【结 构 式】 |
【分子编号】20610 【品名】methyl (2R)-4-amino-6-fluoro-2-methyl-3,4-dihydro-2H-chromene-4-carboxylate 【CA登记号】 |
【 分 子 式 】C12H14FNO3 【 分 子 量 】239.2465032 【元素组成】C 60.24% H 5.9% F 7.94% N 5.85% O 20.06% |
合成路线1
该中间体在本合成路线中的序号:(X)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.
【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 |