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【结 构 式】

【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
Extended Information