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【结 构 式】 
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【分子编号】13878 【品名】methyl (2R)-2-hydroxy-3-phenylpropanoate 【CA登记号】 |
【 分 子 式 】C10H12O3 【 分 子 量 】180.20348 【元素组成】C 66.65% H 6.71% O 26.64% |
合成路线1
该中间体在本合成路线中的序号：(I)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).
| 【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：(IX)Condensation of salicylaldehyde (I) with 2-bromoacetophenone (II) produced benzofuranyl phenyl ketone (III), which was reduced to 2-benzyl benzofuran (IV) under Wolff-Kishner conditions. Subsequent Friedel-Crafts acylation of (IV) with anisoyl chloride (V) employing SnCl4 afforded ketone (VI). Methyl ether cleavage in (VI) with concomitant intramolecular cyclization, followed by dehydration by means of BBr3 gave rise to benzo naphthofuran (VII). This was brominated in AcOH to yield tribromo derivative (VIII). Mitsunobu coupling of (VIII) with (S)-methyl-2-hydroxy-3-phenylpropionate (IX) furnished ether (X). Finally, the methyl ester group of (X) was hydrolyzed with KOH.
| 【1】 Dietrich, A.; Katz, A.; Sullivan, D.; Wrobel, J.; Sawicki, D.R.; Tio, C.; Li, Z.; Seestaller, L.; Wu, L.; Zhang, Z.-Y.; Sredy, J.; Moxham, C.; PTP1B inhibition and antihyperglycemic activity in the ob/ob mouse model of novel 11-arylbenzo[b]naphto[2,3-d]furans and 11-arylbenzo[b]naphtho[2,3-d]thiophenes. J Med Chem 1999, 42, 17, 3199-3202. |
| 【2】 Dietrich, A.J.; Wrobel, J.E.; Li, Z. (American Home Products Corp.); 11-Aryl-benzo[b]naphtho[2,3-d]furans and 11-aryl-benzo[b]naphtho[2,3-d]thiophenes useful in the treatment of insulin resistance and hyperglycemia. WO 9958521 . |
| 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) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
| (II) | 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 |
| (III) | 33663 | 1-benzofuran-2-yl(phenyl)methanone | C15H10O2 | 详情 | 详情 | |
| (IV) | 33664 | 2-benzyl-1-benzofuran | C15H12O | 详情 | 详情 | |
| (V) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
| (VI) | 33665 | (2-benzyl-1-benzofuran-3-yl)(4-methoxyphenyl)methanone | C23H18O3 | 详情 | 详情 | |
| (VII) | 33666 | 4-naphtho[2,3-b][1]benzofuran-11-ylphenol | C22H14O2 | 详情 | 详情 | |
| (VIII) | 33667 | 2,6-dibromo-4-(6-bromonaphtho[2,3-b][1]benzofuran-11-yl)phenol | C22H11Br3O2 | 详情 | 详情 | |
| (IX) | 13878 | methyl (2R)-2-hydroxy-3-phenylpropanoate | C10H12O3 | 详情 | 详情 | |
| (X) | 33668 | methyl (2R)-2-[2,6-dibromo-4-(6-bromonaphtho[2,3-b][1]benzofuran-11-yl)phenoxy]-3-phenylpropanoate | C32H21Br3O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)2-Pyrrolidinone (I) was protected as the N-Boc derivative (II) and then alkylated with 3-bromo-2-methylpropene (III) in the presence of LDA to yield (IV). Further alkylation of (IV) with tert-butyl bromoacetate gave the dialkylated pyrrolidinone (V). Catalytic hydrogenation of the 2-methylpropenyl substituent of (V) produced the racemic isobutyl analogue (VI), which was resolved by means of chiral HPLC. The desired (S)-enantiomer (VII) was deprotected by treatment with magnesium ethoxide, affording pyrrolidinone (VIII). Triflate (XI) was obtained from D-phenyllactic acid (IX) by formation of the methyl ester (X) upon treatment with iodomethane, followed by reaction with trifluoromethanesulfonic anhydride and pyridine. N-Alkylation of the pyrrolidinone (VIII) with triflate (XI) furnished adduct (XII), which was hydrolyzed to carboxylic acid (XIII) with methanolic NaOH. After activation of (XIII) with carbonyl diimidazole, coupling with methylamine gave rise to amide (XIV). Cleavage of the tert-butyl ester group of (XIV) employing trifluoroacetic acid produced carboxylic acid (XV). This was finally coupled with hydroxylamine using EDC and HOBt.
| 【1】 Jacobsen, E.J. (Pharmacia & Upjohn AB); Hydroxamic acid derivs. for use with the treatment of diseases related to connective tissue degradation. EP 0898562; JP 2000506163; US 5712300; WO 9732846 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 | |
| 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 | |
| (I) | 27397 | 2-Pyrrolidinone | 616-45-5 | C4H7NO | 详情 | 详情 |
| (II) | 40014 | tert-butyl 2-oxo-1-pyrrolidinecarboxylate | C9H15NO3 | 详情 | 详情 | |
| (III) | 40015 | 3-bromo-2-methyl-1-propene | 1458-98-6 | C4H7Br | 详情 | 详情 |
| (IV) | 40016 | tert-butyl 3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate | C13H21NO3 | 详情 | 详情 | |
| (V) | 40017 | tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate | C19H31NO5 | 详情 | 详情 | |
| (VI) | 40018 | tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate | C19H33NO5 | 详情 | 详情 | |
| (VII) | 40019 | tert-butyl (3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate | C19H33NO5 | 详情 | 详情 | |
| (VIII) | 40020 | tert-butyl 2-[(3S)-3-isobutyl-2-oxopyrrolidinyl]acetate | C14H25NO3 | 详情 | 详情 | |
| (IX) | 40026 | (2R)-2-hydroxy-3-phenylpropionic acid | 7326-19-4 | C9H10O3 | 详情 | 详情 |
| (X) | 13878 | methyl (2R)-2-hydroxy-3-phenylpropanoate | C10H12O3 | 详情 | 详情 | |
| (XI) | 40027 | methyl (2R)-3-phenyl-2-[[(trifluoromethyl)sulfonyl]oxy]propanoate | C11H11F3O5S | 详情 | 详情 | |
| (XII) | 40028 | methyl (2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-3-phenylpropanoate | C24H35NO5 | 详情 | 详情 | |
| (XIII) | 40029 | (2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-3-phenylpropionic acid | C23H33NO5 | 详情 | 详情 | |
| (XIV) | 40030 | tert-butyl 2-[(3S)-1-[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetate | C24H36N2O4 | 详情 | 详情 | |
| (XV) | 40031 | 2-[(3S)-1-[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetic acid | C20H28N2O4 | 详情 | 详情 |