• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】11540

【品名】(1S)-2-hydroxy-1,2,2-triphenylethyl acetate; (R)-(+)-1,1,2-Triphenyl-1,2-ethanediol 2-acetate

【CA登记号】95061-47-5

【 分 子 式 】C22H20O3

【 分 子 量 】332.399

【元素组成】C 79.5% H 6.06% O 14.44%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(XLI)

2) [2S,3S,5S,6R,7S,8E,9(1'R,3'R,4'R)]-2-Allyl-3-(tert-butyldimethylsilylox y)-6,8-dimethyl-7-(triethylsilyloxy)-5-(triisopropylsilyloxy)-9-[3-meth oxy-4-(triisopropylsilyloxy)cyclohexyl]-8-nonenal (LI). Quinic acid (XXV) is converted into the lactone (XXVI) by known methods. Then this lactone is treated with thiocarbonyldiimidazole in refluxing dichloroethane yielding the bis(thiocarbonyl)lactone (XXVII), which by reaction with tributyltin hydride and AIBN in refluxing xylene is converted into the lactone (XXIX), either directly or through the intermediate thiocarbonyl-lactone (XXVIII). The silylation of (XXIX) with TIPS-SO3CF3 as usual affords the protected lactone (XXX). Opening of the lactone ring with methylchloroaluminum N-methoxy-N-methylamide gives the methoxyamide (XXXI), which is methylated with methyl trifluoromethylsulfonate to the methoxy-N-methoxyamide (XXXII). The reduction of (XXXII) with diisobutylaluminum hydride gives the aldehyde (XXXIII), which is condensed with 2-lithio-2-(triethylsilyl)propanal (XXXIV), yielding unsaturated aldehyde (XXXV). The condensation of (XXXV) with the boron enolate of oxazolidone (XXVI) affords the oxazolidone derivative (XXXVII), which is treated with methylchloroaluminum N-methoxy-N-methylamide to give the methoxyamide (XXXVIII). The silylation of (XXXVIII) with TES-SO3CF3 as usual yields the silylated amide (XXXIX), which is reduced with diisobutylaluminum hydride to the aldehyde (XL). The condensation of (XL) with chiral acetate (XLI) by means of lithium diisopropylamide in THF affords the hydroxy ester (XLII). Transesterification of (XLII) with NaOCH3 and methanol gives methyl ester (XLIII).

1 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
63305 di(1H-imidazol-2-yl)methanethione C7H6N4S 详情 详情
63306   C3H9AlClNO 详情 详情
(XXV) 11524 D-Quinic acid; D-(-)-Chinic acid; D-(-)-Quinic acid; (3R,5R)-1,3,4,5-Tetrahydroxycyclohexanecarboxylic acid 77-95-2 C7H12O6 详情 详情
(XXVI) 11525 (1S,3R,4R,5R)-1,3,4-Trihydroxy-6-oxabicyclo[3.2.1]octan-7-one C7H10O5 详情 详情
(XXVII) 11526 O-[(1R,2S,6R)-9-oxo-4-thioxo-3,5,10-trioxatricyclo[6.2.1.0(2,6)]undec-8-yl] 1H-imidazole-1-carbothioate C12H10N2O5S2 详情 详情
(XXVIII) 11527 (1R,2S,6R,8S)-4-Thioxo-3,5,10-trioxatricyclo[6.2.1.0(2,6)]undecan-9-one C8H8O4S 详情 详情
(XXIX) 11528 (1R,4R,5R)-4-Hydroxy-6-oxabicyclo[3.2.1]octan-7-one C7H10O3 详情 详情
(XXX) 11529 (1R,4R,5R)-4-[(Triisopropylsilyl)oxy]-6-oxabicyclo[3.2.1]octan-7-one C16H30O3Si 详情 详情
(XXXI) 11530 (1R,3R,4R)-3-Hydroxy-N-methoxy-N-methyl-4-[(triisopropylsilyl)oxy]cyclohexanecarboxamide C18H37NO4Si 详情 详情
(XXXII) 11531 (1R,3R,4R)-N,3-Dimethoxy-N-methyl-4-[(triisopropylsilyl)oxy]cyclohexanecarboxamide C19H39NO4Si 详情 详情
(XXXIII) 11532 (1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarbaldehyde C17H34O3Si 详情 详情
(XXXIV) 11533 [1-Methyl-1-[(4-methylphenyl)sulfonyl]-2-oxoethyl]lithium C10H11LiO3S 详情 详情
(XXXV) 11534 (E)-3-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2-methyl-2-propenal C20H38O3Si 详情 详情
(XXXVI) 11535 (4S)-4-Isopropyl-3-propionyl-1,3-oxazolidin-2-one 77877-19-1 C9H15NO3 详情 详情
(XXXVII) 11536 (4S)-3-((2S,3S,4E)-3-Hydroxy-5-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4-dimethyl-4-pentenoyl)-4-isopropyl-1,3-oxazolidin-2-one C29H53NO6Si 详情 详情
(XXXVIII) 11537 (2S,3S,4E)-3-Hydroxy-N-methoxy-5-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-N,2,4-trimethyl-4-pentenamide C25H49NO5Si 详情 详情
(XXXIX) 11538 (2S,3S,4E)-N-Methoxy-5-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-N,2,4-trimethyl-3-[(triethylsilyl)oxy]-4-pentenamide C31H63NO5Si2 详情 详情
(XL) 11539 (2S,3S,4E)-5-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4-dimethyl-3-[(triethylsilyl)oxy]-4-pentenal C29H58O4Si2 详情 详情
(XLI) 11540 (1S)-2-hydroxy-1,2,2-triphenylethyl acetate; (R)-(+)-1,1,2-Triphenyl-1,2-ethanediol 2-acetate 95061-47-5 C22H20O3 详情 详情
(XLII) 11541 (1S)-2-hydroxy-1,2,2-triphenylethyl (3S,4R,5S,6E)-3-hydroxy-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-heptenoate C51H78O7Si2 详情 详情
(XLIII) 11542 methyl (3S,4R,5S,6E)-3-hydroxy-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-heptenoate C32H64O6Si2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XX)

