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【结 构 式】 
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【分子编号】57626 【品名】3-{6-chloro-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)ethynyl]-9H-purin-9-yl}benzonitrile 【CA登记号】 |
【 分 子 式 】C26H19ClFN5O 【 分 子 量 】471.9210632 【元素组成】C 66.17% H 4.06% Cl 7.51% F 4.03% N 14.84% O 3.39% |
合成路线1
该中间体在本合成路线中的序号：(X)Condensation of chloropyrimidinone (I) with 3-aminobenzonitrile (II) produces the anilino pyrimidinone (III). This is subsequently chlorinated to chloropyrimidine (IV) by using phosphoryl chloride in the presence of N,N-dimethylaniline and tetraethylammonium chloride. Reduction of the nitro group of (IV) to amine (V) is performed by means of stannous chloride and sodium borohydride. Condensation of diaminopyrimidine (V) with 3-fluorobenzaldehyde (VI), followed by oxidative treatment with ferric chloride, furnishes the purine derivative (VII). Conversion of aminopurine (VII) to the iodo analogue (VIII) is achieved by diazotization with isoamyl nitrite in the presence of cuprous iodide and diiodomethane. Iodopurine (VIII) is then coupled to 1-ethynylcyclohexanol (IX) in the presence of palladium catalyst to give the disubstituted alkyne (X).
| 【1】 Asano, O.; Kawata, T.; Inoue, T.; Horizoe, T.; Yasuda, N.; Nagata, K.; Nagaoka, J.; Kobayashi, S.; Tanaka, I.; Abe, S.; Harada, H.; Murakami, M.; 2-Alkynyl-8-aryladenines possessing an amide moiety: Their synthesis and structure-activity relationships of effects on hepatic glucose production induced via agonism of the A2B adenosine receptor. Bioorg Med Chem 2001, 9, 10, 2709. |
| 【2】 Asano, O.; Hoshino, Y.; Kobayashi, S.; Nagata, K.; Harada, H.; Yoshikawa, S.; Nagaoka, J.; Inoue, T.; Horizoe, T.; Yasuda, N.; Murakami, M. (Eisai Co., Ltd.); Purine derivs. and adenosine A2 receptor antagonists serving as preventives/remedies for diabetes. EP 1054012; JP 1999263789; WO 9935147 . |
| 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) | 57619 | N-(4-chloro-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinyl)acetamide | C6H5ClN4O4 | 详情 | 详情 | |
| (II) | 28662 | 3-aminobenzonitrile | 2237-30-1 | C7H6N2 | 详情 | 详情 |
| (III) | 57620 | N-[4-(3-cyanoanilino)-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinyl]acetamide | C13H10N6O4 | 详情 | 详情 | |
| (IV) | 57621 | N-[4-chloro-6-(3-cyanoanilino)-5-nitro-2-pyrimidinyl]acetamide | C13H9ClN6O3 | 详情 | 详情 | |
| (V) | 57622 | 3-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]benzonitrile | C11H9ClN6 | 详情 | 详情 | |
| (VI) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (VII) | 57623 | 3-[2-amino-6-chloro-8-(3-fluorophenyl)-9H-purin-9-yl]benzonitrile | C18H10ClFN6 | 详情 | 详情 | |
| (VIII) | 57624 | 3-[6-chloro-8-(3-fluorophenyl)-2-iodo-9H-purin-9-yl]benzonitrile | C18H8ClFIN5 | 详情 | 详情 | |
| (IX) | 57625 | 1-ethynylcyclohexanol | C8H12O | 详情 | 详情 | |
| (X) | 57626 | 3-{6-chloro-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)ethynyl]-9H-purin-9-yl}benzonitrile | C26H19ClFN5O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Displacement of the chloro group of (X) by means of ethanolic ammonia upon heating in a pressure vessel affords the amino purine (XI). The cyano group of (XI) is then hydrolyzed to the target amide with sodium peroxide, and the resultant compound is finally converted to the hydrochloride salt.
| 【1】 Asano, O.; Kawata, T.; Inoue, T.; Horizoe, T.; Yasuda, N.; Nagata, K.; Nagaoka, J.; Kobayashi, S.; Tanaka, I.; Abe, S.; Harada, H.; Murakami, M.; 2-Alkynyl-8-aryladenines possessing an amide moiety: Their synthesis and structure-activity relationships of effects on hepatic glucose production induced via agonism of the A2B adenosine receptor. Bioorg Med Chem 2001, 9, 10, 2709. |
| 【2】 Asano, O.; Hoshino, Y.; Kobayashi, S.; Nagata, K.; Harada, H.; Yoshikawa, S.; Nagaoka, J.; Inoue, T.; Horizoe, T.; Yasuda, N.; Murakami, M. (Eisai Co., Ltd.); Purine derivs. and adenosine A2 receptor antagonists serving as preventives/remedies for diabetes. EP 1054012; JP 1999263789; WO 9935147 . |