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【结 构 式】

【药物名称】

【化学名称】N-(4,6-Dimethyl-1-octyl-2,3-dihydro-1H-indol-7-yl)-2,2-dimethylpropionamide hydrochloride

【CA登记号】178469-58-4

【 分 子 式 】C23H39ClN2O

【 分 子 量 】395.03308

【开发单位】Kyoto Pharmaceutical (Originator)

【药理作用】Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, ACAT Inhibitors, LDL Antioxidants

合成路线1

Indole derivative (I) is converted into acetyl indoline (II) by first reduction with NaBH3CN in HOAc followed by acetylation with Ac2O in benzene or in CHCl3. Bromination of (II) with Br2 in HOAc yields derivative (III), which is then nitrated with fuming nitric acid in H2SO4/HOAc or with HNO3/Ac2O to afford nitroindoline (IV). Removal of the acetyl group of (IV) by means of NaOH or HCl in MeOH, followed by alkylation of the resulting indoline with NaH and octyl iodide (V) or octyl bromide (VI) in DMF, provides derivative (VII). Hydrogenation of (VII) over Pd/C in MeOH or benzene yields aminoindoline derivative (VIII), which is finally condensed with pivaloyl chloride (IX) in CHCl3 in the presence of Et3N to furnish the desired compound. Alternatively, conversion of (IV) into the target compound can be achieved as follows: Hydrogenation of the nitro moiety of (IV) over Pd/C in MeOH gives acetyl aminoindoline derivative (X), which is then coupled to pivaloyl chloride (IX) in CHCl3 in the presence of Et3N to afford derivative (XI). Finally, (XI) is hydrolyzed with NaOH in MeOH and the resulting secondary amide is condensed with octyl bromide (VI) in DMF in the presence of K2CO3.

1 Matsui, H.; Kamiya, S.; Shirahase, H.; Nakamura, S.; Wada, K. (Kyoto Pharmaceutical Industries, Ltd.); Novel heterocyclic derivs., process for producing the same, and medicinal use thereof. EP 0782986; JP 1996092210; US 5990150; WO 9609287 .
2 Yoshimi, A.; Kasai, M.; Shirahase, H.; Matsui, H.; Kanda, M.; Kurahashi, K.; Kamiya, S.; Takahashi, K.; Nakamura, S.; Bioavailable acyl-CoA: Cholesterol acyltransferase inhibitor with anti-peroxidative activity: Synthesis and biological activity of novel indolinyl amide and urea derivatives. Chem Pharm Bull 2000, 48, 6, 817.
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) 40796 4,6-dimethylindoline C10H13N 详情 详情
(II) 40797 1-(4,6-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-ethanone C12H15NO 详情 详情
(III) 40798 1-(5-bromo-4,6-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-ethanone C12H14BrNO 详情 详情
(IV) 40799 1-(5-bromo-4,6-dimethyl-7-nitro-2,3-dihydro-1H-indol-1-yl)-1-ethanone C12H13BrN2O3 详情 详情
(V) 45901 1-heptyl-1lambda(3)-diiodane C7H16I2 详情 详情
(VI) 45902 bromo(heptyl)-lambda(3)-iodane C7H16BrI 详情 详情
(VII) 45903 5-bromo-4,6-dimethyl-7-nitro-1-octylindoline C18H27BrN2O2 详情 详情
(VIII) 45904 5-bromo-4,6-dimethyl-1-octyl-7-indolinamine; 5-bromo-4,6-dimethyl-1-octyl-2,3-dihydro-1H-indol-7-ylamine C18H29BrN2 详情 详情
(IX) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(X) 45905 1-(7-amino-5-bromo-4,6-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-ethanone C12H15BrN2O 详情 详情
(XI) 45906 N-(1-acetyl-5-bromo-4,6-dimethyl-2,3-dihydro-1H-indol-7-yl)-2,2-dimethylpropanamide C17H23BrN2O2 详情 详情
Extended Information