2) The condensation of the previously described aldehyde (XI) with (S)-(+)-2-acetoxy-1,1,2-triphenylethanol (XX) by means of lithium diisopropylamide (LDA) in THF gives 5-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-3(R)-hydroxypentanoic acid 2-hydroxy-1(S),2,2-triphenylethyl ester (XXI), which is trans-esterified with sodium methoxide in methanol/THF yielding the expected methyl ester (XXII). The condensation of (XXII) with tert-butyl acetate (XXIII) by means of LDA in THF affords (R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl) pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid tert-butyl ester (XXIV), which is reduced with triethylborane and NaBH4 in THF, hydrolyzed with NaOH, lactonized by heating in refluxing toluene and finally submitted to fractional crystallization in order to separate the two diastereomers of the obtained lactone, (R,R) and (R,S). The (R,R)-diastereomer (XIX), already obtained, is finally treated with NaOH and then with CaCl2.

1 Roth, B.D.; Blankley, C.J.; Chucholowski, A.W.; Ferguson, E.; Hoefle, M.L.; Ortwine, D.F.; Newton, R.S.; Sekerke, C.S.; Sliskovic, D.R.; Stratton, C.D.; Wilson, M.W.; Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J Med Chem 1991, 34, 1, 357-66.
2 Graul, A.; Castaner, J.; Atorvastatin Calcium. Drugs Fut 1997, 22, 9, 956.
3 Roth, B.D. (Pfizer Inc.); (R-(R*R*)-2-(4-Fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3 -phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereo. EP 0409281; JP 1991058967; US 5273995 .
4 Mills, N.; Muhammad, N.A.; Weiss, J.; Nesbitt, R.U. (Pfizer Inc.); Stable oral CI-981 formulation and process for preparing same. EP 0680320; JP 1996505640; US 5686104; WO 9416693 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 15386 5-(4-fluorophenyl)-2-isopropyl-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide C29H27FN2O2 详情 详情
(XIX) 15391 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide C33H33FN2O4 详情 详情
(XX) 11540 (1S)-2-hydroxy-1,2,2-triphenylethyl acetate; (R)-(+)-1,1,2-Triphenyl-1,2-ethanediol 2-acetate 95061-47-5 C22H20O3 详情 详情
(XXI) 15395 (1S)-2-hydroxy-1,2,2-triphenylethyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate 134394-96-0 C51H47FN2O5 详情 详情
(XXII) 15396 methyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate C32H33FN2O4 详情 详情
(XXIII) 15397 tert-butyl acetate 540-88-5 C6H12O2 详情 详情
(XXIV) 15398 tert-butyl (5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-5-hydroxy-3-oxoheptanoate C37H41FN2O5 详情 详情

合成路线3

该中间体在本合成路线中的序号:(V)

The synthesis of atorvastatin [14C]-labeled on the side chain has been described: The reaction of [14C]-labeled sodium acetate (I) with phthaloyl chloride (II) in refluxing xylene gives the acyl chloride (III), which is treated with 1,2,2-triphenyl-1(S),2-ethanediol (IV) in dichloromethane yielding the expected monoacetate (V). The condensation of (V) with the pyrrolepropionaldehyde (VI) by means of lithium diisopropylamide (LDA) in THF affords the chiral beta-hydroxyester (VII), which is transesterified with sodium methoxide in methanol providing the corresponding methyl ester (VIII). The condensation of (VIII) with tert-butyl acetate (IX) by means of LDA in THF gives the beta-oxo-delta-hydroxyester (X), which is regioselectively reduced to the dihydroxyester (XI) by means of BEt3, NaBH4 and H2O2 in THF. The hydrolysis of (XI) with NaOH in THF/water, followed by acidification yields the free acid (XII), which is heated in refluxing toluene in a Dean-Stark trap to provide lactone (XIII). The reaction of (XIII) with NaOH in THF/methanol gives the corresponding sodium salt (XIV), which is finally treated with CaCl2 in the same solvent.

1 Woo, P.W.K.; Lee, H.T.; Atorvastatin, an HMG-CoA reductase inhibitor and effective lipid-regulating agent. Part II. Synthesis of side-chain-labeled [C-14] atorvastatin. J Label Compd Radiopharm 1999, 42, 2, 129.
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) 27912 Sodium acetate 127-09-3 C2H3NaO2 详情 详情
(I) 45240 sodium acetate C2H3NaO2 详情 详情
(II) 23811 phthaloyl dichloride;1,2-Benzenedicarbonyl dichloride;o-Phthaloyl chloride 88-95-9 C8H4Cl2O2 详情 详情
(III) 19273 acetyl chloride 75-36-5 C2H3ClO 详情 详情
(III) 45241 acetyl chloride C2H3ClO 详情 详情
(IV) 27913 (2S)-1,1,2-triphenyl-1,2-ethanediol 95061-46-4 C20H18O2 详情 详情
(V) 11540 (1S)-2-hydroxy-1,2,2-triphenylethyl acetate; (R)-(+)-1,1,2-Triphenyl-1,2-ethanediol 2-acetate 95061-47-5 C22H20O3 详情 详情
(V) 45242 (1S)-2-hydroxy-1,2,2-triphenylethyl acetate C22H20O3 详情 详情
(VI) 15386 5-(4-fluorophenyl)-2-isopropyl-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide C29H27FN2O2 详情 详情
(VII) 15395 (1S)-2-hydroxy-1,2,2-triphenylethyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate 134394-96-0 C51H47FN2O5 详情 详情
(VII) 45243 (1S)-2-hydroxy-1,2,2-triphenylethyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate C51H47FN2O5 详情 详情
(VIII) 15396 methyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate C32H33FN2O4 详情 详情
(VIII) 45244 methyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate C32H33FN2O4 详情 详情
(IX) 15397 tert-butyl acetate 540-88-5 C6H12O2 详情 详情
(X) 15398 tert-butyl (5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-5-hydroxy-3-oxoheptanoate C37H41FN2O5 详情 详情
(X) 45245 tert-butyl (5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-5-hydroxy-3-oxoheptanoate C37H41FN2O5 详情 详情
(XI) 27914 tert-butyl (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate C37H43FN2O5 详情 详情
(XI) 45246 tert-butyl (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate C37H43FN2O5 详情 详情
(XII) 15390 (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid C33H35FN2O5 详情 详情
(XII) 45247 (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid C33H35FN2O5 详情 详情
(XIII) 15391 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide C33H33FN2O4 详情 详情
(XIII) 45248 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide C33H33FN2O4 详情 详情
(XIV) 27911 sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate C33H34FN2NaO5 详情 详情
(XIV) 45249 sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate C33H34FN2NaO5 详情 详情

合成路线4

该中间体在本合成路线中的序号:(VI)

In an alternative procedure, reaction of quinuclidinone (I) with (R)-2-hydroxy-1,2,2-triphenylethyl acetate (VI) gave adduct (VII) as a single enantiomer. Subsequent ester hydrolysis of (VII) provided the chiral carboxylic acid (VIII). Finally, rearrangement of (VIII) in the presence of diphenyl phosphorylazide yielded the title compound.

1 Napier, J.; Mack, R.; Loch, J. III; et al.; The synthesis and nicotinic receptor subtype profile of AR-R17779, a conformationally restricted analog of acetylcholine. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.149.
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) 16925 3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one 1193-65-3 C7H11NO 详情 详情
(VI) 11540 (1S)-2-hydroxy-1,2,2-triphenylethyl acetate; (R)-(+)-1,1,2-Triphenyl-1,2-ethanediol 2-acetate 95061-47-5 C22H20O3 详情 详情
(VII) 30115 (1S)-2-hydroxy-1,2,2-triphenylethyl 2-[(3R)-3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl]acetate C29H31NO4 详情 详情
(VIII) 30116 2-[(3R)-3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl]acetic acid C9H15NO3 详情 详情
Extended Information