2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone -Drug Synthesis Database

【结构式】

【分子编号】13137

【品名】2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone

【CA登记号】40786-69-4

【分子式】C₁₁H₁₄O₃

【分子量】194.23036

【元素组成】C 68.02% H 7.27% O 24.71%

与该中间体有关的原料药合成路线共 5 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5

合成路线1

该中间体在本合成路线中的序号：(I)

The condensation of 2,4-dihydroxy-3-prop ylacetophenone (I) with 1 4-dibromobutane (II) by means of K2CO3 in refluxing acetone gives 4-(4 acetyl 3-hydroxy-2-propylphenoxy)butyl bromide (III), which is treated with NaCN in hot DMF to yield 5-(4 acetyl-3-hydroxy-2-propylphenoxy)pen tanenitrile (IV). Finally, this compound is cyclized with sodium azide by means of NH4Cl in DMF at 125 C.

参考文献中间体

合成目标

【1】 Marshall, W.S.; Verge, J.P. (Eli Lilly and Company); Leukotriene antagonists. EP 0108592 .
【2】 Chu, S.S.; LY-171883. Drugs Fut 1985, 10, 8, 632.

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)	13137	2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone	40786-69-4	C₁₁H₁₄O₃	详情	详情
(II)	11883	1,4-Dibromobutane; 1,4-Butylene bromide	110-52-1	C₄H₈Br₂	详情	详情
(III)	24757	1-[4-(4-bromobutoxy)-2-hydroxy-3-propylphenyl]-1-ethanone		C₁₅H₂₁BrO₃	详情	详情
(IV)	24758	5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentanenitrile		C₁₆H₂₁NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

By condensation of ethyl 8-propyl-7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate (I) with 4-(2,3-epoxypropoxy)-3-propyl-2-hydroxyacetophenone (II) by means of benzyltrimethylammonium hydroxide in refluxing DMF, followed by hydrolysis with NaHCO3 in refluxing ethanol - water. The starting compounds (I) and (II) are prepared as follows: 1) The condensation of 3-propyl-2,4-dihydroxyacetophenone (III) with diethyl oxalate (IV) by means of sodium ethoxide in refluxing ethanol gives (I). 2) The condensation of acetophenone (III) with 1-chloro-2,3-epoxypropane (V) by means of KOH in refluxing ethanol - water gives (II).

参考文献中间体

合成目标

【1】 Pratt, A.D.; Bantick, J..; Lee, T.B.; Chamberlain, T.R.; Hardern, D.N.; Appleton, R.A.; Antagonits of slow reacting substance od anaphylaxis. Synthesis of a series of chromone-2-carboxylic acids. J Med Chem 1979, 20, 3, 371.
【2】 Augstein, J.; Lee, T.B.; Carter, D. (AstraZeneca plc); Chromone derivs.. FR 2147287 .
【3】 Augstein, J.; Carter, D.; Lee, T.B. (AstraZeneca plc); Chrome cpds. having SRS-A properties. US 3882148 .
【4】 Blancafort, P.; Castaner, J.; Sneddon, J.M.; Serradell, M.N.; FPL-55,712. Drugs Fut 1982, 7, 7, 472.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	37126			C₁₀H₁₈NO	详情	详情
(I)	37124	ethyl 7-hydroxy-4-oxo-8-propyl-4H-chromene-2-carboxylate		C₁₅H₁₆O₅	详情	详情
(II)	37125	1-[2-hydroxy-4-(2-oxiranylmethoxy)-3-propylphenyl]-1-ethanone		C₁₄H₁₈O₄	详情	详情
(III)	13137	2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone	40786-69-4	C₁₁H₁₄O₃	详情	详情
(IV)	17571	Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate	95-92-1	C₆H₁₀O₄	详情	详情
(V)	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	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 2,4-dihydroxy-3-n-propylacetophenone (I) with excess 1,3-dibromopropane in the presence of potassium carbonate in dimethylformamide gives 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (II). Subsequent reaction of (II) with 2-carbomethoxy-7-hydroxy-8-n-propylchromone in dimethylformamide containing anhydrous potassium carbonate furnished 2-carbomethoxy-7-[5-(2-n-propyl-3-hydroxy-4-acetylphenoxy)propoxy]-8-n-propylchromone (III), m.p. 113-115 C. Hydrogenation of (III) in acetic acid with 5% palladium on carbon catalyst generated 2-carbomethoxy-7-[5-(2-n-propyl-3-hydroxy-4-acetylphenoxy)propoxy]-8-n-propylchroman (IV), m.p. 70-72 C. Subsequent alkylation of (IV) with excess methyl iodide in refluxing acetone containing anhydrous potassium carbonate produced O-methyl ester (V). Final hydrolysis of O-methyl ester (V) was carried out with lithium hydroxide in aqueous methanol to provide SC-41930.

