N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine -Drug Synthesis Database

【结构式】

【分子编号】26778

【品名】N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine

【CA登记号】

【分子式】C₂₂H₂₂N₂O₄

【分子量】378.42776

【元素组成】C 69.83% H 5.86% N 7.4% O 16.91%

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：(XI)

4'-Methylacetophenone (I) was condensed with boiling dimethylformamide dimethylacetal, and the resulting enaminoketone (II) was cyclized to the isoxazole (III) with hydroxylamine O-sulfonic acid in MeOH. Benzylic bromination of (III) with N-bromosuccinimide in the presence of benzoyl peroxide gave bromomethyl compound (IV). Subsequent alkylation of diphenylmethylene glycine ethyl ester (V) with (IV) under phase-transfer conditions, followed by acid deprotection furnished isoxazolylphenylalanine ethyl ester (VII). This compound was condensed with 3,5-dimethyl benzoic acid (VIII) using EDC and HOBt to give amide (IX). Further N-methylation of (IX) with MeI and NaH yielded (X), which was hydrolyzed with LiOH to the carboxylic acid (XI).

参考文献中间体

合成目标

【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Frueh, T.; Pitterna, T.; Iwasaki, G.; Oda, K.; Yamamura, T.; Hayakawa, K.; Discovery of IRL 3461: A novel and potent endothelin antagonist with balanced ETA/ETB affinity. Bioorg Med Chem Lett 1998, 8, 16, 2241.
【2】 Fruh, T.; Pitterna, T.; Murata, T.; Svensson, L.D.; Yuumoto, Y.; Sakaki, J. (Novartis Japan KK); Antagonists of endothelin receptors. EP 0753004; JP 1997510720; US 5703106; WO 9526360 .

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)	17145	1-(4-methylphenyl)-1-ethanone; p-methylacetophenone; 4-methylacetophenone; 4-methylphenylethanone	122-00-9	C₉H₁₀O	详情	详情
(II)	26769	(E)-3-(dimethylamino)-1-(4-methylphenyl)-2-propen-1-one		C₁₂H₁₅NO	详情	详情
(III)	26770	5-(4-methylphenyl)isoxazole		C₁₀H₉NO	详情	详情
(IV)	26771	5-[4-(bromomethyl)phenyl]isoxazole		C₁₀H₈BrNO	详情	详情
(V)	26772	ethyl 2-((diphenylmethylene)amino)acetate;N-(Diphenylmethylene)glycine ethyl ester;Ethyl N-(diphenylmethylene)glycinate;ethyl 2-[(dibenzylene)amino]acetate	69555-14-2	C₁₇H₁₇NO₂	详情	详情
(VI)	26773	ethyl 2-[(dibenzylene)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate		C₂₇H₂₄N₂O₃	详情	详情
(VII)	26774	ethyl 2-amino-3-[4-(5-isoxazolyl)phenyl]propanoate		C₁₄H₁₆N₂O₃	详情	详情
(VIII)	26775	3,5-dimethylbenzoic acid	499-06-9	C₉H₁₀O₂	详情	详情
(IX)	26776	ethyl 2-[(3,5-dimethylbenzoyl)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate		C₂₃H₂₄N₂O₄	详情	详情
(X)	26777	ethyl 2-[(3,5-dimethylbenzoyl)(methyl)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate		C₂₄H₂₆N₂O₄	详情	详情
(XI)	26778	N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine		C₂₂H₂₂N₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

1-Butanesulfonyl chloride (XII) was reacted with ammonia in acetonitrile, and the resulting sulfonamide (XIII) was then converted to the N-trimethylsilyl derivative (XIV). This was coupled with acid fluoride (XVII), (obtained from Boc-valine (XV) and cyanuric fluoride (XVI)), to provide Boc-valinesulfonamide (XVIII). The Boc group of (XVIII) was then removed by acid treatment to give (XIX). Finally, coupling of this chiral intermediate with the previously obtained racemic acid (XI) furnished the title compound as a 7:3 mixture of diastereoisomers.

参考文献中间体

合成目标

【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Frueh, T.; Pitterna, T.; Iwasaki, G.; Oda, K.; Yamamura, T.; Hayakawa, K.; Discovery of IRL 3461: A novel and potent endothelin antagonist with balanced ETA/ETB affinity. Bioorg Med Chem Lett 1998, 8, 16, 2241.
【2】 Fruh, T.; Pitterna, T.; Murata, T.; Svensson, L.D.; Yuumoto, Y.; Sakaki, J. (Novartis Japan KK); Antagonists of endothelin receptors. EP 0753004; JP 1997510720; US 5703106; WO 9526360 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	26778	N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine		C₂₂H₂₂N₂O₄	详情	详情
(XII)	26779	1-butanesulfonyl chloride	2386-60-9	C₄H₉ClO₂S	详情	详情
(XIII)	26780	1-butanesulfonamide		C₄H₁₁NO₂S	详情	详情
(XIV)	26781	N-(trimethylsilyl)-1-butanesulfonamide		C₇H₁₉NO₂SSi	详情	详情
(XV)	19733	(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid		C₁₀H₁₉NO₄	详情	详情
(XVI)	26782	Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine	675-14-9	C₃F₃N₃	详情	详情
(XVII)	26783	tert-butyl (1S)-1-(fluorocarbonyl)-2-methylpropylcarbamate		C₁₀H₁₈FNO₃	详情	详情
(XVIII)	26784	tert-butyl (1S)-1-[[(butylsulfonyl)amino]carbonyl]-2-methylpropylcarbamate		C₁₄H₂₈N₂O₅S	详情	详情
(XIX)	26785	N-[(2S)-2-amino-3-methylbutanoyl]-1-butanesulfonamide		C₉H₂₀N₂O₃S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

