2-chloro-N-(hydroxymethyl)acetamide -Drug Synthesis Database

【结构式】

【分子编号】23020

【品名】2-chloro-N-(hydroxymethyl)acetamide

【CA登记号】2832-19-1

【分子式】C₃H₆ClNO₂

【分子量】123.53888

【元素组成】C 29.17% H 4.9% Cl 28.7% N 11.34% O 25.9%

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：(IV)

The Friedel-Kraft's condensation of 4-tert-butylphenol (I) with propionyl chloride (II) by means of FeCl3 in methylene chloride gives 2-hydroxy-5-tert-butylpropiophenone (III), which is then condensed with chloroacetylaminomethanol (IV) by means of H2SO4 in acetic acid affording 3-(chloroacetylaminomethyl)-5-tert-butyl-2-hydroxypropiophenone (V). Finally, this compound is hydrolyzed with HCl in methanol.

参考文献中间体

合成目标

【1】 Hashimoto, K.; ONO-3144. Drugs Fut 1985, 10, 10, 825.

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)	29734	4-(tert-butyl)phenol	98-54-4	C₁₀H₁₄O	详情	详情
(II)	15967	propanoyl chloride; propionyl chloride	79-03-8	C₃H₅ClO	详情	详情
(III)	29735	1-[5-(tert-butyl)-2-hydroxyphenyl]-1-propanone		C₁₃H₁₈O₂	详情	详情
(IV)	23020	2-chloro-N-(hydroxymethyl)acetamide	2832-19-1	C₃H₆ClNO₂	详情	详情
(V)	29736	N-[5-(tert-butyl)-2-hydroxy-3-propionylbenzyl]-2-chloroacetamide		C₁₆H₂₂ClNO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(C)

Friedel-Crafts acylation of 2,3-dichlorophenetole with 4-methoxybenzoyl chloride gives the substituted benzophenone (I). Selective cleavage of the ethyl ether in (I) with AlCl3 produces phenol (II). Alkylation of (II) with ethyl bromoacetate is followed by heating with 48% HBr to give the phenoxyacetic acid derivative (III). Amidomethylation of (III) using the Tscherniac-Einhorn procedure gives (IV), which affords A-49816 after hydrolysis with HCl/EtOH.

参考文献中间体

合成目标

【1】 Plattner, J.J.; Horrom, B.W.; Dodge, P.W.; Ours, C.W.; Lee, C.-M.; Pernet, A.G.; El Masry, S.E.; Smital, J.R.; Bunnell, P.R.; [(Aminomethyl)aryloxy]acetic acid esters. A new cl. J Med Chem 1984, 27, 1579.
【2】 Luther, R.R.; Plattner, J.J.; A-49816. Drugs Fut 1988, 13, 12, 1039.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	22671	4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride	100-07-2	C₈H₇ClO₂	详情	详情
(B)	23019	1,2-dichloro-3-ethoxybenzene; 2,3-dichlorophenyl ethyl ether		C₈H₈Cl₂O	详情	详情
(I)	23021	(2,3-dichloro-4-ethoxyphenyl)(4-methoxyphenyl)methanone		C₁₆H₁₄Cl₂O₃	详情	详情
(II)	23022	(2,3-dichloro-4-hydroxyphenyl)(4-methoxyphenyl)methanone		C₁₄H₁₀Cl₂O₃	详情	详情
(III)	23023	2-[2,3-dichloro-4-(4-hydroxybenzoyl)phenoxy]acetic acid		C₁₅H₁₀Cl₂O₅	详情	详情
(IV)	23024	2-[2,3-dichloro-4-(3-[[(2-chloroacetyl)amino]methyl]-4-hydroxybenzoyl)phenoxy]acetic acid		C₁₈H₁₄Cl₃NO₆	详情	详情
(C)	23020	2-chloro-N-(hydroxymethyl)acetamide	2832-19-1	C₃H₆ClNO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

The condensation of 4-acetoxy-3,5-di-tert-butylphenol (I) with 2-chloro-N-(hydroxymethyl)acetamide (II) by means of H2SO4 in Ac-OH gives 4-acetoxy-3,5-di-tert-butyl-2-(2-chloroacetamidomethyl)phenol (III), which is hydrolyzed with HCl in ethanol to yield 4-acetoxy-2-/aminomethyl)-3,5-di-tert-butylphenol (IV). The oxidation of (IV) by means of hexamethylenetetramine (HMTA) affords the aldehyde (V), which is submitted to a Grignard condensation with 6-undecylmagnesium bromide (VI) in THF, followed by dehydration with conc. HCl to provide 4-acetoxy-3,5-di-tert-butyl-2-(2-pentyl-1-heptenyl)phenol (VII). The cyclization of (VII) by means of BF3/Et2O in dichloromethane gives the dihydrobenzofuran (VIII), which is finally deacetylated by reduction with LiAlH4 in THF to provide the target phenol.

参考文献中间体

合成目标

【1】 Kato, Y.; et al.; Synthesis and reactivity of novel dihydrobenzofuranol antioxidants on various active oxygen species. 17th Symp Med Chem (Nov 19 1997, Tsukuba) 1997, Abst 1-P-20.
【2】 Yoshida, M.; Kato, Y.; Tamura, K.; Ohba, Y.; Cynshi, O. (Chugai Pharmaceutical Co. Ltd.); 4-Alkoxy-2,6-di-tert-butylphenol derivs.. EP 0665208; US 5574178; WO 9408930 .

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)	54387	2,6-di(tert-butyl)-4-hydroxyphenyl acetate		C₁₆H₂₄O₃	详情	详情
(II)	23020	2-chloro-N-(hydroxymethyl)acetamide	2832-19-1	C₃H₆ClNO₂	详情	详情
(III)	54388	2,6-di(tert-butyl)-3-{[(2-chloroacetyl)amino]methyl}-4-hydroxyphenyl acetate		C₁₉H₂₈ClNO₄	详情	详情
(IV)	54389	3-(aminomethyl)-2,6-di(tert-butyl)-4-hydroxyphenyl acetate		C₁₇H₂₇NO₃	详情	详情
(V)	54390	2,6-di(tert-butyl)-3-formyl-4-hydroxyphenyl acetate		C₁₇H₂₄O₄	详情	详情
(VI)	54391	bromo(1-pentylhexyl)magnesium		C₁₁H₂₃BrMg	详情	详情
(VII)	54392	2,6-di(tert-butyl)-4-hydroxy-3-(2-pentyl-1-heptenyl)phenyl acetate		C₂₈H₄₆O₃	详情	详情
(VIII)	54393	4,6-di(tert-butyl)-2,2-dipentyl-2,3-dihydro-1-benzofuran-5-yl acetate		C₂₈H₄₆O₃	详情	详情

Extended Information