bromo[3-(dimethylamino)propyl]magnesium -Drug Synthesis Database

【结构式】

【分子编号】37604

【品名】bromo[3-(dimethylamino)propyl]magnesium

【CA登记号】120615-47-6

【分子式】C₅H₁₂BrMgN

【分子量】190.36602

【元素组成】C 31.55% H 6.35% Br 41.97% Mg 12.77% N 7.36%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(VI)

A new method for the preparation of citalopram has been reported: The Grignard reaction of 1-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (I) with 4-fluorophenylmagnesium bromide (II) in THF gives the hydroxymethyl benzophenone (III), which is esterified with pivaloyl chloride in ethyl ether/THF to yield the ester (V). A new Grignard reaction of (V) with 3-(dimethylamino)propylmagnesium bromide in THF affords citalopram.

参考文献中间体

合成目标

【1】 Ellegaard, P.; Petersen, H.; Rock, M.H. (H. Lundbeck A/S); Method for the preparation of citalopram. WO 0012044 .

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)	37601	1-oxo-1,3-dihydro-2-benzofuran-5-carbonitrile	82104-74-3	C₉H₅NO₂	详情	详情
(II)	13643	4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide	352-13-6	C₆H₄BrFMg	详情	详情
(III)	37602	4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile		C₁₅H₁₀FNO₂	详情	详情
(IV)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(V)	37603	5-cyano-2-(4-fluorobenzoyl)benzyl pivalate		C₂₀H₁₈FNO₃	详情	详情
(VI)	37604	bromo[3-(dimethylamino)propyl]magnesium	120615-47-6	C₅H₁₂BrMgN	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Two new methods for the preparation of citalopram have been developed: 1) The Grignard condensation of 5-bromoisobenzofuran-1(3H)-one (I) with 4-fluorophenylmagnesium bromide (II) in THF gives a nonisolated intermediate, which by a new Grignard condensation with 3-(dimethyiamino)propylmagnesium bromide (III) in THF yields N-[3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]propyl-N,N-dimethylamine (IV). Finally, this compound is treated with Zn(CN) and Pd(PPh3)4 with or without NaCN in refluxing THF. 2) The Grignard condensation of 5-hydroxyisobenzofuran-1(3H)-one (V) with 4-fluorophenylmagnesium bromide (II) in THF gives a nonisolated intermediate, which by a new Grignard condensation with 3-(dimethylamino)propylmagnesium bromide (III) in THF yields N-[3-[5-hydroxy-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]propyl-N,N-dimethylamine (VI). The sulfonation of the hydroxy group of (VI) with trifluromethanesulfonyl chloride affords the triflate (VII), which is finally treated with NaCN, Cul and Pd(PPh3)4 in refluxing acetonitrile.

参考文献中间体

合成目标

【1】 Rock, M.H.; Petersen, H.; Svane, H. (H. Lundbeck A/S); Method for the preparation of citalopram. WO 0013648 .

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)	33229	5-bromophthalide; 5-bromo-2-benzofuran-1(3H)-one	64169-34-2	C₈H₅BrO₂	详情	详情
(II)	13643	4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide	352-13-6	C₆H₄BrFMg	详情	详情
(III)	37604	bromo[3-(dimethylamino)propyl]magnesium	120615-47-6	C₅H₁₂BrMgN	详情	详情
(IV)	37605	5-bromo-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran; N-[3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl]-N,N-dimethylamine; 3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]-N,N-dimethyl-1-propanamine		C₁₉H₂₁BrFNO	详情	详情
(V)	37606	5-hydroxy-2-benzofuran-1(3H)-one		C₈H₆O₃	详情	详情
(VI)	37607	1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-ol		C₁₉H₂₂FNO₂	详情	详情
(VII)	37608	1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl trifluoromethanesulfonate		C₂₀H₂₁F₄NO₄S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IX)

