(2R,3S)-N,6-dimethoxy-2-(4-methoxyphenyl)-N-methyl-2,3-dihydro-1-benzothiophene-3-carboxamide -Drug Synthesis Database

【结构式】

【分子编号】30912

【品名】(2R,3S)-N,6-dimethoxy-2-(4-methoxyphenyl)-N-methyl-2,3-dihydro-1-benzothiophene-3-carboxamide

【CA登记号】

【分子式】C₁₉H₂₁NO₄S

【分子量】359.44608

【元素组成】C 63.49% H 5.89% N 3.9% O 17.8% S 8.92%

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：(VIII)

The hydrolysis of 2-(dimethylamino)-6-methoxybenzo[b]thiophene (I) with HCl in refluxing THF gives 6-methoxybenzo[b]thiophen-2(3H)-one (II), which is condensed with 4-methoxybenzaldehyde (III) by means of piperidine in methanol yielding the 3-benzylidene derivative (IV). The rearrangement of (IV) with the same catalyst and solvent affords trans-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydrobenzo[b]thiophene-3-carboxylic acid methyl ester (V), which is hydrolyzed with NaOH in methanol to the corresponding acid (VI). The reaction of (VI) with SOCl2 in dichloromethane gives the acyl chloride (VII), which is condensed with N,O-dimethylhydroxylamine by means of triethylamine in dichloromethane providing the N-methoxy-N-methylamide (VIII). The condensation of (VIII) with the Grignard reagent (IX) in THF affords the dimethyl ether of the target compound (X), which is finally demethylated with AlCl3 and propanethiol in dichloromethane. The intermediate Grignard reagent (IX) has been obtained by condensation of 4-bromophenol (XI) with 1-(2-chloroethyl)piperidine (XII) by means of K2CO3 in hot DMF to give 1-[2-(4-bromophenoxy)ethyl]piperidine (XIII), which is then treated with magnesium in THF to afford (IX).

参考文献中间体

合成目标

【1】 Stephenson, G.A.; Glasebrook, A.L.; Schmid, C.R.; Misner, J.W.; Synthesis and biological activity of trans-2,3-dihydroraloxifene. Bioorg Med Chem Lett 1999, 9, 8, 1137.
【2】 Glasebrook, A.L.; Schmid, C.R.; Stephenson, G.A.; Misner, J.W.; Synthesis and biological activity of dihydroraloxifene. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 072.
【3】 Misner, J.W.; Schmid, C.R. (Eli Lilly and Company); Intermediates and processes for preparing benzo[b]thiophenes. EP 0979076; WO 9848793 .

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)	30906	N-(6-methoxy-1-benzothiophen-2-yl)-N,N-dimethylamine; 6-methoxy-N,N-dimethyl-1-benzothiophen-2-amine		C₁₁H₁₃NOS	详情	详情
(II)	30907	6-methoxy-1-benzothiophen-2(3H)-one		C₉H₈O₂S	详情	详情
(III)	27251	4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde	123-11-5	C₈H₈O₂	详情	详情
(IV)	30908	6-methoxy-3-[(Z)-(4-methoxyphenyl)methylidene]-1-benzothiophen-2-one		C₁₇H₁₄O₃S	详情	详情
(V)	30909	methyl (2R,3S)-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1-benzothiophene-3-carboxylate		C₁₈H₁₈O₄S	详情	详情
(VI)	30910	(2R,3S)-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1-benzothiophene-3-carboxylic acid		C₁₇H₁₆O₄S	详情	详情
(VII)	30911	(2R,3R)-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1-benzothiophene-3-carbonyl chloride		C₁₇H₁₅ClO₃S	详情	详情
(VIII)	30912	(2R,3S)-N,6-dimethoxy-2-(4-methoxyphenyl)-N-methyl-2,3-dihydro-1-benzothiophene-3-carboxamide		C₁₉H₂₁NO₄S	详情	详情
(IX)	30913	bromo[4-[2-(1-piperidinyl)ethoxy]phenyl]magnesium		C₁₃H₁₈BrMgNO	详情	详情
(X)	30914	[(2R,3S)-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone		C₃₀H₃₃NO₄S	详情	详情
(XI)	25313	4-bromophenol	106-41-2	C₆H₅BrO	详情	详情
(XII)	10117	1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine	1932-03-2	C₇H₁₄ClN	详情	详情
(XIII)	30915	4-bromophenyl 2-(1-piperidinyl)ethyl ether; 1-[2-(4-bromophenoxy)ethyl]piperidine		C₁₃H₁₈BrNO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reaction of pyrimidine-2,4(1H,3H)-dione (I) with benzyl 2-bromoacetate (II) by means of K2CO3 in DMF gives the pyrimidine-1-acetic acid benzyl ester (III), which is condensed with tert-butyl 2-bromoacetate (IV) by means of NaH in DMF to yield the pyrimidine bis acetate (V). Selective deprotection of the benzyl ester of (V) by means of H2 over Pd(OH)2 in ethyl acetate affords the mono acetic acid derivative (VI), which is condensed with the free amino group of the tripeptide analogue (VII) by means of EDC in pyridine to provide the acylated tripeptide analogue (VIII). The oxidation of the secondary OH group of (VIII) by means of DMP in dichloromethane furnishes the acylated 2-(L-valyl-L-prolyl-L-valyl)benzoxazole derivative (IX), which is finally deprotected with TFA in dichloromethane to give the target tripeptide analogue.

参考文献中间体

合成目标

【1】 Sato, F.; Inoue, Y.; Honda, S.; Komiya, M.; Takemura, T.; Omodani, T.; Shiratake, R. (Dainippon Pharmaceutical Co., Ltd.); Heterocyclic cpds., intermediates thereof and elastase inhibitors. EP 1157998; JP 2000256396; WO 0052032 .

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)	30912	(2R,3S)-N,6-dimethoxy-2-(4-methoxyphenyl)-N-methyl-2,3-dihydro-1-benzothiophene-3-carboxamide		C₁₉H₂₁NO₄S	详情	详情
(II)	12869	benzyl 2-bromoacetate	5437-45-6	C₉H₉BrO₂	详情	详情
(III)	55789	benzyl 2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]acetate		C₁₃H₁₂N₂O₄	详情	详情
(IV)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(V)	55790	tert-butyl 2-[3-[2-(benzyloxy)-2-oxoethyl]-2,6-dioxo-1(2H,6H)-pyrimidinyl]acetate		C₁₉H₂₂N₂O₆	详情	详情
(VI)	55791	2-[3-[2-(tert-butoxy)-2-oxoethyl]-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]acetic acid		C₁₂H₁₆N₂O₆	详情	详情
(VII)	55792	(2S)-1-[(2S)-2-amino-3-methylbutanoyl]-N-{(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}-2-pyrrolidinecarboxamide		C₂₂H₃₂N₄O₄	详情	详情
(VIII)	55793	tert-butyl 2-[3-(2-{[(1S)-1-({(2S)-2-[({(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}amino)carbonyl]pyrrolidinyl}carbonyl)-2-methylpropyl]amino}-2-oxoethyl)-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]acetate		C₃₄H₄₆N₆O₉	详情	详情
(IX)	55794	tert-butyl 2-[3-{2-[((1S)-1-{[(2S)-2-({[(1S)-1-(1,3-benzoxazol-2-ylcarbonyl)-2-methylpropyl]amino}carbonyl)pyrrolidinyl]carbonyl}-2-methylpropyl)amino]-2-oxoethyl}-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]acetate		C₃₄H₄₄N₆O₉	详情	详情

Extended Information