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【结 构 式】 
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【药物名称】KF-24345 【化学名称】3-[1-[6,7-Diethoxy-2-(4-morpholinyl)quinazolin-4-yl]piperidin-4-yl]-1,6-dimethylquinazolin-2,4(1H,3H)-dione 【CA登记号】178750-21-5, 178750-22-6 (monohydrochloride) 【 分 子 式 】C31H38N6O5 【 分 子 量 】574.68571 |
【开发单位】Kyowa Hakko (Originator) 【药理作用】Cardioprotective Agents, CARDIOVASCULAR DRUGS, PHARMACOLOGICAL TOOLS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Adenosine Reuptake Inhibitors |
合成路线1
4-Amino-1-benzylpiperidine (II) was acylated with 5-methyl-2-nitrobenzoyl chloride (I) to afford the ortho-nitrobenzamide (III), which was reduced to the amino derivative (IV) by catalytic hydrogenation in the presence of Pd/C. Treatment of (IV) with ethyl chloroformate produced the bis-carbamate (V) with concomitant cleavage of the N-benzyl group. This was cyclized to the dioxoquinazoline (VI) upon treatment with KOH in refluxing EtOH. After N-methylation employing iodomethane and NaH in DMF, hydrolysis of the carbamate group with concentrated HBr yielded the piperidinylquinazoline (VIII). This was then condensed with 2,4-dichloro-6,7-diethoxyquinazoline (IX) to furnish adduct (X). Finally, displacement of the remaining chlorine of (X) with morpholine (XI) in hot NMP gave rise to the title compound.
| 【1】 Kase, H.; Fujiwara, S.; Okamura, Y.; Karasawa, A.; Nonaka, H.; Yao, K.; Takai, H.; Synthesis and evaluation of adenosine transporter inhibitors. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PC-19. |
| 【2】 Fujiwara, S.; Okamura, Y.; Takai, H.; Nonaka, H.; Moriyama, T. (Kyowa Hakko Kogyo Co., Ltd.); Quinazoline deriv.. EP 0726267; JP 1997165385; US 5948784; WO 9606841 . |
| 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) | 44744 | 5-methyl-2-nitrobenzoyl chloride | C8H6ClNO3 | 详情 | 详情 | |
| (II) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (III) | 44746 | N-(1-benzyl-4-piperidinyl)-5-methyl-2-nitrobenzamide | C20H23N3O3 | 详情 | 详情 | |
| (IV) | 44747 | 2-amino-N-(1-benzyl-4-piperidinyl)-5-methylbenzamide | C20H25N3O | 详情 | 详情 | |
| (V) | 44748 | ethyl 4-([2-[(ethoxycarbonyl)amino]-5-methylbenzoyl]amino)-1-piperidinecarboxylate | C19H27N3O5 | 详情 | 详情 | |
| (VI) | 44749 | ethyl 4-[6-methyl-2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl]-1-piperidinecarboxylate | C17H21N3O4 | 详情 | 详情 | |
| (VII) | 44750 | ethyl 4-[1,6-dimethyl-2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl]-1-piperidinecarboxylate | C18H23N3O4 | 详情 | 详情 | |
| (VIII) | 44751 | 1,6-dimethyl-3-(4-piperidinyl)-2,4(1H,3H)-quinazolinedione | C15H19N3O2 | 详情 | 详情 | |
| (IX) | 44752 | 2,4-dichloro-6,7-diethoxyquinazoline; 2,4-dichloro-6-ethoxy-7-quinazolinyl ethyl ether | C12H12Cl2N2O2 | 详情 | 详情 | |
| (X) | 44753 | 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione | C27H30ClN5O4 | 详情 | 详情 | |
| (XI) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |