15H15N | 详情 | 详情 | |
| (VI) | 26012 | ethyl (1S)-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C18H19NO2 | 详情 | 详情 | |
| (VII) | 16152 | (3R)-1-azabicyclo[2.2.2]octan-3-ol; (R)-(-)-Quinuclidinol | 42437-96-7 | C7H13NO | 详情 | 详情 |