The reaction of terephthalic acid (I) with trioxane and oleum at 140-150 C gives 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (II), which is treated with SOCl2 in refluxing toluene to yield the acyl chloride (III). The condensation of (III) with 2-hydroxy-1,1-dimethylethylamine (IV) in the same solvent affords the amide (V), which is cyclized by means of SOCl2 in dichloromethane to provide the oxazoline (VI). The Grignard condensation of (VI) with 4-fluorophenylmagnesium bromide (VII) in THF gives the benzophenone (VIII), which is submitted to a new Grignard condensation with 3-(dimethylamino)propylmagnesium bromide (IX) in the same solvent to yield the diol (X). Finally, this compound is treated with POCl3 or SOCl2 and POCl3 in hot pyridine to afford the target citalopram. Alternatively, the cleavage of the oxazoline ring of (X) with H2SO4 and then with NaOH gives the sodium carboxylate (XI), which is treated with SOCl2 in dichloromethane to yield the corresponding acyl chloride (XII). The reaction of (XII) with dry ammonia in the same solvent affords the carboxamide (XIII), which is finally dehydrated with POCl3 in refluxing acetonitrile to provide the target citalopram.

参考文献中间体

合成目标

【1】 Greenwood, A.K.; McHattie, D.; Rechka, J.A.; Hedger, P.C.M.; Gamble, M.P. (Resolution Chemicals Ltd.); Process for the preparation of citalopram. WO 0166536 .

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)	54025	1,4-Benzenedicarboxylic acid; Benzene-1,4-dicarboxylic acid; p-Benzenedicarboxylic acid; p-Phthalic acid; Terephthalic acid	100-21-0	C₈H₆O₄	详情	详情
(II)	37594	1-oxo-1,3-dihydro-2-benzofuran-5-carboxylic acid		C₉H₆O₄	详情	详情
(III)	37595	1-oxo-1,3-dihydro-2-benzofuran-5-carbonyl chloride		C₉H₅ClO₃	详情	详情
(IV)	21513	2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol	124-68-5	C₄H₁₁NO	详情	详情
(V)	37596	N-(2-hydroxy-1,1-dimethylethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-carboxamide		C₁₃H₁₅NO₄	详情	详情
(VI)	37597	5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-benzofuran-1(3H)-one		C₁₃H₁₃NO₃	详情	详情
(VII)	13643	4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide	352-13-6	C₆H₄BrFMg	详情	详情
(VIII)	37598	[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanone		C₁₉H₁₈FNO₃	详情	详情
(IX)	37604	bromo[3-(dimethylamino)propyl]magnesium	120615-47-6	C₅H₁₂BrMgN	详情	详情
(X)	37599	4-(dimethylamino)-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-1-butanol		C₂₄H₃₁FN₂O₃	详情	详情
(XI)	55284	sodium 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboxylate		C₂₀H₂₁FNNaO₃	详情	详情
(XII)	55285	1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonyl chloride		C₂₀H₂₁ClFNO₂	详情	详情
(XIII)	55286	1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboxamide		C₂₀H₂₃FN₂O₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(C)

The Grignard reaction of dibenzo[a,d]cyclohepta-1,4,6-triene-5-one (I) with dimethylaminopropyl magnesium (C) chloride in ethyl ether gives 5-hydroxy-5-(3-dimethylaminopropyl)dibenzo[a,d]cyclohepta-1,4,6-triene (IV), which is then treated with HCl in refluxing acetic acid. Alternatively, it can also be obtained by methylation of 5-(3-methylaminopropylidene)dibenzo[a,d]cyclohepta-1,4,6-triene (IX) with formic acid and formaldehyde at 100 C.

参考文献中间体

合成目标

【1】 Protiva, M.; Vera, S.; CZ 136585 .
【2】 Roberts, P.J.; Castañer, J.; Cyclobenzaprine. Drugs Fut 1977, 2, 5, 299.
【3】 Vilani, F.J. (Schering Corp.); 5-(3'-Dimethylamino-2'-methylpropyl)dibenzocycloheptenes. US 3409640 .

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)	29151	5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone	2222-33-5	C₁₅H₁₀O	详情	详情
(IV)	40127	5-[3-(dimethylamino)propyl]-5H-dibenzo[a,d]cyclohepten-5-ol	18029-54-4	C₂₀H₂₃NO	详情	详情
(IX)	40128	N-[3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-N-methylamine; 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine		C₁₉H₁₉N	详情	详情
(C)	37604	bromo[3-(dimethylamino)propyl]magnesium	120615-47-6	C₅H₁₂BrMgN	详情	详情

Extended Information