(E)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal -Drug Synthesis Database

【结构式】

【分子编号】34794

【品名】(E)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal

【CA登记号】

【分子式】C₁₇H₁₅ClO₃

【分子量】302.757

【元素组成】C 67.44% H 4.99% Cl 11.71% O 15.85%

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)

Condensation of (4-methoxyphenyl)acetic acid (I) with anisole (II) in hot PPA produced ketone (III). Subsequent treatment of (III) with the Vilsmeier reagent afforded chloroaldehyde (IV). The required thiophene (VI) was then obtained by cyclization with ethyl mercaptoacetate (V) in the presence of NaOEt. After basic hydrolysis of the ester group of (VI), the resulting acid (VII) was decarboxylated by means of copper in quinoline at 180 C, yielding thiophene (VIII). Stannic chloride-promoted Friedel-Crafts acylation of (VIII) with 3-(methoxycarbonyl)propionyl chloride (IX) gave ketoester (X). The keto group of (X) was further reduced employing triethylsilane in trifluoroacetic acid to afford (XI). Hydrolysis of the methyl ester of (XI), followed by treatment with oxalyl chloride furnished acid chloride (XII). The title hydroxamic acid was then obtained by coupling of (XII) with O-(tert-butyldimethylsilyl)-N-methylhydroxylamine and subsequent acid-catalyzed desilylation.

参考文献中间体

合成目标

【1】 Wierzbicki, M.; Sauveur, F.; Bonnet, J.; Tordjman, C. (ADIR et Cie.); Thiophene cpds., process for their preparation and pharmaceutical compsns. containing them. EP 0728755; FR 2730996; JP 1996253470 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40600	tert-butyl(dimethyl)[(methylamino)oxy]silane; O-[tert-butyl(dimethyl)silyl]-N-methylhydroxylamine		C₇H₁₉NOSi	详情	详情
(I)	34793	2-(4-methoxyphenyl)acetic acid; p-Methoxyphenyl formate; Homoanisic acid; p-Methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid	104-01-8	C₉H₁₀O₃	详情	详情
(II)	23767	Methoxybenzene; Methyl phenyl ether; Anisole	100-66-3	C₇H₈O	详情	详情
(III)	22991	1,2-bis(4-methoxyphenyl)-1-ethanone	120-44-5	C₁₆H₁₆O₃	详情	详情
(IV)	34794	(E)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal		C₁₇H₁₅ClO₃	详情	详情
(V)	23995	ethyl 2-sulfanylacetate	2713-34-0	C₄H₈O₂S	详情	详情
(VI)	34795	ethyl 4,5-bis(4-methoxyphenyl)-2-thiophenecarboxylate		C₂₁H₂₀O₄S	详情	详情
(VII)	34796	4,5-bis(4-methoxyphenyl)-2-thiophenecarboxylic acid		C₁₉H₁₆O₄S	详情	详情
(VIII)	34797	2,3-bis(4-methoxyphenyl)thiophene; 4-[2-(4-methoxyphenyl)-3-thienyl]phenyl methyl ether		C₁₈H₁₆O₂S	详情	详情
(IX)	18060	4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate	1490-25-1	C₅H₇ClO₃	详情	详情
(X)	34798	methyl 4-[4,5-bis(4-methoxyphenyl)-2-thienyl]-4-oxobutanoate		C₂₃H₂₂O₅S	详情	详情
(XI)	34799	methyl 4-[4,5-bis(4-methoxyphenyl)-2-thienyl]butanoate		C₂₃H₂₄O₄S	详情	详情
(XII)	34800	4-[4,5-bis(4-methoxyphenyl)-2-thienyl]butanoyl chloride		C₂₂H₂₁ClO₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The intermediate phenylacetic acid allyl ester (IV) is prepared by two methods. Reaction of trans-1,4-dibromo-2-butene (I) with benzyl alcohol under phase-transfer conditions provides the benzyl ether (II). Subsequent DBU-mediated coupling of (II) with (4-methoxyphenyl)acetic acid (III) yields ester (IV).

参考文献中间体

合成目标

【1】 Kottirsch, G.; et al.; beta-Aryl-succinic acid hydroxamates as dual inhibitors of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme. J Med Chem 2002, 45, 11, 2289.
【2】 Kottirsch, G.; Neumann, U. (Novartis AG); Hydroxamic acid derivs.. EP 0929517; JP 2000508338; US 2002003804; US 6500983; WO 9814424 .

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)	18349	(E)-1,4-dibromo-2-butene；trans-1,4-dibromo-2-butene	821-06-7	C₄H₆Br₂	详情	详情
(II)	61680	benzyl (E)-4-bromo-2-butenyl ether; 1-({[(E)-4-bromo-2-butenyl]oxy}methyl)benzene		C₁₁H₁₃BrO	详情	详情
(III)	34794	(E)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal		C₁₇H₁₅ClO₃	详情	详情
(IV)	61681	(E)-4-(benzyloxy)-2-butenyl 2-(4-methoxyphenyl)acetate		C₂₀H₂₂O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

In an alternative synthesis of (IV), alkylation of propargyl alcohol (V) with benzyl bromide in a two-phase system gives ether (VI). Subsequent addition of paraformaldehyde to the lithium acetylide derived from (VI) furnishes alcohol (VII). Selective reduction of acetylene (VII) to the trans olefin (VIII) is accomplished by means of Red-Al in cold THF. The allylic alcohol (VIII) is then esterified with (4-methoxyphenyl)acetic acid (III) in the presence of DCC to form ester (IV).

参考文献中间体

合成目标

【1】 Koch, G.; Kottirsch, G.; Wietfeld, B.; Kusters, E.; Process development of a dual MMP/TNF inhibitor (SDZ 242-484). Org Process Res Dev 2002, 6, 5, 652.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	34794	(E)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal		C₁₇H₁₅ClO₃	详情	详情
(IV)	61681	(E)-4-(benzyloxy)-2-butenyl 2-(4-methoxyphenyl)acetate		C₂₀H₂₂O₄	详情	详情
(V)	16664	Propargyl Alcohol; 2-propyn-1-ol	107-19-7	C₃H₄O	详情	详情
(VI)	16663	benzyl 2-propynyl ether; 1-[(2-propynyloxy)methyl]benzene		C₁₀H₁₀O	详情	详情
(VII)	61682	4-(benzyloxy)-2-butyn-1-ol		C₁₁H₁₂O₂	详情	详情
(VIII)	61683	(E)-4-(benzyloxy)-2-buten-1-ol		C₁₁H₁₄O₂	详情	详情

Extended Information