2-(benzyloxy)aniline; 2-(benzyloxy)phenylamine -Drug Synthesis Database

【结构式】

【分子编号】18065

【品名】2-(benzyloxy)aniline; 2-(benzyloxy)phenylamine

【CA登记号】

【分子式】C₁₃H₁₃NO

【分子量】199.25236

【元素组成】C 78.36% H 6.58% N 7.03% O 8.03%

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：(I)

2-Benzyloxyaniline (I) was acylated with N-tert-butoxycarbonyl glycine (II) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide.HCl (EDC) to give amide (III). Alkylation with bromoacetamide (IV) in the presence of NaH in THF provided (V), and then removal of the Boc protecting group with trifluoroacetic acid gave amine (VI). This amine was condensed with 3-tolyl isocyanate (VII) to give the phenylurea (VIII). Cleavage of the benzyl group by hydrogenolysis on Pd/C provided phenol (IX), which was alkylated with methyl bromoacetate in the presence of K2CO3 to give ether (X). Alkaline hydrolysis of the ester group gave acid (XI), which was finally condensed with N-methylaniline (XII) by means of EDC to yield the target compound.

参考文献中间体

合成目标

【1】 Takeda, Y.; et al.; Synthesis of phenoxyacetic acid derivatives as highly potent antagonists of gastrin/cholecystokinin-B receptors. Chem Pharm Bull 1998, 46, 3, 434-444.

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)	18065	2-(benzyloxy)aniline; 2-(benzyloxy)phenylamine		C₁₃H₁₃NO	详情	详情
(II)	18066	N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid	4530-20-5	C₇H₁₃NO₄	详情	详情
(III)	18067	tert-butyl 2-[2-(benzyloxy)anilino]-2-oxoethylcarbamate		C₂₀H₂₄N₂O₄	详情	详情
(IV)	18068	2-bromo-N-methyl-N-phenylacetamide		C₉H₁₀BrNO	详情	详情
(V)	18069	tert-butyl 2-[2-(benzyloxy)[2-(methylanilino)-2-oxoethyl]anilino]-2-oxoethylcarbamate		C₂₉H₃₃N₃O₅	详情	详情
(VI)	18070	2-amino-N-[2-(benzyloxy)phenyl]-N-[2-(methylanilino)-2-oxoethyl]acetamide		C₂₄H₂₅N₃O₃	详情	详情
(VII)	18071	m-Tolyl Isocyanate; 1-isocyanato-3-methylbenzene; 3-methylphenyl isocyanate	621-29-4	C₈H₇NO	详情	详情
(VIII)	18072	2-(2-(benzyloxy)[2-[(3-toluidinocarbonyl)amino]acetyl]anilino)-N-methyl-N-phenylacetamide		C₃₂H₃₂N₄O₄	详情	详情
(IX)	18073	2-(2-hydroxy[2-[(3-toluidinocarbonyl)amino]acetyl]anilino)-N-methyl-N-phenylacetamide		C₂₅H₂₆N₄O₄	详情	详情
(X)	18074	methyl 2-[2-([2-(methylanilino)-2-oxoethyl][2-[(3-toluidinocarbonyl)amino]acetyl]amino)phenoxy]acetate		C₂₈H₃₀N₄O₆	详情	详情
(XI)	18075	2-[2-([2-(methylanilino)-2-oxoethyl][2-[(3-toluidinocarbonyl)amino]acetyl]amino)phenoxy]acetic acid		C₂₇H₂₈N₄O₆	详情	详情
(XII)	10409	N-Methyl-N-phenylamine; N-methylaniline; Monomethylaniline	100-61-8	C₇H₉N	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Coupling of 2-benzyloxyaniline (I) with N-Boc-glycine (II) by means of EDC aforded amide (III). Subsequent N-alkylation of (III) with N-methyl-N-phenyl-2-bromoacetamide (IV) in the presence of NaH provided diamide (V). Hydrogenolysis of the benzyl ether of (V) over Pd/C gave phenol derivative (VI) (1). Phenol (VI) was then alkylated with bromoamide (IV) to furnish ether (VII). After cleavage of the Boc group of (VII) with trifluoroacetic acid, the resulting amine (VIII) was reacted with carbonyldiimidazole to produce imidazolide (IX), which was subsequently coupled with aniline (X) yielding urea (XI). Finally, basic hydrolysis of the methyl ester group of (XI) gave the title carboxylic acid.

参考文献中间体

合成目标

【1】 Yokomizo, A.; Takeda, Y.; Kawagoe, K.; et al.; Synthesis of phenoxyacetic acid derivatives as highly potent antagonists of gastrin/cholecystokinin-B receptors. II. Chem Pharm Bull 1998, 46, 6, 951.
【2】 Yokohama, S.; Kawagoe, K.; Takeda, Y.; Yokomizo, Y.; Yokomizo, A. (Daiichi Pharmaceutical Co., Ltd.); Aminophenol derivs.. EP 0985660; US 5919824; WO 9628416 .

