4-amino-6-fluoro-4-chromanecarboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】20834

【品名】4-amino-6-fluoro-4-chromanecarboxylic acid

【CA登记号】

【分子式】C₁₀H₁₀FNO₃

【分子量】211.1927432

【元素组成】C 56.87% H 4.77% F 9% N 6.63% O 22.73%

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)

The condensation of 4-fluorophenol (I) with 1,2-dibromoethane (II) in basic medium gives 2-(4-fluorophenyl)ethyl bromide (III), which by reaction with N-benzoyl-2-hydroxyglycine (IV) in methanesulfonic acid yields N-benzoyl-2-[2-(2-bromoethoxy)-5-fluorophenyl]glycine (V). The cyclization of (V) with acetic anhydride and triethylamine at 50 C affords 6-fluoro-2'-phenylspiro[2,3-dihydro-4H-1-benzopyran-4,4'-oxazolidine]-5'-one (VI), which is hydrolyzed with refluxing formic acid-HCl giving the amino acid (VII). The esterification of (VII) with SOCl2 and methanol in the usual way yields the methyl ester (VIII), which is submitted to optical resolution by selective hydrolysis with alpha-chymotrypsine affording methyl 4(S)-amino-6-fluoro-2,3-dihydro-4H-1-benzopyrano-4-carboxylate (IX). Finally, this compound is converted into sorbinil by cyclization with sodium cyanate in acetic acid at room temperature.

参考文献中间体

合成目标

【1】 Dirlam, N.L.; Moore, B.S.; Urban, F.J.; Novel synthesis of the aldose reductase inhibitor sorbinil via amidoalkylation, intramolecular oxazolidin-5-one alkylation, and chymotrypsin resolution. J Org Chem 1987, 52, 16, 3587-91.

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)	19369	2-iodopropane	75-30-9	C₃H₇I	详情	详情
(II)	10252	1,2-Dibromoethane; Ethylene dibromide	106-93-4	C₂H₄Br₂	详情	详情
(III)	20830	1-(2-bromoethoxy)-4-fluorobenzene; 2-bromoethyl 4-fluorophenyl ether	332-48-9	C₈H₈BrFO	详情	详情
(IV)	20606	2-(benzoylamino)-2-hydroxyacetic acid	16555-77-4	C₉H₉NO₄	详情	详情
(V)	20832	2-(benzoylamino)-2-[2-(2-bromoethoxy)-5-fluorophenyl]acetic acid		C₁₇H₁₅BrFNO₄	详情	详情
(VI)	20833	6-Fluoro-2'-phenyl-3,4,4',5'-tetrahydro-2H-spiro[1-benzopyran-4,4'-oxazol]-5'-one		C₁₇H₁₂FNO₃	详情	详情
(VII)	20834	4-amino-6-fluoro-4-chromanecarboxylic acid		C₁₀H₁₀FNO₃	详情	详情
(VIII)	20835	methyl 4-amino-6-fluoro-4-chromanecarboxylate		C₁₁H₁₂FNO₃	详情	详情
(IX)	20836	[(4S)-4-amino-6-fluoro-3,4-dihydro-2H-chromen-4-yl]methyl formate		C₁₁H₁₂FNO₃	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 sorbinil (I) is hydrolyzed with barium hydroxide in refluxing water to give amino acid (II), which by reaction with potassium cyanate in water yields (RS)-6-fluoro-4-ureido-2,3-dihydro-4H-1-benzoyran-4-carboxylic acid (III). The optical resolution of (III) with D-(+)-(1-phenylethyl)amine or L-(-)-ephedrine affords 6-fluoro-4(S)-ureido-2,3-dihydro-4H-1-benzopyran-4-carboxylic acid (IV), which is finally cyclized to sorbinil by means of hot acetic acid.

参考文献中间体

合成目标

【1】 Cue, B.W. Jr.; Moore, B.S. (Pfizer Inc.); Sorbinyl by optical resolution of precursor 6-fluoro-4-ureidochroman-4-carboxylic acid. JP 1988211278; JP 1988211281; JP 1988211282; US 4435578 .

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)	10057	6-Fluorospiro[chroman-4,4'-imidazolidine]-2',4'-dione	69684-83-9	C₁₁H₉FN₂O₃	详情	详情
(II)	20834	4-amino-6-fluoro-4-chromanecarboxylic acid		C₁₀H₁₀FNO₃	详情	详情
(III)	20838	4-[(aminocarbonyl)amino]-6-fluoro-4-chromanecarboxylic acid		C₁₁H₁₁FN₂O₄	详情	详情
(IV)	20839	(4R)-4-[(aminocarbonyl)amino]-6-fluoro-3,4-dihydro-2H-chromen-4-yl formate		C₁₁H₁₁FN₂O₄	详情	详情

Extended Information