Palonidipine hydrochloride, TC-81, -Drug Synthesis Database

【结构式】

【药物名称】Palonidipine hydrochloride, TC-81

【化学名称】(±)-3-(N-Benzyl-N-methylamino)-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(2-fluoro-5-nitrophenyl)-1,4-di-hydropyridine-3,5-dicarboxylate hydrochloride
　　　　　　(±)-3-(N-Benzyl-N-methylamino)-2,2-dimethylpropyl 3-methoxycarbonyl-2,6-dimethyl-4-(2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-5-carboxylate hydrochloride

【CA登记号】96515-73-0 (free base, non-specified stereoch.), 96515-74-1 (monoHCl salt, non-specified stereoch.)

【分子式】C₂₉H₃₅ClFN₃O₆

【分子量】576.0702

【开发单位】Teijin (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Calcium Channel Blockers

合成路线1 合成路线2 合成路线3

合成路线1

A new synthesis for TC-81 has been described: By condensation of 2-(2-fluoro-5-nitrobenzylidene)acetoacetic acid methyl ester (I) with 3-aminocrotonic acid 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl ester (II) by means of triethylamine in refluxing isopropanol. The starting products (I) and (II) are prepared as follows: The condensation of 2-fluoro-5-nitrobenzaldehyde (III) with methylacetoacetate (IV) by means of HCl in toluene gives the benzylidene derivative (I). The condensation of 3-(N-benzyl-N-methylamino)-2,2-dimethylpropanol (V) with diketene (VI) in hot benzene gives the acetoacetic ester (VII), which is treated with gaseous ammonia in ethanol, yielding crotonate (III).

参考文献中间体

【1】 Okamiya, Y.; Yamaguchi, H.; Takeshita, T.; Sunakawa, K.; Kanno, H.; Synthesis and antihypertensive activity of 1,4-dihydropyridine derivatives with a 4-(disubstituted phenyl)ring and an aminoalkyl ester group: Highly potent and long-lasting calcium antagonists. Chem Pharm Bull 1992, 40, 8, 2049.

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)	12106	methyl (Z)-2-acetyl-3-(2-fluoro-5-nitrophenyl)-2-propenoate		C₁₂H₁₀FNO₅	详情	详情
(II)	12107	3-[benzyl(methyl)amino]-2,2-dimethylpropyl (E)-3-amino-2-butenoate		C₁₇H₂₆N₂O₂	详情	详情
(III)	12108	2-Fluoro-5-nitrobenzaldehyde	27996-87-8	C₇H₄FNO₃	详情	详情
(IV)	11791	methyl 3-oxobutanoate; Methyl acetoacetate	105-45-3	C₅H₈O₃	详情	详情
(V)	12110	3-[Benzyl(methyl)amino]-2,2-dimethyl-1-propanol		C₁₃H₂₁NO	详情	详情
(VI)	11367	4-Methylene-2-oxetanone; Acetyl ketene	674-82-8	C₄H₄O₂	详情	详情
(VII)	12112	3-[benzyl(methyl)amino]-2,2-dimethylpropyl 3-oxobutanoate		C₁₇H₂₅NO₃	详情	详情

合成路线2

1) The reaction of N-methyl-N-benzylamine (I) with isobutyraldehyde (II) and formaldehyde (III) in refluxing isopropanol, followed by hydrogenation with NaBH4 gives 3-(N-benzyl-N-methylamino)-2,2-dimethylpropanol (IV), which is condensed with diketene (V) in refluxing benzene to yield 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate (VI). Finally, this compound is submitted to cyclization with 2-fluoro-5-nitrobenzeldehyde (VII) (prepared by oxidation of 2-fluoro-5-nitrotoluene (VIII) with CrO3 in acetic ahydride-H2SO4) and methyl 3-aminocrotonate (IX) in refluxing isopropanol.

参考文献中间体

【1】 Yamaguchi, H.; Odamiya, Y.; Kanno, H.; Sunakawa, K. (Teijin Ltd.); 1,4-Dihydropyridine derivs., process for production thereof and pharmaceutical use thereof. EP 0128010; JP 1984222474; JP 1984227859; JP 1985104065; US 4578395 .
【2】 Prous, J.; Castaner, J.; TC-81. Drugs Fut 1989, 14, 3, 239.

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)	11969	N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine	103-67-3	C₈H₁₁N	详情	详情
(II)	13226	2-Methylpropanal; Isobutyraldehyde	78-84-2	C₄H₈O	详情	详情
(IV)	12110	3-[Benzyl(methyl)amino]-2,2-dimethyl-1-propanol		C₁₃H₂₁NO	详情	详情
(V)	11367	4-Methylene-2-oxetanone; Acetyl ketene	674-82-8	C₄H₄O₂	详情	详情
(VI)	12112	3-[benzyl(methyl)amino]-2,2-dimethylpropyl 3-oxobutanoate		C₁₇H₂₅NO₃	详情	详情
(VII)	12108	2-Fluoro-5-nitrobenzaldehyde	27996-87-8	C₇H₄FNO₃	详情	详情
(VIII)	20560	1-fluoro-2-methyl-4-nitrobenzene	455-88-9	C₇H₆FNO₂	详情	详情
(IX)	11372	Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate		C₅H₉NO₂	详情	详情

合成路线3

2) The condensation of acetoacetic ester (VI) with aldehyde (VII) gives the benzylidene derivative (X), which is then submitted to cyclization with crotonate (IX) as before. 3) Finally, the title product can also be obtained by cyclization of benzylidene derivative (X) with methyl acetoacetate (XI) and concentrated aqueous ammonia in refluxing isopropanol.

参考文献中间体

【1】 Yamaguchi, H.; Odamiya, Y.; Kanno, H.; Sunakawa, K. (Teijin Ltd.); 1,4-Dihydropyridine derivs., process for production thereof and pharmaceutical use thereof. EP 0128010; JP 1984222474; JP 1984227859; JP 1985104065; US 4578395 .
【2】 Prous, J.; Castaner, J.; TC-81. Drugs Fut 1989, 14, 3, 239.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	12112	3-[benzyl(methyl)amino]-2,2-dimethylpropyl 3-oxobutanoate		C₁₇H₂₅NO₃	详情	详情
(VII)	12108	2-Fluoro-5-nitrobenzaldehyde	27996-87-8	C₇H₄FNO₃	详情	详情
(IX)	11372	Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate		C₅H₉NO₂	详情	详情
(X)	20565	3-[benzyl(methyl)amino]-2,2-dimethylpropyl (Z)-2-acetyl-3-(2-fluoro-5-nitrophenyl)-2-propenoate		C₂₄H₂₇FN₂O₅	详情	详情
(XI)	11791	methyl 3-oxobutanoate; Methyl acetoacetate	105-45-3	C₅H₈O₃	详情	详情

Extended Information