参考文献中间体

合成目标

【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Hayakawa, K.; Stereoselective synthesis of a novel and bifunctional endothelin antagonist, IRL 3630. Bioorg Med Chem Lett 1998, 8, 16, 2247.
【2】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Okada, T. (Novartis Japan KK); Antagonists of endothelin receptors. JP 1999512702; WO 9711960 .

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)	17145	1-(4-methylphenyl)-1-ethanone; p-methylacetophenone; 4-methylacetophenone; 4-methylphenylethanone	122-00-9	C₉H₁₀O	详情	详情
(II)	26769	(E)-3-(dimethylamino)-1-(4-methylphenyl)-2-propen-1-one		C₁₂H₁₅NO	详情	详情
(III)	26770	5-(4-methylphenyl)isoxazole		C₁₀H₉NO	详情	详情
(IV)	26771	5-[4-(bromomethyl)phenyl]isoxazole		C₁₀H₈BrNO	详情	详情
(V)	26772	ethyl 2-((diphenylmethylene)amino)acetate;N-(Diphenylmethylene)glycine ethyl ester;Ethyl N-(diphenylmethylene)glycinate;ethyl 2-[(dibenzylene)amino]acetate	69555-14-2	C₁₇H₁₇NO₂	详情	详情
(VI)	26773	ethyl 2-[(dibenzylene)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate		C₂₇H₂₄N₂O₃	详情	详情
(VII)	26774	ethyl 2-amino-3-[4-(5-isoxazolyl)phenyl]propanoate		C₁₄H₁₆N₂O₃	详情	详情
(VIII)	26775	3,5-dimethylbenzoic acid	499-06-9	C₉H₁₀O₂	详情	详情
(IX)	26776	ethyl 2-[(3,5-dimethylbenzoyl)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate		C₂₃H₂₄N₂O₄	详情	详情
(X)	26777	ethyl 2-[(3,5-dimethylbenzoyl)(methyl)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate		C₂₄H₂₆N₂O₄	详情	详情
(XI)	26778	N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine		C₂₂H₂₂N₂O₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XI)

1-Butanesulfonyl chloride (XII) was reacted with ammonia in acetonitrile, and the resulting sulfonamide (XIII) was then converted to the N-trimethylsilyl derivative (XIV). This compound was coupled with acid fluoride (XVII), (obtained from Boc-valine (XV) and cyanuric fluoride (XVI)), to provide Boc-valinesulfonamide (XVIII). The Boc group of (XVIII) was then removed by acid treatment to give (XIX). Coupling of this chiral intermediate (XIX) with racemic acid (XI) in a biphasic solvent system, with partial isomerization of acid (XI), furnished the amide (XX) as a 12:1 diastereomeric mixture. The major D,L diastereoisomer was then isolated either by preparative HPLC or by recrystallization from isopropanol.

参考文献中间体

合成目标

【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Hayakawa, K.; Stereoselective synthesis of a novel and bifunctional endothelin antagonist, IRL 3630. Bioorg Med Chem Lett 1998, 8, 16, 2247.
【2】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Okada, T. (Novartis Japan KK); Antagonists of endothelin receptors. JP 1999512702; WO 9711960 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	26778	N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine		C₂₂H₂₂N₂O₄	详情	详情
(XII)	26779	1-butanesulfonyl chloride	2386-60-9	C₄H₉ClO₂S	详情	详情
(XIII)	26780	1-butanesulfonamide		C₄H₁₁NO₂S	详情	详情
(XIV)	26781	N-(trimethylsilyl)-1-butanesulfonamide		C₇H₁₉NO₂SSi	详情	详情
(XV)	19733	(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid		C₁₀H₁₉NO₄	详情	详情
(XVI)	26782	Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine	675-14-9	C₃F₃N₃	详情	详情
(XVII)	26783	tert-butyl (1S)-1-(fluorocarbonyl)-2-methylpropylcarbamate		C₁₀H₁₈FNO₃	详情	详情
(XVIII)	26784	tert-butyl (1S)-1-[[(butylsulfonyl)amino]carbonyl]-2-methylpropylcarbamate		C₁₄H₂₈N₂O₅S	详情	详情
(XIX)	26785	N-[(2S)-2-amino-3-methylbutanoyl]-1-butanesulfonamide		C₉H₂₀N₂O₃S	详情	详情
(XX)	26786	N-[2-[((1S)-1-[[(butylsulfonyl)amino]carbonyl]-2-methylpropyl)amino]-1-[4-(5-isoxazolyl)benzyl]-2-oxoethyl]-N,3,5-trimethylbenzamide		C₃₁H₄₀N₄O₆S	详情	详情

Extended Information