Bromo(3,4-dichlorophenyl)magnesium -Drug Synthesis Database

【结构式】

【分子编号】10069

【品名】Bromo(3,4-dichlorophenyl)magnesium

【CA登记号】79175-35-2

【分子式】C₆H₃BrCl₂Mg

【分子量】250.20422

【元素组成】C 28.8% H 1.21% Br 31.94% Cl 28.34% Mg 9.71%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(V)

A new synthesis of [7-3H]-sertraline has been described: The optical resolution of 7-bromo-1-(methylamino)tetraline (I) with N-acetyl-D-phenylalanine gives the (R)-isomer (II), which is acylated with formic acid - acetic anhydride to the formamide (III). The oxidation of (III) with KMnO4 in acetone - water yields 6-bromo-4(R)-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (IV), which, by a Grignard condensation with 3,4-dichlorophenylmagnesium bromide (V) in ether - toluene, affords 6-bromo-1(S)-(3,4-dichlorophenyl)-4(R)-(N-methylformamido)-1,2,3,4-tetrahydronaphthalen-1-ol (VI). The reduction of (VI) with triethylsilane tetrafluoroborate in dichloromethane gives 6-bromo-1(S)-(3,4-dichlorophenyl)-4(R)-(N-methylformamido)tetraline (VII), which is hydrolyzed with HCl in isopropanol to the corresponding methylamine (VIII). Oxidation of (VIII) with NaClO NaOCH3 in methanol - water yields the imine (IX), which is reduced with NaBH4 in THF - methanol to 6-bromo-1(S)-(3,4-dichlorophenyl)-4(S)-(methylamino)tetraline (X), along with starting (VIII). After separation by column chromatography, (X) is reduced with H2 over Pd/C or with T2 over Pd/C in THF containing triethylamine.

参考文献中间体

合成目标

【1】 Williams, M.T.; Welch, W.M.; Synthesis of 7-3H-(IS,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-I-naphthalenamine hydrochloride (7-3H-sertraline). J Label Compd Radiopharm 1993, 33, 2, 119.

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)	10065	N-(7-Bromo-1,2,3,4-tetrahydro-1-naphthalenyl)-N-methylamine; 7-Bromo-N-methyl-1,2,3,4-tetrahydro-1-naphthalenamine		C₁₁H₁₄BrN	详情	详情
(II)	10066	(1R)-7-Bromo-N-methyl-1,2,3,4-tetrahydro-1-naphthalenamine; N-[(1R)-7-Bromo-1,2,3,4-tetrahydro-1-naphthalenyl]-N-methylamine		C₁₁H₁₄BrN	详情	详情
(III)	10067	N-[(1R)-7-Bromo-1,2,3,4-tetrahydro-1-naphthalenyl]-N-methylformamide		C₁₂H₁₄BrNO	详情	详情
(IV)	10068	N-[(1R)-7-Bromo-4-oxo-1,2,3,4-tetrahydro-1-naphthalenyl]-N-methylformamide		C₁₂H₁₂BrNO₂	详情	详情
(V)	10069	Bromo(3,4-dichlorophenyl)magnesium	79175-35-2	C₆H₃BrCl₂Mg	详情	详情
(VI)	10070	N-[(1R,4S)-7-Bromo-4-(3,4-dichlorophenyl)-4-hydroxy-1,2,3,4-tetrahydro-1-naphthalenyl]-N-methylformamide		C₁₈H₁₆BrCl₂NO₂	详情	详情
(VII)	10071	N-[(1R,4S)-7-Bromo-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl]-N-methylformamide		C₁₈H₁₆BrCl₂NO	详情	详情
(VIII)	10072	N-[(1R,4S)-7-Bromo-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl]-N-methylamine; (1R,4S)-7-Bromo-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthalenamine		C₁₇H₁₆BrCl₂N	详情	详情
(IX)	10073	N-[(4S)-7-Bromo-4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine; N-[(4S)-7-Bromo-4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-N-methylamine		C₁₇H₁₄BrCl₂N	详情	详情
(X)	10074	N-[(1S,4S)-7-Bromo-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl]-N-methylamine; (1S,4S)-7-Bromo-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthalenamine		C₁₇H₁₆BrCl₂N	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

A new total synthesis of sertraline has been described: The reduction of N,N-dibenzyl-D-phenylglycine methyl ester (I) with LiAlH4 in THF gives alcohol (II), which is oxidized to aldehyde (III) with oxalyl chloride in dichloromethane. The condensation of (III) with the phosphorane (IV) in benzene yields the unsaturated ester (V), which is reduced with Mg in methanol affording the saturated methyl ester (VI). Reduction of (VI) with LiAlH4 in THF provides the corresponding butanol derivative (VII), which is oxidized to the aldehyde (VIII) with pyridinium dichromate (PDC) in dichloromethane. The Grignard reaction of (VIII) with 3,4-dichlorophenylmagnesium bromide (IX) in THF affords the secondary alcohol (X), which is cyclized by means of AlCl3 in dichloromethane yielding a mixture of the desired cis-isomer (XI) along with some trans-isomer separated by column chromatography. Debenzylation of (XI) by H2 over Pd(OH)2 in methanol, followed by protection with Boc2O yields the carbamate (XII), which is methylated with methyl iodide and NaH in THF to afford the protected intermediate (XIII). Finally, compound (XIII) is deprotected with TFA in dichloromethane.

参考文献中间体

合成目标

【1】 Chandrasekhar, S.; Reddy, M.V.; An expedient total synthesis of cis-(+)-sertraline from D-phenylglycine. Tetrahedron 2000, 56, 8, 1111.

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)	46527	methyl (2R)-2-(dibenzylamino)-2-phenylethanoate		C₂₃H₂₃NO₂	详情	详情
(II)	46528	(2R)-2-(dibenzylamino)-2-phenyl-1-ethanol		C₂₂H₂₃NO	详情	详情
(III)	46529	(2R)-2-(dibenzylamino)-2-phenylethanal		C₂₂H₂₁NO	详情	详情
(IV)	14182	ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane	1099-45-2	C₂₂H₂₁O₂P	详情	详情
(V)	46530	ethyl (E,4S)-4-(dibenzylamino)-4-phenyl-2-butenoate		C₂₆H₂₇NO₂	详情	详情
(VI)	46531	methyl (4S)-4-(dibenzylamino)-4-phenylbutanoate		C₂₅H₂₇NO₂	详情	详情
(VII)	46532	(4S)-4-(dibenzylamino)-4-phenyl-1-butanol		C₂₄H₂₇NO	详情	详情
(VIII)	46533	(4S)-4-(dibenzylamino)-4-phenylbutanal		C₂₄H₂₅NO	详情	详情
(IX)	10069	Bromo(3,4-dichlorophenyl)magnesium	79175-35-2	C₆H₃BrCl₂Mg	详情	详情
(X)	46534	(4S)-4-(dibenzylamino)-1-(3,4-dichlorophenyl)-4-phenyl-1-butanol		C₃₀H₂₉Cl₂NO	详情	详情
(XI)	46535	N,N-dibenzyl-N-[(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl]amine; (1S,4S)-N,N-dibenzyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine		C₃₀H₂₇Cl₂N	详情	详情
(XII)	46536	tert-butyl (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenylcarbamate		C₂₁H₂₃Cl₂NO₂	详情	详情
(XIII)	46537	tert-butyl (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl(methyl)carbamate		C₂₂H₂₅Cl₂NO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

The hydrolysis of (1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester (I) with refluxing 1M HCl gives the corresponding hydroxy acid (II), which is dehydrated with refluxing POCl3 and treated with methanol to the unsaturated methyl ester (III). The reaction of (III) with 3,4-dichlorophenylmagnesium bromide in ether yields a mixture of (1R,2S,3S,5S)- and (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl esters (V) and (VI), respectively. Enantiomer (V) is isomerized to (VI) by treating the mixture with sodium methoxide in refluxing methanol. The reduction of (VI) with LiAlH4 in ethyl ether gives (1R,2R,3S,5S)-[3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]methanol (VII), which is oxidized with oxalyl chloride in dichloromethane, affording aldehyde (VIII). Finally, this compound is treated with methoxyammonium chloride and Na2CO3 in methanol, giving brasofensine as an oil. Several salts of brasofensine were obtained by addition of the acid to a solution of brasofensine in ethanol and recrystallization from either water or isopropanol.

参考文献中间体

合成目标

【1】 Castañer, J.; Graul, A.; Brasofensine Sulfate . Drugs Fut 1999, 24, 2, 128.
【2】 Moldt, P.; Watjen, F.; Scheel-Kruger, J. (NeuroSearch A/S); Tropane-2-aldoxine derivs. as neurotransmitter reuptake inhibitors. EP 0756596; JP 1997505607; US 5736556; WO 9528401 .

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)	21116	methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate		C₁₇H₂₁NO₄	详情	详情
(II)	21117	(1R,2R,3S,5S)-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid		C₉H₁₅NO₃	详情	详情
(III)	21118	methyl (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate		C₁₀H₁₅NO₂	详情	详情
(IV)	10069	Bromo(3,4-dichlorophenyl)magnesium	79175-35-2	C₆H₃BrCl₂Mg	详情	详情
(V)	21120	methyl (1R,2S,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate		C₁₆H₁₉Cl₂NO₂	详情	详情
(VI)	21121	methyl (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate		C₁₆H₁₉Cl₂NO₂	详情	详情
(VII)	21122	[(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methanol		C₁₅H₁₉Cl₂NO	详情	详情
(VIII)	21123	(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carbaldehyde		C₁₅H₁₇Cl₂NO	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XVI)

The intermediate 3-(3,4-dichlorophenyl)-3-buten-1-ol silyl ether (XII) was prepared by several procedures: 1) Addition of the organozinc reagent (IX) (generated from 1-bromo-3,4-dichlorobenzene (VIII)) to diketene (X) in the presence of palladium catalyst, followed by esterification with MeOH and H2SO4 furnished 3-arylbutenoate methyl ester (XI), which was reduced to alcohol with LiAlH4 and then silylated with tert-butyldimethylsilyl chloride to give silyl ether (XII). 2) In an alternative procedure, ethyl 3-(3,4-dichlorophenyl)-3-oxopropionate (XIII) was protected with triethyl orthoformate in the presence of p-toluenesulfonic acid and then reduced to alcohol (XIV) with LiAlH4. Ketal deprotection of (XIV) with trifluoroacetic acid provided hydroxy ketone (XV). After silylation of (XV) with tert-butyldimethylsilyl chloride, subsequent Wittig condensation with methylene triphenylphosphorane gave intermediate silyl eher (XII). 3) In a further procedure, the Grignard reagent (XVI) (generated from 1-bromo-3,4-dichlorobenzene (VIII)) was coupled with 3-iodo-3-buten-1-ol silyl ether (XVII) in the presence of palladium catalyst to furnish intermediate ether (XII).

参考文献中间体

合成目标

【1】 Kurata, H.; Ito, K.; Nakajima, K.; Yamaguchi, T.; Ishibashi, K.; Fukuzawa, T.; Nishi, T. (Sankyo Co., Ltd.); Azaheterocyclic cpds. having tachykinin receptor antagonist activity; NK1 and NK2. EP 0776893; JP 1998152478; JP 1998182649; JP 1998182650 .
【2】 Nishi, T.; Yamaguchi, T. (Sankyo Co., Ltd.); Salts of optically active sulfoxide deriv.. EP 0987269; JP 1999043490; WO 9854191 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	38427	4-bromo-1,2-dichlorobenzene	18282-59-2	C₆H₃BrCl₂	详情	详情
(IX)	38428	chloro(3,4-dichlorophenyl)zinc		C₆H₃Cl₃Zn	详情	详情
(X)	11367	4-Methylene-2-oxetanone; Acetyl ketene	674-82-8	C₄H₄O₂	详情	详情
(XI)	38429	methyl 3-(3,4-dichlorophenyl)-3-butenoate		C₁₁H₁₀Cl₂O₂	详情	详情
(XII)	38430	tert-butyl[[3-(3,4-dichlorophenyl)-3-butenyl]oxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(3,4-dichlorophenyl)-3-butenyl ether		C₁₆H₂₄Cl₂OSi	详情	详情
(XIII)	38431	ethyl 3-(3,4-dichlorophenyl)-3-oxopropanoate		C₁₁H₁₀Cl₂O₃	详情	详情
(XIV)	38432	3-(3,4-dichlorophenyl)-3,3-diethoxy-1-propanol		C₁₃H₁₈Cl₂O₃	详情	详情
(XV)	38433	1-(3,4-dichlorophenyl)-3-hydroxy-1-propanone		C₉H₈Cl₂O₂	详情	详情
(XVI)	10069	Bromo(3,4-dichlorophenyl)magnesium	79175-35-2	C₆H₃BrCl₂Mg	详情	详情
(XVII)	38434	tert-butyl[(3-iodo-3-butenyl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-iodo-3-butenyl ether		C₁₀H₂₁IOSi	详情	详情

合成路线5

该中间体在本合成路线中的序号：(II)

Reaction of 2-chloropyrazine (I) with 3,4-dichlorophenylmagnesium bromide (II) in the presence of [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride produced the 2-arylpyrazine (III), which was reduced to the corresponding piperazine (IV) by means of DIBAL in THF. In a different procedure, bromination of methyl 3,4-dichlorophenylacetate (V) using N-bromosuccinimide, followed by reaction of the resulting bromo ester (VI) with ethylenediamine (VII) afforded the piperazinone (VIII), which was further reduced to (IV) by using LiAlH4 in Et2O.

参考文献中间体

合成目标

【1】 Anthes, J.C.; McPhail, A.T.; Blythin, D.J.; Shue, H.-J.; Chen, X.; Piwinski, J.J.; shih, N.-Y.; Discovery of Sch 62373 and analogs, of novel series of 2-phenylpiperazines exhibiting potent dual NK1/NK2 antagonist activity. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 244.
【2】 Shue, H.-J.; Shih, N.-Y.; Blythin, D.J.; Chen, X.; Tom, W.C.; Piwinski, J.J.; McCormick, K.D. (Schering Corp.); Piperazino derivs. as neurokinin antagonists. EP 0823906; US 5719156; WO 9634864 .
【3】 Piwinski, J.J.; McCormick, K.D.; Shue, H.-J.; Chen, X.; Shih, N.-Y.; Blythin, D.J. (Schering Corp.); Piperazino derivs. as neurokinin antagonists. EP 0850236; JP 2000344766; US 5795894; US 5892039; WO 9708166 .

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)	24075	2-chloropyrazine	14508-49-7	C₄H₃ClN₂	详情	详情
(II)	10069	Bromo(3,4-dichlorophenyl)magnesium	79175-35-2	C₆H₃BrCl₂Mg	详情	详情
(III)	47945	2-(3,4-dichlorophenyl)pyrazine		C₁₀H₆Cl₂N₂	详情	详情
(IV)	47946	2-(3,4-dichlorophenyl)piperazine		C₁₀H₁₂Cl₂N₂	详情	详情
(V)	47947	methyl 2-(3,4-dichlorophenyl)acetate		C₉H₈Cl₂O₂	详情	详情
(VI)	47948	methyl 2-bromo-2-(3,4-dichlorophenyl)acetate		C₉H₇BrCl₂O₂	详情	详情
(VII)	14754	ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine	107-15-3	C₂H₈N₂	详情	详情
(VIII)	47949	3-(3,4-dichlorophenyl)-2-piperazinone		C₁₀H₁₀Cl₂N₂O	详情	详情

Extended Information