ethyl (2R)-3,4-dihydro-2H-chromene-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】13885

【品名】ethyl (2R)-3,4-dihydro-2H-chromene-2-carboxylate

【CA登记号】

【分子式】C₁₂H₁₄O₃

【分子量】206.24136

【元素组成】C 69.89% H 6.84% O 23.27%

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)-R)

CP-72467-2 has been prepared by two synthetic routes which share a common intermediate. 1) In the initial route, diazotization of D-phenylalanine followed by esterification afforded the methyl ester of (R)-phenyllactic acid (I). Mitsunobu coupling with methyl 4-hydroxybenzoate using diisopropyl azodicarboxylate, selective reduction with sodium borohydride, and conversion to the bromide by in situ generation of triphenylphosphine dibromide produced intermediate (II). Friedel-Crafts alkylation of (II) using alpha-hydroxyhippuric acid/methanesulfonic acid, azalactone formation with acetic anhydride/triethylamine, followed by in situ spiroalkylation produced the N-benzoyl amino acid (III). Oxidative decarboxylation of (III) with 15% sodium hypochlorite led to the chromanone (V), presumably through hydrolysis of the intermediate N-benzoyl imine (IV). Catalytic hydrogenation over 10% Pd on carbon of the chromanone (V), reduction of the ester with Red-Al, and subsequent oxidation of the alcohol with manganese dioxide afforded the key aldehyde intermediate (VI). Condensation of aldehyde (VI) with 2,4-thiazolidinedione/pyridine, catalytic hydrogenation of the resultant olefin, and salt formation with sodium methoxide produced CP-72467-2. 2) An alternative synthesis of the key intermediate aldehyde (VI) utilizes an enzymatic resolution of the benzopyran ester (VII). Reduction of the 2(R)-ester with sodium borohydride followed by reaction with triflic anhydride generates the triflate (VIII). Copper-catalyzed reaction of the triflate (VIII) with phenyl magnesium bromide afforded the benzyl derivative (IX), which is readily formylated with phosphorous oxychloride/N-methyl formanilide to produce aldehyde (VI).

参考文献中间体

合成目标

【1】 Clark, D.A.; Goldstein, S.W.; Volkmann, R.A.; et al.; Substituted dihydrobenzopyran and dihydrobenzofuran thiazolidine-2,4-diones as hypoglycemic agents. J Med Chem 1991, 34, 1, 319.
【2】 Stevenson, R.W.; Urban, F.J.; Clark, D.A.; Englitazone Sodium. Drugs Fut 1992, 17, 3, 182.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11703	D-Phenylalanine; (R)-Phenylalanine	673-06-3	C₉H₁₁NO₂	详情	详情
((VII)-R)	13885	ethyl (2R)-3,4-dihydro-2H-chromene-2-carboxylate		C₁₂H₁₄O₃	详情	详情
(I)	13878	methyl (2R)-2-hydroxy-3-phenylpropanoate		C₁₀H₁₂O₃	详情	详情
(II)	13879	methyl 4-[[(1S)-1-benzyl-2-bromoethyl]oxy]benzoate		C₁₇H₁₇BrO₃	详情	详情
(III)	13880	(2S)-4-(Benzoylamino)-2-benzyl-6-(methoxycarbonyl)-3,4-dihydro-2H-chromene-4-carboxylic acid		C₂₆H₂₃NO₆	详情	详情
(IV)	13881	methyl (2S)-4-(acetylimino)-2-benzyl-2,3-dihydro-4H-chromene-6-carboxylate		C₂₀H₁₉NO₄	详情	详情
(V)	13882	methyl (2S)-2-benzyl-4-oxo-3,4-dihydro-2H-chromene-6-carboxylate		C₁₈H₁₆O₄	详情	详情
(VI)	13883	(2R)-2-Benzyl-3,4-dihydro-2H-chromene-6-carbaldehyde		C₁₇H₁₆O₂	详情	详情
(VII)	13884	ethyl 2-chromanecarboxylate		C₁₂H₁₄O₃	详情	详情
(VIII)	13886	(2R)-3,4-dihydro-2H-chromen-2-ylmethyl trifluoromethanesulfonate		C₁₁H₁₁F₃O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Racemic 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (I) is resolved into the corresponding enantiomers by recrystallization of the diastereomeric salts with (+)-(R)-alpha-methylbenzylamine, and the desired (R)-carboxylic acid is further esterified with H2SO4/EtOH to furnish the ethyl ester (II). Subsequent reduction of ester (II) with NaBH4 in toluene/EtOH leads to alcohol (III), which is converted into mesylate (IV) employing methanesulfonyl chloride and triethylamine. Mesylate (IV) is finally condensed with 1-(3-aminopropyl)-hexahydro-2-pyrimidinone (V) by heating with CaO at 100 C in THF in an autoclave to provide the title compound

参考文献中间体

合成目标

【1】 De Bruyn, M.F.L.; Schroven, M.F.J.; Wigerinck, P.T.B.P.; Verschueren, W.G. (Janssen Pharmaceutica NV); (Benzodioxan, benzofuran or benzopyran) derivs. having fundic relaxation properties. WO 9929687 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	17037	2-chromanecarboxylic acid	C₁₀H₁₀O₃	详情	详情
(II)	13885	ethyl (2R)-3,4-dihydro-2H-chromene-2-carboxylate	C₁₂H₁₄O₃	详情	详情
(III)	62037	(2R)-3,4-dihydro-2H-chromen-2-ylmethanol	C₁₀H₁₂O₂	详情	详情
(IV)	62038	(2R)-3,4-dihydro-2H-chromen-2-ylmethyl methanesulfonate	C₁₁H₁₄O₄S	详情	详情
(V)	62039	1-(3-aminopropyl)tetrahydro-2(1H)-pyrimidinone	C₇H₁₅N₃O	详情	详情

Extended Information