2-(benzoylamino)-2-hydroxyacetic acid -Drug Synthesis Database

【结构式】

【分子编号】20606

【品名】2-(benzoylamino)-2-hydroxyacetic acid

【CA登记号】16555-77-4

【分子式】C₉H₉NO₄

【分子量】195.1748

【元素组成】C 55.39% H 4.65% N 7.18% O 32.79%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IV)

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：(VI)

2) The condensation of 4-fluorophenol (I) with ethyl (S)-lactate (II) by means of diethyl azodicarboxylate and triphenylphosphine in THF gives ethyl 2(R)-(4-fluorophenoxy)propionate (III), which is reduced with LiAlH4 in THF yielding 2(R)-(4-fluorophenoxy)propanol (IV). The reaction of (IV) with Br2 and triphenylphosphine in DMF affords 1-bromo-2(R)-(4-fluorophenoxy)propane (V), which is condensed with N-benzoyl-2-hydroxyglycine (VI) by means of methanesulfonic acid to give (RS)-N-benzoyl-2-[2-(1-bromo-2(R)propoxy)-5-fluorophenyl]glycine (VII). The cyclization of (VII) by means of acetic anhydride and K2CO3 in acetone yields 6-fluoro-2(R)-methyl-2'-phenylspiro[2,3-dihydro-4H-1-benzopyran-4(RS),4'-oxazolidin]-5'-one (VIII), which is hydrolyzed with refluxing formic acid-HCl affording 4(RS)-amino-6-fluoro-2(R)-methyl-2,3-dihydro-4H-1-benzopyran-4-carboxylic acid (IX). The esterification of (IX) with Cl2SO and methanol gives the corresponding methyl ester (X), which is submitted to optical resolution with alpha-chymotrypsine to yield methyl 4(S)-amino-6-fluoro-2(R)-methyl-2,3-dihydro-4H-1-benzopyran-4-carboxylate (XI). Finally, this compound is cyclized with sodium cyanate in acetic acid.

参考文献中间体

合成目标

【1】 Prous, J.; Castaner, J.; METHOSORBINIL. Drugs Fut 1989, 14, 4, 325.
【2】 Moore, B.S.; Urban, F.J.; Dirlam, N.L.; 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.

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)	19639	4-fluorophenol	371-41-5	C₆H₅FO	详情	详情
(II)	16659	ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate	687-47-8	C₅H₁₀O₃	详情	详情
(III)	20603	ethyl (2R)-2-(4-fluorophenoxy)propanoate		C₁₁H₁₃FO₃	详情	详情
(IV)	20604	(2R)-2-(4-fluorophenoxy)-1-propanol		C₉H₁₁FO₂	详情	详情
(V)	20605	1-[[(1R)-2-bromo-1-methylethyl]oxy]-4-fluorobenzene; (1R)-2-bromo-1-methylethyl 4-fluorophenyl ether		C₉H₁₀BrFO	详情	详情
(VI)	20606	2-(benzoylamino)-2-hydroxyacetic acid	16555-77-4	C₉H₉NO₄	详情	详情
(VII)	20607	2-(benzoylamino)-2-(2-[[(1R)-2-bromo-1-methylethyl]oxy]-5-fluorophenyl)acetic acid		C₁₈H₁₇BrFNO₄	详情	详情
(VIII)	20608	6-Fluoro-2(R)-methyl-2'-phenyl-3,4,4',5'-tetrahydro-2H-spiro[1-benzopyran-4,4'-oxazol]-5'-one		C₁₈H₁₄FNO₃	详情	详情
(IX)	20609	(2R)-4-amino-6-fluoro-2-methyl-3,4-dihydro-2H-chromene-4-carboxylic acid		C₁₁H₁₂FNO₃	详情	详情
(X)	20610	methyl (2R)-4-amino-6-fluoro-2-methyl-3,4-dihydro-2H-chromene-4-carboxylate		C₁₂H₁₄FNO₃	详情	详情
(XI)	20611	(2R,4S)-4-amino-6-fluoro-2-methyl-3,4-dihydro-2H-chromene-4-carboxylic acid		C₁₁H₁₂FNO₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Condensation of alpha-hydroxyhippuric acid (II) with bromobenzene (I) in methanesulfonic acid afforded the phenylglycine derivative (III). Further incorporation of the phosphonic acid was effected by palladium-catalyzed displacement of the bromide by diethyl phosphite to give (IV). Finally, acid hydrolysis of the benzamide and phosphite ester groups furnished the title compound.

参考文献中间体

合成目标

【1】 Bigge, C.F.; et al.; Exploration of phenyl-spaced 2-amino-(5-9)-phosphonoalkanoic acids as competitive N-methyl-D-aspartic acid antagonists. J Med Chem 1989, 32, 7, 1580-90.

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)	13365	Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene	108-86-1	C₆H₅Br	详情	详情
(II)	20606	2-(benzoylamino)-2-hydroxyacetic acid	16555-77-4	C₉H₉NO₄	详情	详情
(III)	35750	2-(benzoylamino)-2-(4-bromophenyl)acetic acid		C₁₅H₁₂BrNO₃	详情	详情
(IV)	35751	2-(benzoylamino)-2-[4-(diethoxyphosphoryl)phenyl]acetic acid		C₁₉H₂₂NO₆P	详情	详情

Extended Information