(E)-3-(3,4-dimethoxyphenyl)-2-propenoic acid -Drug Synthesis Database

【结构式】

【分子编号】28568

【品名】(E)-3-(3,4-dimethoxyphenyl)-2-propenoic acid

【CA登记号】2316-26-9

【分子式】C₁₁H₁₂O₄

【分子量】208.21388

【元素组成】C 63.45% H 5.81% O 30.74%

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：(VII)

Cyclization of N,N'-diethylurea (I) with cyanoacetic acid (II) in hot acetic anhydride gives 6-amino-1,3-diethyluracil (III) which is nitrosated with NaNO2/HOAc in water to yield 6-amino-1,3-diethyl-5-nitrosouracil (IV). The reduction of (IV) with Na2S2O4 and K2CO3 in concentrated aqueous ammonia affords 5,6-diamino-1,3-diethyluracil (V), which is condensed with either 3-(3,4-dimethoxyphenyl)-2(E)-propenoyl chloride (VI) in EtOH/water or 3-(3,4-dimethoxyphenyl)-2(E)-propenoic acid (VII) and 3-[3-(diethylamino)propyl]-1-ethylcarbodiimide (EDAC) in dioxane/water to provide the corresponding amide (VIII). Cyclization of (VIII) by means of NaOH in the same solvent furnishes the xanthine derivative (IX), which is finally methylated with methyl iodide and K2CO3 in DMF.

参考文献中间体

合成目标

【1】 Blicke, F.F.; Godt, H.C. Jr.; Reactions of 1,3-dimethyl-5,6-diaminouracil. J Am Chem Soc 1954, 76, 2798.
【2】 Leeson, P.A.; Castañer, J.; Sorbera, L.A.; Martín, L.; Rabasseda, X.; KW-6002. Drugs Fut 2001, 26, 1, 21.
【3】 Shimada, J.; Koike, N.; Nonaka, H.; et al.; Adenosine A2A antagonists with potent anti-cataleptic activity. Bioorg Med Chem Lett 1997, 7, 18, 2349.
【4】 Suzuki, F.; Shimada, J.; Ishii, A.; Nakamura, J.; Ichikawa, S.; Kitamura, S.; Koike, N. (Kyowa Hakko Kogyo Co., Ltd.); Antidepressant. EP 0628311; JP 1994502746; WO 9401114 .
【5】 Suzuki, F.; Shimada, J.; Koike, N.; Nakamura, J.; Shiozaki, S.; Ichikawa, S.; Nonaka, H. (Kyowa Hakko Kogyo Co., Ltd.); Therapeutic agents for Parkinson's disease. EP 0590919; JP 1994211856; US 5484920 .
【6】 Miwa, K.; Ito, K.; Kato, N.; Kuge, Y.; Kousai, M.; Tomioka, S. (Kyowa Hakko Kogyo Co., Ltd.); Preparation of uracil derivs.. JP 1997040652 .

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)	43818	N,N'-diethylurea	623-76-7	C₅H₁₂N₂O	详情	详情
(II)	12591	Cyanoacetic Acid; 2-Cyanoacetic acid	372-09-8	C₃H₃NO₂	详情	详情
(III)	43819	6-amino-1,3-diethyl-2,4(1H,3H)-pyrimidinedione		C₈H₁₃N₃O₂	详情	详情
(IV)	43820	6-amino-1,3-diethyl-5-nitroso-2,4(1H,3H)-pyrimidinedione		C₈H₁₂N₄O₃	详情	详情
(V)	28567	5,6-diamino-1,3-diethyl-2,4(1H,3H)-pyrimidinedione		C₈H₁₄N₄O₂	详情	详情
(VI)	33601	(E)-3-(3,4-dimethoxyphenyl)-2-propenoyl chloride		C₁₁H₁₁ClO₃	详情	详情
(VII)	28568	(E)-3-(3,4-dimethoxyphenyl)-2-propenoic acid	2316-26-9	C₁₁H₁₂O₄	详情	详情
(VIII)	43821	(E)-N-(6-amino-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-3-(3,4-dimethoxyphenyl)-2-propenamide		C₁₉H₂₄N₄O₅	详情	详情
(IX)	28569	8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-3,7-dihydro-1H-purine-2,6-dione		C₁₉H₂₂N₄O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Knoevenagel condensation of 3,4-dimethoxybenzaldehyde (I) with malonic acid produced the cinnamic acid (II), which was further reduced to (III) by catalytic hydrogenation using Pd/C. Conversion of (III) to the corresponding acid chloride (IV), followed by Friedel-Crafts intramolecular cyclization gave the indanone (V). Nitrosation of (V) yielded the oximino derivative (VI), which was subsequently silylated with t-butyldimethylsilyl chloride and imidazole to afford the O-silyl oxime (VII). Reduction of (VII) with borane-dimethyl sulfide complex produced the amino alcohol (VIII). Without isolation, (VIII) was converted to the dipropylamino compound (IX) by reductive alkylation with propionaldehyde and NaBH(OAc)3. Amino alcohol (IX) was finally deoxygenated by means of triethylsilane in the presence of boron trifluoride etherate.

参考文献中间体

合成目标

【1】 Haadsma-Svensson, S.R.; Cleek, K.A.; Dinh, D.M.; et al.; Dopamine D3 receptor antagonists. 1. Synthesis and structure-activity relationships of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans. J Med Chem 2001, 44, 26, 4716.

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)	18304	3,4-Dimethoxybenzaldehyde; Veratraldehyde	120-14-9	C₉H₁₀O₃	详情	详情
(II)	28568	(E)-3-(3,4-dimethoxyphenyl)-2-propenoic acid	2316-26-9	C₁₁H₁₂O₄	详情	详情
(III)	40182	3-(3,4-dimethoxyphenyl)propionic acid	2107-70-2	C₁₁H₁₄O₄	详情	详情
(IV)	56565	3-(3,4-dimethoxyphenyl)propanoyl chloride		C₁₁H₁₃ClO₃	详情	详情
(V)	13430	5,6-Dimethoxy-1-indanone; 2,3-Dihydro-5,6-dimethoxy-1H-inden-1-one	2107-69-9	C₁₁H₁₂O₃	详情	详情
(VI)	27302	5,6-dimethoxy-1H-indene-1,2(3H)-dione 2-oxime		C₁₁H₁₁NO₄	详情	详情
(VII)	56566	5,6-dimethoxy-1H-indene-1,2(3H)-dione 2-{O-[tert-butyl(dimethyl)silyl]oxime}		C₁₇H₂₅NO₄Si	详情	详情
(VIII)	56567	2-amino-5,6-dimethoxy-1-indanol		C₁₁H₁₅NO₃	详情	详情
(IX)	56568	2-(dipropylamino)-5,6-dimethoxy-1-indanol		C₁₇H₂₇NO₃	详情	详情

Extended Information