ethyl (E)-3-methyl-4-oxo-2-butenoate -Drug Synthesis Database

【结构式】

【分子编号】40061

【品名】ethyl (E)-3-methyl-4-oxo-2-butenoate

【CA登记号】62054-49-3

【分子式】C₇H₁₀O₃

【分子量】142.1546

【元素组成】C 59.14% H 7.09% O 33.76%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(D)

The reaction of 2,3,5-trimethylanisole (II) [prepared by alkylation of 2,3,5-trimethylphenol (I) with methyl iodide] with DMF and POCl3 affords 4-(4-methoxy-2,3,6-trimethylbenzaldehyde (V), which is condensed with propanone (B) in aqueous NaOH giving 4-(4-methoxy-2,3,6-trimethylphenyl)-but-3-en-2-one (VI). The Grignard reaction of (VI) with ethynylmagnesium bromide (C) in THF yields 5-(4-methoxy-2,3,6-trimethylphe-nyl)-3-methyl-3-hydroxypenta-4-en-1-yne (VII), which is partially hydrogenated with H2 over deactivated Pd in hexane to give 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxypenta-1,4-diene (VIII). The reaction of (VIII) with triphenylphosphonium hydrobromide in benzene affords 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (IX). Finally, this compound is submitted to a Wittig reaction with ethyl 3,4-formylcrotonate (D) in DMF (NaH is used as base).

参考文献中间体

合成目标

【1】 Bollag, W. et al.; Polyene derivatives. DE 2414619; ES 424750; FR 2223037; GB 1468401; GB 1468402 .
【2】 Castaner, J.; Thorpe, P.; RO 10/9359. Drugs Fut 1977, 2, 3, 199.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	33481	4-methoxy-2,3,6-trimethylbenzaldehyde		C₁₁H₁₄O₂	详情	详情
(D)	40061	ethyl (E)-3-methyl-4-oxo-2-butenoate	62054-49-3	C₇H₁₀O₃	详情	详情
(I)	33479	2,3,5-trimethylphenol	697-82-5	C₉H₁₂O	详情	详情
(II)	33480	1-methoxy-2,3,5-trimethylbenzene; methyl 2,3,5-trimethylphenyl ether	20469-61-8	C₁₀H₁₄O	详情	详情
(V)	23199	2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether	67-64-1	C₃H₆O	详情	详情
(VI)	33482	(E)-4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one	54757-47-0	C₁₄H₁₈O₂	详情	详情
(VII)	33483	(E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1-penten-4-yn-3-ol		C₁₆H₂₀O₂	详情	详情
(VIII)	33484	(1E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1,4-pentadien-3-ol		C₁₆H₂₂O₂	详情	详情
(IX)	33485	[(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl](triphenyl)phosphonium bromide		C₃₄H₃₆BrOP	详情	详情
(C)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情

合成路线2

该中间体在本合成路线中的序号：(Iva)

The photoisomerization of trans-retinoic acid (I) in hot acetonitrile using a tungsten lamp produces an equilibrium mixture containing the target 9-cis-retinoic acid, which can be isolated by recrystallization from EtOH (1, 2). A number of methods are based on the preparation of the ethyl (IIa) and methyl (IIb) esters of alitretinoin, which can be hydrolyzed to the corresponding carboxylic acid under alkaline conditions (3-11). In an alternative procedure, Wittig reaction of the 9-cis-phosphonium salts (IIIa) or (IIIb) (which can be isolated as byproducts in the production of the analogous all-trans derivatives) with 3-methyl-4-oxocrotonate esters (IVa/b), with concomitant ester group hydrolysis in the reaction medium, provides directly the target 9-cis-retinoic acid (12, 13). A different strategy consists of the condensation of the β-ionylideneacetaldehyde (V) with dimethyl β-methylglutaconate (VI) under strongly alkaline conditions to provide the diacid adduct (VII), which is mono-decarboxylated to 9,13-di-cis-retinoic acid (VIII) in the presence of copper acetate in hot 2,4-lutidine. Subsequent isomerization of (VIII) to the title 9-cis-tretinoin is accomplished by light irradiation in the presence of a trace of iodine (14). In a further synthetic route to the title compound, rearrangement of the propargylic alcohol (IX) with phenylsulfenyl chloride and triethylamine results in the conjugated sulfoxide (X) which, after desulfuration with t-BuLi and MeLi and desilylation with TBAF, gives 9-cis-retinol (XI). Finally, oxidation of alcohol (XI) utilizing MnO2 and AgO in MeOH furnishes the target carboxylic acid (15). Scheme 1.