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)	18065	2-(benzyloxy)aniline; 2-(benzyloxy)phenylamine		C₁₃H₁₃NO	详情	详情
(II)	18066	N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid	4530-20-5	C₇H₁₃NO₄	详情	详情
(III)	18067	tert-butyl 2-[2-(benzyloxy)anilino]-2-oxoethylcarbamate		C₂₀H₂₄N₂O₄	详情	详情
(IV)	18068	2-bromo-N-methyl-N-phenylacetamide		C₉H₁₀BrNO	详情	详情
(V)	18069	tert-butyl 2-[2-(benzyloxy)[2-(methylanilino)-2-oxoethyl]anilino]-2-oxoethylcarbamate		C₂₉H₃₃N₃O₅	详情	详情
(VI)	41107	tert-butyl 2-[2-hydroxy[2-(methylanilino)-2-oxoethyl]anilino]-2-oxoethylcarbamate		C₂₂H₂₇N₃O₅	详情	详情
(VII)	41108	tert-butyl 2-[2-[2-(methylanilino)-2-oxoethoxy][2-(methylanilino)-2-oxoethyl]anilino]-2-oxoethylcarbamate		C₃₁H₃₆N₄O₆	详情	详情
(VIII)	41109	2-amino-N-[2-[2-(methylanilino)-2-oxoethoxy]phenyl]-N-[2-(methylanilino)-2-oxoethyl]acetamide		C₂₆H₂₈N₄O₄	详情	详情
(IX)	41110	N-(2-[2-[2-(methylanilino)-2-oxoethoxy][2-(methylanilino)-2-oxoethyl]anilino]-2-oxoethyl)-1H-imidazole-1-carboxamide		C₃₀H₃₀N₆O₅	详情	详情
(X)	41111	methyl 2-(3-aminophenyl)acetate		C₉H₁₁NO₂	详情	详情
(XI)	41112	methyl 2-[3-([[(2-[2-[2-(methylanilino)-2-oxoethoxy][2-(methylanilino)-2-oxoethyl]anilino]-2-oxoethyl)amino]carbonyl]amino)phenyl]acetate		C₃₆H₃₇N₅O₇	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

The reaction of 2-(benzyloxy)aniline (I) with acetic anhydride and pyridine gives the acetanilide (II), which is treated with P2S5 in hot toluene to yield the thioacetamide (III). The reaction of (III) with methyl iodide and K2CO3 in hot acetonitrile affords the methylated thioimidate (IV), which is cyclized with biphenyl-4-carbohydrazide (V) in hot DMF to provide 4-(2-benzyloxyphenyl)-3-(4-biphenylyl)-5-methyl-4H-1,2,4-triazole (VI). The hydrogenation of (VI) with H2 over Pd/C in methanol gives the corresponding phenol (VII), which is finally alkylated by means of 4-(2-chloroethyl)morpholine (VIII) and NaH in hot DMF to yield the target triazole. (1,2)

参考文献中间体

合成目标

【1】 Kakefuda, A.; Suzuki, T.; Tobe, T.; Tahara, A.; Sakamoto, S.; Tsukamoto, S.-I.; Discovery of 4,5-diphenyl-1,2,4-triazole derivatives as a novel class of selective antagonists for the human V1A receptor. Bioorg Med Chem 2002, 10, 6, 1905.
【2】 Suzuki, T.; Murakami, T.; Tobe, T.; Tahara, A. (Yamanouchi Pharmaceutical Co., Ltd.); Novel triazole derivs.. WO 0158880 .

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)	18065	2-(benzyloxy)aniline; 2-(benzyloxy)phenylamine		C₁₃H₁₃NO	详情	详情
(II)	56977	N-[2-(benzyloxy)phenyl]acetamide		C₁₅H₁₅NO₂	详情	详情
(III)	56978	N-[2-(benzyloxy)phenyl]ethanethioamide		C₁₅H₁₅NOS	详情	详情
(IV)	56979	methyl N-[2-(benzyloxy)phenyl]ethanimidothioate		C₁₆H₁₇NOS	详情	详情
(V)	56980	4-Biphenylcarboxylic acid hydrazide; 4-Phenylbenzhydrazide	18622-23-6	C₁₃H₁₂N₂O	详情	详情
(VI)	56981	benzyl 2-(3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazol-4-yl)phenyl ether; 4-[2-(benzyloxy)phenyl]-3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazole		C₂₈H₂₃N₃O	详情	详情
(VII)	56982	2-(3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazol-4-yl)phenol		C₂₁H₁₇N₃O	详情	详情
(VIII)	27355	4-(2-chloroethyl)morpholine	3647-69-6	C₆H₁₂ClNO	详情	详情

Extended Information