methyl 2-chloro-3-[4-[4-(2-chloro-3-methoxy-3-oxopropyl)benzyl]phenyl]propanoate -Drug Synthesis Database

【结构式】

【分子编号】36324

【品名】methyl 2-chloro-3-[4-[4-(2-chloro-3-methoxy-3-oxopropyl)benzyl]phenyl]propanoate

【CA登记号】

【分子式】C₂₁H₂₂Cl₂O₄

【分子量】409.30868

【元素组成】C 61.62% H 5.42% Cl 17.32% O 15.64%

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：(X)

The bromination of tetraline (XIX) with Br2 in hexane gives trans-1,2-dibromotetraline (XX), which by treatment with H2O and NaHCO3 yields trans-2-bromotetralin-1-ol (XXI) [also obtained by reaction of 1,2-dihydronaphthalene (XXII) with 1,3-dibromo-5,5-dimethylhydantoin (DBDH) and perchloric acid]. The reaction of (XXI) with methylamine affords the intermediate epoxide (XXIII), which without isolation with more methylamine gives trans 1-(methylamino) tetralin-2-ol as a racemic mixture rac-(XXIV). The optical resolution of this mixture with (+)-L-tartaric acid yields the desired enantiomer (R,R)(XXIV), which is condensed with 2-bromoacetaldehyde dimethyl acetal (XXV) by means of K2CO3 in acetonitrile furnishing the chiral tertiary amine (XXVI). The cyclization of (XXVI) with BuLi and TsCl provides the intermediate aziridinium salt (XXVII), which without isolation, is condensed with 4-chloro-3-methoxyphenyl-magnesium bromide (X) in THF to give the chiral tertiary amine (XXVIII). The cyclization of (XXVIII) by means of methanesulfonic acid yields the chiral tetracyclic compound (XXIX), which is hydrogenated by means of BH3/t-Bu-NH2 to afford (6aS,13bR)(VIII). Finally, this compound is demethylated with 48% HBr in acetic acid. The chiral secondary amine (XXVI) can also be obtained as follows: The enantioselective epoxidation of 1,2-dihydronaphthalene (XXII) by means of a chiral manganese catalyst and sodium hypochlorite gives the chiral epoxide (1S,2R)(XXIII), which is cleaved with 2-(methylamino)acetaldehyde dimethylacetal (XXX) at 95 C in a pressure vessel to yield the desired chiral secondary amine (XXVI).

参考文献中间体

合成目标

【1】 Berger, J.G.; Clader, J.W.; Chang, W.K.; Gold, E.H. (Schering Corp.); Fused benzazepines. EP 0230270; EP 0254737; JP 1988502348; WO 8704430 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11021	Methanamine; Methylamine	74-89-5	CH₅N	详情	详情
(VIII)	31779	(3aS,9bR)-12-chloro-11-methoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine; (3aS,9bR)-12-chloro-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether		C₂₀H₂₂ClNO	详情	详情
(X)	36324	methyl 2-chloro-3-[4-[4-(2-chloro-3-methoxy-3-oxopropyl)benzyl]phenyl]propanoate		C₂₁H₂₂Cl₂O₄	详情	详情
(XIX)	36632	1,2,3,4-tetrahydronaphthalene	119-64-2	C₁₀H₁₂	详情	详情
(XX)	36633	(1S,2S)-1,2-dibromo-1,2,3,4-tetrahydronaphthalene		C₁₀H₁₀Br₂	详情	详情
(XXI)	36634	(1S,2S)-2-bromo-1,2,3,4-tetrahydro-1-naphthalenol		C₁₀H₁₁BrO	详情	详情
(XXII)	36635	1,2-dihydronaphthalene	447-53-0	C₁₀H₁₀	详情	详情
(XXIII)	36636	(1aR,7bS)-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene		C₁₀H₁₀O	详情	详情
(XXIV)	36637	(1R,2R)-1-(methylamino)-1,2,3,4-tetrahydro-2-naphthalenol		C₁₁H₁₅NO	详情	详情
(XXV)	13183	2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal	7252-83-7	C₄H₉BrO₂	详情	详情
(XXVI)	36638	(1R,2R)-1-[(2,2-dimethoxyethyl)(methyl)amino]-1,2,3,4-tetrahydro-2-naphthalenol		C₁₅H₂₃NO₃	详情	详情
(XXVII)	36639		n/a	AB	详情	详情
(XXVIII)	36640	N-[(1S,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)-N-methylamine; (1S,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine		C₂₂H₂₈ClNO₃	详情	详情
(XXIX)	36641	(3aS,9bR)-12-chloro-3-methyl-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether; (3aS,9bR)-12-chloro-11-methoxy-3-methyl-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepine		C₂₀H₂₀ClNO	详情	详情
(XXX)	36650	2,2-dimethoxy-N-methyl-1-ethanamine;1,1-Dimethoxy-2-(methylamino)-ethane;Methylaminoacetaldehyde dimethyl acetal;N-(2,2-dimethoxyethyl)-N-methylamine	122-07-6	C₅H₁₃NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Diazotization of 4,4'-diaminodiphenylmethane (I) with NaNO2 and HCl, followed by copper-catalyzed coupling with methyl acrylate afforded the alpha,alpha'-dichloro diester (II). Subsequent cyclization of (II) with thiourea (III) in refluxing EtOH produced the bis(iminothiazolidinone) (IV). Finally, acid hydrolysis of (IV) yielded the title compound.

参考文献中间体

合成目标

【1】 Niigata, K.; Takahashi, T.; Iwaoka, K.; Yoneda, T.; Noshiro, O.; Koike, R. (Yamanouchi Pharmaceutical Co., Ltd.); Bisheterocyclic cpd.. EP 0533933; JP 1992511153; WO 9200967 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(I)	36325	4-(4-aminobenzyl)phenylamine; 4-(4-aminobenzyl)aniline	101-77-9	C₁₃H₁₄N₂	详情	详情
(II)	36324	methyl 2-chloro-3-[4-[4-(2-chloro-3-methoxy-3-oxopropyl)benzyl]phenyl]propanoate		C₂₁H₂₂Cl₂O₄	详情	详情
(III)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(IV)	36326	2-imino-5-(4-[4-[(2-imino-4-oxo-1,3-thiazolidin-5-yl)methyl]benzyl]benzyl)-1,3-thiazolidin-4-one		C₂₁H₂₀N₄O₂S₂	详情	详情

Extended Information