参考文献中间体

合成目标

【1】 Coe, J.W. (Pfizer, Inc.). Method for the preparation of 9-cis retinoic acid. WO 9422818.
【2】 Coe, J.W., O’Connell, T. Convenient preparation of 9-cis-retinoic acid. Bioorg Med Chem Lett 1994, 4(2): 349-50.
【3】 Boehm, M.F., McClurg, M.R., Pathirana, C. et al. Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties. J Med Chem 1994, 37(3): 408-14.
【4】 Bennani, Y.L. An efficient and stereoselective synthesis of 9-cis-retinoic acid. J Org Chem 1996, 61(10): 3542-4.
【5】 Wada, A., Hiraishi, S., Takamura, N., Date, T., Aoe, K., Ito, M. A novel method for a stereoselective synthesis of trisubstituted olefin using tricarbonyliron complex: A highly stereoselective synthesis of (all-E)- and (9Z)-retinoic acids. J Org Chem 1997, 62(13): 4343-8.
【6】 Wada, A., Fukunaga, K., Ito, M., Mizuguchi, Y., Nakagawa, K., Okano, T. Preparation and biological activity of 13-substituted retinoic acids. Bioorg Med Chem 2004, 12(14): 3931-42.
【7】 Pazos, Y., de Lera, A.R. Stereoselective synthesis of 9-cis-retinoic acid by Suzuki reaction. Tetrahedron Lett 1999, 40(47): 8287-90.
【8】 Pazos, Y., Iglesias, B., de Lera, A.R. The Suzuki coupling reaction in the stereocontrolled synthesis of 9-cis-retinoic acid and its ring-demethylated analogues. J Org Chem 2001, 66(25): 8483-9.
【9】 Bennani, Y.L., Boehm, M.F. Synthesis of high specific activity 2,3- and 3,4-[3H]2-9-cis-retinoic acid. J Org Chem 1995, 60(5): 1195-200.
【10】 Tadikonda, P.K., Lacy, J.M., Rigdon, M.G., DeLuca, H.F. Synthesis of 9-cis-retinoic acid and C-20-[3H3C]-9-cis-retinoic acid with high specific activity. J Label Comp Radiopharm 1997, 34(1): 1-10.
【11】 DeLuca, H.F., Tadikonda, P.K. (Wisconsin Alumni Res. Found.). Method of synthesis of retinoic acid. US 5808120.
【12】 John, M., Paust, J. (BASF AG). Preparation of 9-(Z)-retinoic acid. US 5504230.
【13】 Soukup, M., Thomessen, R. (F. Hoffmann-la Roche AG). Process for the production of 9-cis retinoic acid. CA 2520018, EP 1615879, JP 2006522757, US 2004235951, US 7015353, WO 2004089887.
【14】 Robeson, C.D., Cawley, J.D., Weisler, L., Stern, M.H., Eddinger, C.C., Chechak, A.J. Chemistry of vitamin A. XXIV. The synthesis of geometric isomers of vitamin A via methyl beta-methylglutaconate. J Am Chem Soc 1955, 77(15): 4111.
【15】 de Lera, A.R., Castro, A., Torrado, A., Lopez, S. Stereoselective isomerization of 10-arylsulfenate-11,12-dehydroretinoids to 9-cis-retinoids. Tetrahedron Lett 1998, 39(25): 4575-8.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Iia)	65476	9-cis-Retinoic acid ethyl ester; Ethyl (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate		C₂₂H₃₂O₂	详情	详情
(IIb)	65477	9-cis-Retinoic acid methyl ester; Methyl (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate		C₂₁H₃₀O₂	详情	详情
(IIIa)	65478	(E,E)-[3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexen-1-yl)Penta-2,4-Dienyl]Triphenylphosphonium Chloride	53282-28-3	C₃₃H₃₈ClP	详情	详情
(IIIb)	65479	(E,E)-[3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexen-1-yl)Penta-2,4-Dienyl]Triphenylphosphonium bisulfate		C₃₃H₃₈P.HSO₄	详情	详情
(Iva)	40061	ethyl (E)-3-methyl-4-oxo-2-butenoate	62054-49-3	C₇H₁₀O₃	详情	详情
(Ivb)	65480	Methyl (E)-3-methyl-4-oxocrotonate		C₆H₈O₃	详情	详情
(I)	32679	(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid; Retinoic acid	302-79-4	C₂₀H₂₈O₂	详情	详情
(V)	65481	(2E,4E)-3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexenyl)Penta-2,4-Dienal	1209-68-3	C₁₅H₂₂O	详情	详情
(VI)	65482	Dimethyl 3-methylpent-2-enedioate	52313-87-8	C₈H₁₂O₄	详情	详情
(VII)	65483			C₂₁H₂₈O₄	详情	详情
(VIII)	65484	9-cis-Retinoic acid; (2E,4E,6Z,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoic acid	5300-03-8	C₂₀H₂₈O₂	详情	详情
(IX)	65485			C₂₇H₄₄O₂Si	详情	详情
(X)	65486			C₃₂H₅₂O₂SSi	详情	详情
(XI)	65487	9-cis Retinol; 9-Cis-Retinol; Retinol, 9-Cis-; 13-Cis-Retinol	22737-97-9	C₂₀H₃₀O	详情	详情

Extended Information