参考文献中间体

合成目标

【1】 Djuric, S.W.; Collins, P.W.; Jones, P.H.; et al.; 7-[3-(4-Acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl- 2H-1-benzopyran-2-carboxylic acid: An orally active selective leukotriene B4 receptor antagonist. J Med Chem 1989, 32, 6, 1145-7.
【2】 Shone, R.L.; Djuric, S.W.; Tsai, B.S.; Fretland, D.J.; Gaginella, T.S.; Cook, C.S.; SC-41930. Drugs Fut 1990, 15, 7, 695.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	63538	methyl 7-hydroxy-4-oxo-8-propyl-2-chromanecarboxylate		C₁₄H₁₆O₅	详情	详情
(I)	13137	2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone	40786-69-4	C₁₁H₁₄O₃	详情	详情
(II)	13138	1-[4-(3-Bromopropoxy)-2-hydroxy-3-propylphenyl]-1-ethanone		C₁₄H₁₉BrO₃	详情	详情
(III)	13139	methyl 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-4-oxo-8-propyl-2-chromanecarboxylate		C₂₈H₃₄O₈	详情	详情
(IV)	13140	methyl 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-8-propyl-2-chromanecarboxylate		C₂₈H₃₆O₇	详情	详情
(V)	13141	methyl 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-8-propyl-2-chromanecarboxylate		C₂₉H₃₈O₇	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XI)

The condensation of 3-(trifluoromethyl)benzaldehyde (I) with phosphonate (II) by means of NaH in THF gives the unsaturated ester (III), which is reduced with DIBAL in ethyl ether / hexane, yielding 3-[3-(trifluoromethyl)phenyl]allyl alcohol (IV). The Sharpless asymmetric epoxidation of (IV) affords the epoxyalcohol (V), which is oxidized with pyridine·SO3 to the corresponding aldehyde and condensed with phosphorane (A) to provide the unsaturated epoxyaldehyde (VI). The condensation of aldehyde (VI) with the pentylphosphonium derivative (VII) by means of NaNH2 in THF gives the corresponding adduct (VIII). The addition of 4-oxo-7-sulfanyl-4H-1-benzopyran-2-carboxylic acid methyl ester (IX) to the epoxide group of (VIII) by means of Et3N in methanol yields the expected alpha-hydroxy thioether (X), which is finally hydrolyzed with NaOH in THF/water to afford the target sodium salt. The intermediate pentylphosphonium derivative (VII) has been obtained by selective alkylation of 2,4-dihydroxy-3-propylacetophenone (XI) with 1,5-dibromopentane (XII) followed by reaction of the resulting ether with triphenylphosphine in refluxing toluene.

