SYNTHESIS OF SYNVINOLIN - EXTREMELY HIGH CONVERSION ALKYLATION OF AN ESTER ENOLATE

被引：36

作者：

ASKIN, D

VERHOEVEN, TR

LIU, TMH

SHINKAI, I

机构：

[1] Department of Process Research, Merck, Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065

来源：

JOURNAL OF ORGANIC CHEMISTRY | 1991年 / 56卷 / 16期

关键词：

D O I：

10.1021/jo00016a023

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

A efficient process for the commercial preparation of the therapeutically important cholesterol lowering drug synvinolin (2: simvastatin, ZOCOR) from mevinolin (1: lovastatin, MEVACOR) is reported. The synthesis relies upon deactivation of the delta-lactone carbonyl toward enolization via conversion to the bis[(tert-butyldimethylsilyl)oxy] butylamide 7. An extremely high conversion (99.7%) ester enolate alkylation of 7 affords 8 and 9. Subsequent desilylation and intramolecularly assisted basic amide hydrolysis in the presence of the dimethylbutyrate ester moiety yields 12, which is lactonized to 2. The overall yield from 1 to 2 is 86%.

引用

页码：4929 / 4932

页数：4

共 21 条

[1] MEVINOLIN - A HIGHLY POTENT COMPETITIVE INHIBITOR OF HYDROXYMETHYLGLUTARYL-COENZYME-A REDUCTASE AND A CHOLESTEROL-LOWERING AGENT
ALBERTS, AW
CHEN, J
KURON, G
HUNT, V
HUFF, J
HOFFMAN, C
ROTHROCK, J
LOPEZ, M
JOSHUA, H
HARRIS, E
PATCHETT, A
MONAGHAN, R
CURRIE, S
STAPLEY, E
ALBERSSCHONBERG, G
HENSENS, O
HIRSHFIELD, J
HOOGSTEEN, K
LIESCH, J
SPRINGER, J
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1980, 77 (07): : 3957 - 3961
[2] TOTAL SYNTHESIS OF BOTH (+)-COMPACTIN AND (+)-MEVINOLIN - A GENERAL STRATEGY BASED ON THE USE OF A SPECIAL TICL3/C8K MIXTURE FOR DICARBONYL COUPLING
CLIVE, DLJ
MURTHY, KSK
WEE, AGH
PRASAD, JS
DASILVA, GVJ
MAJEWSKI, M
ANDERSON, PC
HAUGEN, RD
HEERZE, LD
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1988, 110 (20) : 6914 - 6916
[3] Dawber T. R., 1980, FRAMINGHAM STUDY EPI
[4] SYNTHESIS OF (+)-DIHYDROMEVINOLIN BY SELECTIVE REDUCTION OF MEVINOLIN
DECAMP, AE
VERHOEVEN, TR
SHINKAI, I
[J]. JOURNAL OF ORGANIC CHEMISTRY, 1989, 54 (13) : 3207 - 3208
[5] MONACOLIN-K, A NEW HYPOCHOLESTEROLEMIC AGENT THAT SPECIFICALLY INHIBITS 3-HYDROXY-3-METHYLGLUTARYL COENZYME A REDUCTASE
ENDO, A
[J]. JOURNAL OF ANTIBIOTICS, 1980, 33 (03) : 334 - 336
[6] MONACOLIN-K, A NEW HYPOCHOLESTEROLEMIC AGENT PRODUCED BY A MONASCUS SPECIES
ENDO, A
[J]. JOURNAL OF ANTIBIOTICS, 1979, 32 (08) : 852 - 854
[7] COMPACTIN (ML-236B) AND RELATED-COMPOUNDS AS POTENTIAL CHOLESTEROL-LOWERING AGENTS THAT INHIBIT HMG-COA REDUCTASE
ENDO, A
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1985, 28 (04) : 401 - 405
[8] CARBON ACIDITY .76. THE REMARKABLY LOW 2ND PKA OF 1-NAPHTHYLACETIC ACID - LITHIUM ION-PAIR ACIDITY IN TETRAHYDROFURAN
GRONERT, S
STREITWIESER, A
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1988, 110 (13) : 4418 - 4419
[9] CHOLESTEROL AND CORONARY HEART-DISEASE - A NEW ERA
GRUNDY, SM
[J]. JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1986, 256 (20): : 2849 - 2858
[10] TOTAL SYNTHESIS OF (+)-MONACOLIN-K (MEVINOLIN)
HIRAMA, M
IWASHITA, M
[J]. TETRAHEDRON LETTERS, 1983, 24 (17) : 1811 - 1812

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