-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】4-[9-[N-(2,2,2-Trifluoroethyl)carbamoyl]-9H-fluoren-9-yl]butylphosphonic acid bis(6-methylpyridin-2-ylmethyl) diester

【CA登记号】

【分子式】C₃₄H₃₅F₃N₃O₄P

【分子量】637.64475

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Microsomal Triglyceride Transfer Protein (MTTP) Inhibitors

合成路线1

Alkylation of the dilithio derivative of fluorene-9-carboxylic acid (I) with diethyl 4-bromobutylphosphonate (II) affords adduct (III). After conversion of acid (III) to the corresponding acid chloride (IV), condensation with 2,2,2-trifluoroethylamine (V) affords amide (VI). The phosphonate ethyl ester (VI) is cleaved by means of bromotrimethylsilane yielding phosphonic acid (VII), which is further activated as the phosphonic acid chloride (VIII) by using oxalyl chloride in the presence of DMF. Finally, condensation of acid chloride (VIII) with (6-methylpyridin-2-yl)methanol (IX) leads to the target bis-pyridinylmethyl ester.

参考文献中间体

【1】 Magnin, D.R.; Biller, S.A.; Wetterau, J.; Robl, J.A.; Dickson, J.K. Jr.; Prakash, T.; Harrity, T.W.; Lawrence, R.M.; Sun, C.-Q.; Wang, T.; Logan, J.; Fryszman, O.; Connolly, F.; Jolibois, K.; Kunselman, L.; Microsomal triglyceride transfer protein inhibitors: Discovery and synthesis of alkyl phosphonates as potent MTP inhibitors and cholesterol lowering agents. Bioorg Med Chem Lett 2003, 13, 7, 1337.

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)	47744	9H-fluorene-9-carboxylic acid; 9-Fluorenecarboxylic acid; Diphenyleneacetic acid; Fluorene-9-carboxylic acid	1989-33-9	C₁₄H₁₀O₂	详情	详情
(II)	64229	diethyl 4-bromobutylphosphonate		C₈H₁₈BrO₃P	详情	详情
(III)	64230	9-[4-(diethoxyphosphoryl)butyl]-9H-fluorene-9-carboxylic acid		C₂₂H₂₇O₅P	详情	详情
(IV)	64231	diethyl 4-[9-(chlorocarbonyl)-9H-fluoren-9-yl]butylphosphonate		C₂₂H₂₆ClO₄P	详情	详情
(V)	42542	2,2,2-trifluoroethylamine; 2,2,2-trifluoro-1-ethanamine	753-90-2	C₂H₄F₃N	详情	详情
(VI)	64232	diethyl 4-(9-{[(2,2,2-trifluoroethyl)amino]carbonyl}-9H-fluoren-9-yl)butylphosphonate		C₂₄H₂₉F₃NO₄P	详情	详情
(VII)	64233	4-(9-{[(2,2,2-trifluoroethyl)amino]carbonyl}-9H-fluoren-9-yl)butylphosphonic acid		C₂₀H₂₁F₃NO₄P	详情	详情
(VIII)	64234	4-(9-{[(2,2,2-trifluoroethyl)amino]carbonyl}-9H-fluoren-9-yl)butylphosphonic dichloride		C₂₀H₁₉Cl₂F₃NO₂P	详情	详情
(IX)	64235	(6-methyl-2-pyridinyl)methanol		C₇H₉NO	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)