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【结 构 式】 
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【分子编号】32540 【品名】ethyl 1-[(phenethylamino)carbonyl]cyclopentanecarboxylate 【CA登记号】 |
【 分 子 式 】C17H23NO3 【 分 子 量 】289.37456 【元素组成】C 70.56% H 8.01% N 4.84% O 16.59% |
合成路线1
该中间体在本合成路线中的序号：(XI)Carbethoxylation of cyclopentanecarboxylic acid (VIII) with ethyl chloroformate and LDA afforded monoethyl cyclopentane-1,1-dicarboxylate (IX), which was coupled with phenethylamine (X) in the presence of TBTU, yielding amide (XI). Subsequent saponification of the ethyl ester group of (XI) gave carboxylic acid (XII), which was activated as the mixed anhydride (XIII) with isobutyl chloroformate and triethylamine. Coupling of this anhydride with aminoboronate (VII) produced the bisamide (XIV). After displacement of the bromine of (XIV) with NaN3, the resulting azide (XV) was reduced to amine (XVI) by hydrogenation over Pd/C. The required guanidine (XVII) was then obtained by condensation of (XVI) with cyanamide in refluxing EtOH. Finally, cleavage of the boronate ester by exchange with phenylboronic acid in the presence of benzenesulfonic acid furnished the title compound.
| 【1】 Verbeuren, T.; Rupin, A.; De Nanteuil, G.; Gloanec, P.; New dicarbonyl cycloalkyl based thrombin inhibitors with improved activity and selectivity compared to (D)-Phe-Pro-boroArg derivatives . 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 201. |
| 【2】 Gloanec, P.; Portevin, B.; Lila, C.; Rupin, A.; de Nanteuil, G.; Simonet, S.; Verbeuren, T. (ADIR et Cie.); Cpds. derived from boronic acid. EP 0792883; FR 2745288; US 5814622 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 35561 | (1R)-4-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]-1-butanamine; (1R)-4-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butylamine | C14H25BBrNO2 | 详情 | 详情 | |
| (VIII) | 20734 | cyclopentanecarboxylic acid | 3400-45-1 | C6H10O2 | 详情 | 详情 |
| (IX) | 32539 | 1-(ethoxycarbonyl)cyclopentanecarboxylic acid | C9H14O4 | 详情 | 详情 | |
| (X) | 18333 | Phenethylamine; 2-Phenyl-1-ethanamine | 64-04-0 | C8H11N | 详情 | 详情 |
| (XI) | 32540 | ethyl 1-[(phenethylamino)carbonyl]cyclopentanecarboxylate | C17H23NO3 | 详情 | 详情 | |
| (XII) | 32541 | 1-[(phenethylamino)carbonyl]cyclopentanecarboxylic acid | C15H19NO3 | 详情 | 详情 | |
| (XIII) | 32542 | 1-[N-(2-Phenylethyl)carbamoyl]cyclopentylcarbonyl isobutoxycarbonyl anhydride | C20H27NO5 | 详情 | 详情 | |
| (XIV) | 35562 | N(1)-[(1R)-4-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butyl]-N(1)-phenethyl-1,1-cyclopentanedicarboxamide | C29H42BBrN2O4 | 详情 | 详情 | |
| (XV) | 35563 | N(1)-[(1R)-4-azido-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butyl]-N(1)-phenethyl-1,1-cyclopentanedicarboxamide | C29H42BN5O4 | 详情 | 详情 | |
| (XVI) | 35564 | N(1)-[(1R)-4-amino-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butyl]-N(1)-phenethyl-1,1-cyclopentanedicarboxamide | C29H44BN3O4 | 详情 | 详情 | |
| (XVII) | 35565 | N(1)-[(1R)-4-[[amino(imino)methyl]amino]-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butyl]-N(1)-phenethyl-1,1-cyclopentanedicarboxamide | C30H46BN5O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Condensation of cyclopentanecarboxylic acid (VIII) with ethyl chloroformate in the presence of LDA afforded 1,1-cyclopentanedicarboxylic acid monoethyl ester (IX), which was coupled with phenethylamine (X) by means of TBTU to produce amide (XI). Ester hydrolysis of (XI) with NaOH gave carboxylic acid (XII), which was activated as the mixed anhydride (XIII) with isobutyl chloroformate, and then coupled to the chiral aminoboronate (VII), yielding diamide (XIV). Displacement of the bromine of (XIV) with NaN3, followed by hydrogenation of the resulting azide (XV) gave rise to amine (XVI). The chiral auxiliary of (XVI) was finally removed by treatment with phenylboronic acid.
| 【1】 Verbeuren, T.; Rupin, A.; De Nanteuil, G.; Gloanec, P.; New dicarbonyl cycloalkyl based thrombin inhibitors with improved activity and selectivity compared to (D)-Phe-Pro-boroArg derivatives . 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 201. |
| 【2】 Gloanec, P.; Portevin, B.; Lila, C.; Rupin, A.; de Nanteuil, G.; Simonet, S.; Verbeuren, T. (ADIR et Cie.); Cpds. derived from boronic acid. EP 0792883; FR 2745288; US 5814622 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 | |
| (VII) | 32538 | (1R)-5-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]-1-pentanamine; (1R)-5-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentylamine | C15H27BBrNO2 | 详情 | 详情 | |
| (VIII) | 20734 | cyclopentanecarboxylic acid | 3400-45-1 | C6H10O2 | 详情 | 详情 |
| (IX) | 32539 | 1-(ethoxycarbonyl)cyclopentanecarboxylic acid | C9H14O4 | 详情 | 详情 | |
| (X) | 18333 | Phenethylamine; 2-Phenyl-1-ethanamine | 64-04-0 | C8H11N | 详情 | 详情 |
| (XI) | 32540 | ethyl 1-[(phenethylamino)carbonyl]cyclopentanecarboxylate | C17H23NO3 | 详情 | 详情 | |
| (XII) | 32541 | 1-[(phenethylamino)carbonyl]cyclopentanecarboxylic acid | C15H19NO3 | 详情 | 详情 | |
| (XIII) | 32542 | 1-[N-(2-Phenylethyl)carbamoyl]cyclopentylcarbonyl isobutoxycarbonyl anhydride | C20H27NO5 | 详情 | 详情 | |
| (XIV) | 32543 | N(1)-[(1R)-5-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentyl]-N(1)-phenethyl-1,1-cyclopentanedicarboxamide | C30H44BBrN2O4 | 详情 | 详情 | |
| (XV) | 32544 | N(1)-[(1R)-5-azido-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentyl]-N(1)-phenethyl-1,1-cyclopentanedicarboxamide | C30H44BN5O4 | 详情 | 详情 | |
| (XVI) | 32545 | N(1)-[(1R)-5-amino-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentyl]-N(1)-phenethyl-1,1-cyclopentanedicarboxamide | C30H46BN3O4 | 详情 | 详情 |