ethyl 2-(4-aminophenyl)-3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】23156

【品名】ethyl 2-(4-aminophenyl)-3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate

【CA登记号】

【分子式】C₃₂H₂₉F₂N₃O₃S

【分子量】573.6634864

【元素组成】C 67% H 5.1% F 6.62% N 7.32% O 8.37% S 5.59%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XIV)

Compound (XI) was condensed with methyl benzyl amine (XII) to furnish tertiary amine (XIII). The nitro group of (XIII) was then reduced with iron powder and HCl to afford amine (XIV). Subsequent acylation of (XIV) with isobutyric anhydride (XV) in the presence of Et3N produced amide (XVI). The title compound was then obtained by transesterification between (XVI) and titanium isopropoxide in isopropanol, followed by treatment with ethanolic HCl.

参考文献中间体

合成目标

【1】 Cho, N.; Harada, M.; Imaeda, T.; Imada, T.; Matsumoto, H.; Hayase, Y.; Sasaki, S,; Furuya, S.; Suzuki, N.; Okubo, S.; Ogi, K.; Endo, S.; Onda, H.; Fujino, M.; Discovery of a novel, potent, and orally active no. J Med Chem 1998, 41, 22, 4190.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	11969	N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine	103-67-3	C₈H₁₁N	详情	详情
(XIII)	23155	ethyl 3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₃₂H₂₇F₂N₃O₅S	详情	详情
(XIV)	23156	ethyl 2-(4-aminophenyl)-3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₃₂H₂₉F₂N₃O₃S	详情	详情
(XV)	22334	1-methylpropionic anhydride	97-72-3	C₈H₁₄O₃	详情	详情
(XVI)	23158	ethyl 3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-2-[4-(isobutyrylamino)phenyl]-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₃₆H₃₅F₂N₃O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

The cyclization of phenylacetone (I) with ethyl cyanoacetate (II) by means of HOAc and AcONH4 in refluxing benzene, followed by a treatment with sulfur in hot ethanol gives 2-amino-4-methyl-5-phenylthiophene-3-carboxylic acid ethyl ester (III). The condensation of (III) with diethyl ethoxymethylene malonate (IV) by heating at 120 C yields the adduct (V), which is submitted to a selective hydrolysis with KOH in hot ethanol to afford the carboxylic acid (VI). The cyclization of (VI) by means of PPE at 120 C provides the thienopyridine (VII), which is nitrated with NaNO3 and H2SO4 to give the 4-nitrophenyl derivative (VIII). The alkylation of the hydroxy-thienopyridine (VIII) with 2,6-difluorobenzyl chloride (IX) by means of NaH in DMF yields the benzylated thienopyridinone (X), which is brominated with NBS and AIBN in refluxing CCl4 to afford the bromomethyl derivative (XI). The condensation of (XI) with N-benzyl-N-methylamine (XII) by means of TEA in DMF provides the tertiary amine (XIII). The reduction of the nitro group of (XIII) by means of Fe and HCl in ethanol gives the 4-aminophenyl derivative (XIV), which is acylated with trifluoroacetic anhydride and TEA to yield the acetamide (XV). The reaction of (XV) with N,O-dimethylhydroxylamine (XVI) and TEA in CH2Cl2 affords the methoxyamide (XVII).

参考文献中间体

合成目标

【1】 Imada, T.; Fujino, M.; Suzuki, N.; Harada, M.; Kasai, S.; Sasaki, S.; Endo, S.; Hayase, Y.; Furuya, S.; Cho, N.; Discovery of the thieno[2,3-b]pyridin-4-one derivative TAK-810: Highly potent and orally active nonpeptide LHRH (GnRH) antagonist (I). 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 353.
【2】 Suzuki, N.; Furuya, S.; Choh, N.; Imada, T. (Takeda Chemical Industries, Ltd.); Thienopyridine cpds., their production and use. EP 1090010; JP 2000219690; JP 2000219691; US 6262267; US 6329388; WO 0000493 .

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)	23143	1-Phenylacetone; Methyl benzyl ketone; Benzyl methyl ketone; phenylacetone; Phenyl-2-propanone	103-79-7	C₉H₁₀O	详情	详情
(II)	11877	Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate	105-56-6	C₅H₇NO₂	详情	详情
(III)	23145	ethyl 2-amino-4-methyl-5-phenyl-3-thiophenecarboxylate		C₁₄H₁₅NO₂S	详情	详情
(IV)	14088	Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate	87-13-8	C₁₀H₁₆O₅	详情	详情
(V)	23147	diethyl 2-([[3-(ethoxycarbonyl)-4-methyl-5-phenyl-2-thienyl]amino]methylene)malonate		C₂₂H₂₅NO₆S	详情	详情
(VI)	23148	2-[[3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-propenyl]amino]-4-methyl-5-phenyl-3-thiophenecarboxylic acid		C₂₀H₂₁NO₆S	详情	详情
(VII)	23149	ethyl 4-hydroxy-3-methyl-2-phenylthieno[2,3-b]pyridine-5-carboxylate		C₁₇H₁₅NO₃S	详情	详情
(VIII)	58691	ethyl 4-hydroxy-3-methyl-2-(4-nitrophenyl)thieno[2,3-b]pyridine-5-carboxylate		C₁₇H₁₄N₂O₅S	详情	详情
(IX)	23150	2-(chloromethyl)-1,3-difluorobenzene	697-73-4	C₇H₅ClF₂	详情	详情
(X)	23152	ethyl 7-(2,6-difluorobenzyl)-3-methyl-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₂₄H₁₈F₂N₂O₅S	详情	详情
(XI)	23153	ethyl 3-(bromomethyl)-7-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₂₄H₁₇BrF₂N₂O₅S	详情	详情
(XII)	11969	N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine	103-67-3	C₈H₁₁N	详情	详情
(XIII)	23155	ethyl 3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₃₂H₂₇F₂N₃O₅S	详情	详情
(XIV)	23156	ethyl 2-(4-aminophenyl)-3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₃₂H₂₉F₂N₃O₃S	详情	详情
(XV)	58692	ethyl 3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-4-oxo-2-{4-[(2,2,2-trifluoroacetyl)amino]phenyl}-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₃₄H₂₈F₅N₃O₄S	详情	详情
(XVI)	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(XVII)	58693	3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-N-methoxy-N-methyl-4-oxo-2-{4-[(2,2,2-trifluoroacetyl)amino]phenyl}-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide		C₃₄H₂₉F₅N₄O₄S	详情	详情

Extended Information