3-(chloromethyl)benzoyl chloride -Drug Synthesis Database

【结构式】

【分子编号】25107

【品名】3-(chloromethyl)benzoyl chloride

【CA登记号】63024-77-1

【分子式】C₈H₆Cl₂O

【分子量】189.04044

【元素组成】C 50.83% H 3.2% Cl 37.51% O 8.46%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VII)

The esterification of (S)-3-amino-2-(benzyloxycarbonylamino)propionic acid (I) with methanol/HCl gives the expected methyl ester (II), which is protected with di-tert-butyl dicarbonate and triethylamine in chloroform to the fully protected compound (III). The debenzylation of (III) by treatment with formic acid over Pd/C in methanol yields the 2-amino compound (IV), which is acylated with butyl chloroformate and NaHCO3 in THF affording 2(S)-(n-butoxycarbonylamino)-3-(tert-butoxycarbonylamino)propionic acid methyl ester (V).The selctive deacylation of (V) with trifluoroacetic acid in dichloromethane affords the 3-amino-2(S)-(n-butoxycarbonylamino)propionic ester (VI), which is acylated with 3-(chloromethyl)benzoyl chloride (VII) and triethylamine in dichloromethane giving the benzamido ester (VIII). The condensation of (VIII) with 4-hydroxybenzonitrile (IX) by means of NaH or K2CO3 yields the precursor (X), which is finally treated first with HCl in methanol, and then with NH3 in the same solvent to providde the target compound.

参考文献中间体

合成目标

【1】 Degrado, W.F.; Xue, C.-B. (DuPont Pharmaceuticals Co.); Cpds. containing basic and acidic termini useful as fibrinogen receptor antagonists. US 5563158; WO 9518111 .

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)	18008	(2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid	35761-26-3	C₁₁H₁₄N₂O₄	详情	详情
(II)	25093	methyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate		C₁₂H₁₆N₂O₄	详情	详情
(III)	25094	methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate		C₁₇H₂₄N₂O₆	详情	详情
(IV)	25095	methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate		C₉H₁₈N₂O₄	详情	详情
(V)	25096	methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[(butoxycarbonyl)amino]propanoate		C₁₄H₂₆N₂O₆	详情	详情
(VI)	25097	methyl (2S)-3-amino-2-[(butoxycarbonyl)amino]propanoate		C₉H₁₈N₂O₄	详情	详情
(VII)	25107	3-(chloromethyl)benzoyl chloride	63024-77-1	C₈H₆Cl₂O	详情	详情
(VIII)	25108	methyl (2S)-2-[(butoxycarbonyl)amino]-3-[[3-(chloromethyl)benzoyl]amino]propanoate		C₁₇H₂₃ClN₂O₅	详情	详情
(IX)	25109	4-hydroxybenzonitrile	767-00-0	C₇H₅NO	详情	详情
(X)	25110	methyl (2S)-2-[(butoxycarbonyl)amino]-3-([3-[(4-cyanophenoxy)methyl]benzoyl]amino)propanoate		C₂₄H₂₇N₃O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Amide (III) was prepared by acylation of L-methionine methyl ester (I) with 3-(chloromethyl)benzoyl chloride (II). Displacement of the halogen atom of (III) with LiN3 gave azide (IV), which was reduced to amine (V) by catalytic hydrogenation in the presence of Pd/C. Reductive coupling of (V) with protected imidazole-4-carboxaldehyde (VI) provided the (imidazolylmethyl)amine (VII), and a second reductive coupling of (VII) with benzaldehyde (VIII) furnished the trisubstituted amine (IX). The regioselective imidazole alkylation of (IX) with bromide (X), followed by trityl group deprotection with trifluoroacetic acid yielded (XI). Finally, the methyl ester group of (XI) was hydrolyzed with methanolic NaOH to afford the title carboxylic acid.

