TAK-810, -Drug Synthesis Database

【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)