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【结 构 式】

【药物名称】TAK-810

【化学名称】N-[4-[3-(N-Benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-5-isobutyryl-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl]phenyl]-1-hydroxycyclopropanecarboxamide

【CA登记号】253433-89-5, 253433-90-8 (monohydrochloride)

【 分 子 式 】C37H35F2N3O4S

【 分 子 量 】655.77

【开发单位】Takeda (Originator)

【药理作用】ENDOCRINE DRUGS, Endometriosis Therapy, Gynecological Disorders, Treatment of , GnRH (LHRH) Antagonists

合成路线1合成路线2合成路线3

合成路线1

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
【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

合成路线2

The reaction of the methoxyamide (XVII) with isopropylmagnesium bromide (XVIII) in dioxane gives the isobutyryl derivative (XIX), which is deacylated by means of TFA in dichloromethane to yield the aromatic amine (XX). The acylation of (XX) with 1-acetoxycyclopropanecarbonyl chloride (XXI) by means of TEA in dichloromethane affords the corresponding amide (XXII), which is finally deacetylated by means of NaOH in MeOH to provide the target thienopyridinone derivative.

参考文献 中间体
【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.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(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
(XVIII) 33398 bromo(isopropyl)magnesium 920-39-8 C3H7BrMg 详情 详情
(XIX) 58694 N-{4-[3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-5-isobutyryl-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide C35H30F5N3O3S 详情 详情
(XX) 58695 2-(4-aminophenyl)-3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-5-isobutyrylthieno[2,3-b]pyridin-4(7H)-one C33H31F2N3O2S 详情 详情
(XXI) 58696 1-(chlorocarbonyl)cyclopropyl acetate C6H7ClO3 详情 详情
(XXII) 58697 1-({4-[3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-5-isobutyryl-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl]anilino}carbonyl)cyclopropyl acetate C39H37F2N3O5S 详情 详情

合成路线3

Alternatively, the ethyl ester group of (XIII) is treated with N,O-dimethylhydroxylamine (XVI) and TEA as before to give the methoxyamide (XXIII), which is treated with isopropylmagnesium bromide (XVIII) in dioxane to yield the isobutyryl derivative (XXIV). The reduction of the nitro group of (XXIV) by means of Fe and HCl in ethanol affords the aromatic amine (XX), which is finally acylated with 1-hydroxycyclopropanecarboxylic acid (XXV) by means of BOP and DIEA in CH2Cl2 to provide the target thienopyridinone derivative.

参考文献 中间体
【1】 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
(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
(XVI) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(XVIII) 33398 bromo(isopropyl)magnesium 920-39-8 C3H7BrMg 详情 详情
(XX) 58695 2-(4-aminophenyl)-3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-5-isobutyrylthieno[2,3-b]pyridin-4(7H)-one C33H31F2N3O2S 详情 详情
(XXIII) 58698 3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-N-methoxy-N-methyl-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide C32H28F2N4O5S 详情 详情
(XXIV) 58699 3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-5-isobutyryl-2-(4-nitrophenyl)thieno[2,3-b]pyridin-4(7H)-one C33H29F2N3O4S 详情 详情
(XXV) 58700 1-Hydroxy-1-cyclopropanecarboxylic acid 17994-25-1 C4H6O3 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)