参考文献中间体

合成目标

【1】 Ciccarone, T.M.; MacTough, S.C.; Williams, T.M.; et al.; Non-thiol 3-aminomethylbenzamide inhibitor of farnesyl-protein transferase. Bioorg Med Chem Lett 1999, 9, 14, 1991.

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)	17950	D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride	21691-49-6	C₆H₁₃NO₂S	详情	详情
(II)	25107	3-(chloromethyl)benzoyl chloride	63024-77-1	C₈H₆Cl₂O	详情	详情
(III)	33729	methyl (2S)-2-[[3-(chloromethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate		C₁₄H₁₈ClNO₃S	详情	详情
(IV)	33730	methyl (2S)-2-[[3-(azidomethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate		C₁₄H₁₈N₄O₃S	详情	详情
(V)	33731	methyl (2S)-2-[[3-(aminomethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate		C₁₄H₂₀N₂O₃S	详情	详情
(VI)	27712	1-trityl-1H-imidazole-4-carbaldehyde；1-Tritylimidazole-4-carboxaldehyde	33016-47-6	C₂₃H₁₈N₂O	详情	详情
(VII)	33732	methyl (2S)-4-(methylsulfanyl)-2-[[3-([[(1-trityl-1H-imidazol-4-yl)methyl]amino]methyl)benzoyl]amino]butanoate		C₃₇H₃₈N₄O₃S	详情	详情
(VIII)	17552	4-formylbenzonitrile; 4-Cyanobenzaldehyde	105-07-7	C₈H₅NO	详情	详情
(IX)	33733	methyl (2S)-2-[[3-([(4-cyanobenzyl)[(1-trityl-1H-imidazol-4-yl)methyl]amino]methyl)benzoyl]amino]-4-(methylsulfanyl)butanoate		C₄₅H₄₃N₅O₃S	详情	详情
(X)	14200	4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile	17201-43-3	C₈H₆BrN	详情	详情
(XI)	33734	methyl (2S)-2-([3-[((4-cyanobenzyl)[[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl]amino)methyl]benzoyl]amino)-4-(methylsulfanyl)butanoate		C₃₄H₃₄N₆O₃S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

The condensation of BMS-207147 (I) with 3-(chloromethyl)benzoic acid chloromethyl ester (II) (obtained by esterification of 3-(chloromethyl)benzoyl chloride (III) with paraformaldehyde and ZnCl2) by means of KH in THF gives the adduct (IV), which is condensed with phosphoric acid di-tert-butyl ester (V) to yield the phosphate (V). Finally, this compound is hydrolyzed with TFA in dichloromethane and treated with NaHCO3 to provide the target sodium salt.

参考文献中间体

合成目标

【1】 Hudyma, T.W.; Zheng, X.; Clark, J.; et al.; BMS-292655, a soluble prodrug of the clinically efficacious antifungal triazole, BMS-207147 (ravuconazole). 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-816.
【2】 Hudyma, T.W.; Kim, O.K.; Zheng, X. (Bristol-Myers Squibb Co.); Water soluble prodrugs of azole cpds.. WO 0030655 .

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)	60212	4-{2-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile		C₂₂H₁₇F₂N₅OS	详情	详情
(II)	60213	chloromethyl 3-(chloromethyl)benzoate		C₉H₈Cl₂O₂	详情	详情
(III)	25107	3-(chloromethyl)benzoyl chloride	63024-77-1	C₈H₆Cl₂O	详情	详情
(IV)	20214	ethyl (3S)-3-benzyl-2-oxo-3-piperidinecarboxylate		C₁₅H₁₉NO₃	详情	详情
(V)	60215	bis(1,1-dimethylethyl) hydrogen phosphate		C₈H₁₉O₄P	详情	详情
(VI)	60216	{[2-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyl]oxy}methyl 3-[({bis[(1,1-dimethylethyl)oxy]phosphoryl}oxy)methyl]benzoate		C₃₉H₄₂F₂N₅O₇PS	详情	详情

Extended Information