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【结 构 式】 
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【分子编号】20734 【品名】cyclopentanecarboxylic acid 【CA登记号】3400-45-1 |
【 分 子 式 】C6H10O2 【 分 子 量 】114.1442 【元素组成】C 63.14% H 8.83% O 28.03% |
合成路线1
该中间体在本合成路线中的序号：(IV)CPX has been obtained by two related ways: 1) Nitrosation of 6-amino-1,3-dipropyluracil (I) with NaNO2 in acetic acid gives the 5-nitrosouracil derivative (II), which is reduced with H2 over Pd/C in ethanol to yield 5,6-diamino-1,3-dipropyluracil (III). Acylation of (III) with cyclopentanecarboxylic acid (IV) by heating up to the mixture's melting point or by treatment with diisopropylcarbodiimide (DIC) gives the amide (V), which is finally cyclized by means of NaOH in refluxing water or refluxing methanol/water. 2) Acylation of the 5-nitrosouracil (II) with cyclopentanecarbonyl chloride (VI) by means of lithium hexamethyldisilazane (LHMDS) in THF gives the amide (VII), which is submitted to a reductive cyclization with Sn(OAc)2 in the same solvent.
| 【1】 Castaner, J.; Martin, L.; Sorbera, L.A.; CPX. Drugs Fut 2000, 25, 10, 1011. |
| 【2】 Hiner, R.N.; Rzeszotarski, W.J.; Hicks, R.P.; Costello, D.G.; Feeney, S.W.; Blake, P.R.; Erickson, R.H.; Abreu, M.E.; 1,3,8-Trisubstituted xanthines. Effects of substitution pattern upon adenosine receptor A1/A2 affinity. J Med Chem 1991, 34, 4, 1431. |
| 【3】 Schow, S.R.; Lum, R.T.; Melville, C.R.; Nelson, M.G.; Moore, A.G.; Convenient one-pot synthesis of xanthines from 6-amino-5-nitrosouracils. Synthesis 1999, 7, 1123. |
| 【4】 Hong, O.; Ukena, D.; Padgett, W.L.; Daly, J.W.; Shamim, M.T.; 8-Aryl- and 8-cycloalkyl-1,3-dipropylxanthines: Further potent and selective antagonists for A1-adenosine receptors. J Med Chem 1988, 31, 3, 613. |
| 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) | 41030 | 6-amino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | 41862-14-0 | C10H17N3O2 | 详情 | 详情 |
| (II) | 41031 | 6-amino-5-nitroso-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H16N4O3 | 详情 | 详情 | |
| (III) | 14628 | 5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H18N4O2 | 详情 | 详情 | |
| (IV) | 20734 | cyclopentanecarboxylic acid | 3400-45-1 | C6H10O2 | 详情 | 详情 |
| (V) | 41034 | N-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-5-pyrimidinyl)cyclopentanecarboxamide | C16H26N4O3 | 详情 | 详情 | |
| (VI) | 41032 | cyclopentanecarbonyl chloride | 4524-93-0 | C6H9ClO | 详情 | 详情 |
| (VII) | 41033 | N-(5-nitroso-2,6-dioxo-1,3-dipropyl-1,2,3,6-tetrahydro-4-pyrimidinyl)cyclopentanecarboxamide | C16H24N4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)2b) The alkylation of 2-(dimethoxyphosphoryl)acetic acid tert-butyl ester (XII) with 2-phenylethyl bromide (XIII) by means of potassium tert-butoxide in DMF gives 2-(dimethoxyphosphoryl)-4-phenylbutyric acid tert-butyl ester (XIV), which is allowed to react with formaldehyde/potasium tert-butoxide in THF to afford the tert-butyl acrylate (XV). The condensation of (XV) with cyclopentanecarboxylic acid (XVI) by means of butyllithium/diisopropylamine in THF affords racemic (II), which is finally submitted to optical resolution with L-(-)-alpha-methylbenzylamine to afford the chiral (R)-intermediate (II).
| 【1】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 . |
| 【2】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(II) | 20753 | 1-[2-(tert-butoxycarbonyl)-4-phenylbutyl]cyclopentanecarboxylic acid | C21H30O4 | 详情 | 详情 | |
| (XII) | 20748 | tert-butyl 2-(dimethoxyphosphoryl)acetate | C8H17O5P | 详情 | 详情 | |
| (XIII) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
| (XIV) | 20750 | tert-butyl 2-(dimethoxyphosphoryl)-4-phenylbutanoate | C16H25O5P | 详情 | 详情 | |
| (XV) | 20751 | tert-butyl 2-phenethylacrylate | C15H20O2 | 详情 | 详情 | |
| (XVI) | 20734 | cyclopentanecarboxylic acid | 3400-45-1 | C6H10O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)2b) The chiral intermediate acid (II) has been obtained as follows: The alkylation of diethyl malonate (XII) with 2-phenylethyl bromide (XIII) by means of potassium tert-butoxide in DMF gives diethyl 2-(2-phenylethyl)malonate (XIV), which is treated with KOH in ice-cooled water to afford the corresponding monoester monoacid (XV). The reacction of (XV) with formaldehyde in piperidine/water gives teh acrylate (XVI), which is condensed with cyclopentanecarboxylic acid (XVII) by meansof butyllithium/diisopropylamine in THF to afford racemic (II). Finally, this racemate is submitted to optical resolution with L-(-)-alpha-methylbenzylamine to afford the chiral (R)-intermediate (II).
| 【1】 Sorbera, L.A.; Leeson, P.A.; Castañer, J.; SLV-306. Drugs Fut 2002, 27, 1, 27. |
| 【2】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 . |
| 【3】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(II) | 20735 | 1-[2-(ethoxycarbonyl)-4-phenylbutyl]cyclopentanecarboxylic acid | C19H26O4 | 详情 | 详情 | |
| (XIII) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
| (XIV) | 20731 | diethyl 2-phenethylmalonate | C15H20O4 | 详情 | 详情 | |
| (XV) | 20732 | 2-(ethoxycarbonyl)-4-phenylbutyric acid | C13H16O4 | 详情 | 详情 | |
| (XVI) | 20733 | ethyl 2-phenethylacrylate | C13H16O2 | 详情 | 详情 | |
| (XVII) | 20734 | cyclopentanecarboxylic acid | 3400-45-1 | C6H10O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)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5
该中间体在本合成路线中的序号：(VIII)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 |