参考文献中间体

合成目标

【1】 Von Sprecher, A.; Beck, A.; Sallmann, A.; Breitenstein, W.; Wiestner, H.; Kimmel, S.; Anderson, G.P.; Subramanian, N.; Bray, M.A.; Peptidoleukotriene antagonists: Structural analogs of leukotriene D4 with special emphasis on CGP 45715A. Drugs Fut 1991, 16, 9, 827.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	20110	2-(triphenylphosphoranyl)acetaldehyde		C₂₀H₁₉OP	详情	详情
(I)	35964	3-(trifluoromethyl)benzaldehyde	454-89-7	C₈H₅F₃O	详情	详情
(II)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(III)	42936	ethyl (E)-3-[3-(trifluoromethyl)phenyl]-2-propenoate	113048-68-3	C₁₂H₁₁F₃O₂	详情	详情
(IV)	42937	(E)-3-[3-(trifluoromethyl)phenyl]-2-propen-1-ol		C₁₀H₉F₃O	详情	详情
(V)	42938	[(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]methanol		C₁₀H₉F₃O₂	详情	详情
(VI)	42939	(E)-3-[(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]-2-propenal		C₁₂H₉F₃O₂	详情	详情
(VII)	42940	[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl](triphenyl)phosphonium bromide		C₃₄H₃₈BrO₃P	详情	详情
(VIII)	42941	1-[2-hydroxy-3-propyl-4-[((5Z,7E)-8-[(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]-5,7-octadienyl)oxy]phenyl]-1-ethanone		C₂₈H₃₁F₃O₄	详情	详情
(IX)	42942	methyl 4-oxo-7-sulfanyl-4H-chromene-2-carboxylate		C₁₁H₈O₄S	详情	详情
(X)	42943	methyl 7-[((1S,2E,4Z)-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-[(R)-hydroxy[3-(trifluoromethyl)phenyl]methyl]-2,4-nonadienyl)sulfanyl]-4-oxo-4H-chromene-2-carboxylate		C₃₉H₃₉F₃O₈S	详情	详情
(XI)	13137	2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone	40786-69-4	C₁₁H₁₄O₃	详情	详情
(XII)	30560	1,5-dibromopentane	111-24-0	C₅H₁₀Br₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VII)

The Eastern fragment (XIV) was derived from 2',4'-dihydroxy-3'-propylacetophenone (VII). This material could be converted into (X) using identical procedures to those developed in house for the synthesis of SC-41930. (X) was resolved into its two homochiral components using enzymatic methods (Amano lipase AK, pH 7.4 buffer followed by selective methylation [CH3l, KHCO3, DMSO] and recrystallization. The overall yield for this process was 33% [based on a resolution yield of 40%]) and afforded the desired (-)-isomer (XII) in > 99% e.e. This material was silylated (TBDMS chloride, DMF, imidazole) and reduced to the primary carbinol with DIBAL-H. Conversion to the Eastern fragment (XIV) was accomplished by an efficient 3-step process involving triflation (Tf2O, CH2Cl2), homologation with lithium tert-butyl acetate and protective group removal/transesterification with ethanolic hydrogen chloride (92% for the three steps). The overall yield of Eastern fragment (> 99% e.e.) was 17% based on 2',4'-dihydroxy-3'-propylacetophenone (VII) as starting material.

参考文献中间体

合成目标

【1】 Smith, P.F.; Paulson, S.K.; Tsai, B.S.; Fretland, D.J.; Dygos, J.H.; Yu, S.S.; Djuric, S.W.; SC-53228. Drugs Fut 1994, 19, 12, 1093.
【2】 Yu, S.; Docter, S.; Djuric, S.; et al.; Synthesis and pharmacological activity of SC-53228, a leukotriene B4 receptor antagonist with high intrinsic potency and selectivity. Bioorg Med Chem Lett 1994, 4, 6, 811-6.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	13137	2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone	40786-69-4	C₁₁H₁₄O₃	详情	详情
(VIII)	16630	methyl 4-(2,4-dihydroxy-3-propylphenyl)-2,4-dioxobutanoate		C₁₄H₁₆O₆	详情	详情
(IX)	16631	methyl 7-hydroxy-4-oxo-8-propyl-4H-chromene-2-carboxylate		C₁₄H₁₄O₅	详情	详情
(X)	16632	methyl 7-hydroxy-8-propyl-2-chromanecarboxylate		C₁₄H₁₈O₄	详情	详情
(XI)	16633	7-hydroxy-8-propyl-2-chromanecarboxylic acid		C₁₃H₁₆O₄	详情	详情
(XII)	16632	methyl 7-hydroxy-8-propyl-2-chromanecarboxylate		C₁₄H₁₈O₄	详情	详情
(XIII)	16635	(7-[[tert-butyl(dimethyl)silyl]oxy]-8-propyl-3,4-dihydro-2H-chromen-2-yl)methanol		C₁₉H₃₂O₃Si	详情	详情
(XIV)	16636	ethyl 3-(7-hydroxy-8-propyl-3,4-dihydro-2H-chromen-2-yl)propanoate		C₁₇H₂₄O₄	详情	详情

Extended Information