CN100522942C - Synthesized intermediate compound of Rosuvastain, preparation method and application - Google Patents
Synthesized intermediate compound of Rosuvastain, preparation method and application Download PDFInfo
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- CN100522942C CN100522942C CNB2005100695586A CN200510069558A CN100522942C CN 100522942 C CN100522942 C CN 100522942C CN B2005100695586 A CNB2005100695586 A CN B2005100695586A CN 200510069558 A CN200510069558 A CN 200510069558A CN 100522942 C CN100522942 C CN 100522942C
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Abstract
The present invention relates to a synthetic intermediate of fluvastatin and its preparation method. Said invention utilizes two compounds and makes them react to obtain the synthetic intermediate compound of fluvastatin. Said invention also relates to a cis (E)-fluvastatin photoactive isomer prepared by using the above-mentioned synthetic intermediate compound, its preparation method and application. Said compound can be used as medicinal active component.
Description
Technical field
The present invention relates to organic chemistry and pharmaceutical chemistry field, particularly, the present invention relates to midbody compound of synthesis of fluvastatin (Fluvastatin) medicine and its production and use.The present invention relates to selectivity synthetic suitable-(E)-7-[3-(4-fluorophenyl)-1-sec.-propyl-2-indoles]-3,5-dihydroxyl-6-enanthic acid (fluvastatin, I) and the new synthetic intermediate of pharmaceutically acceptable ester and salt and new synthetic method.Particularly, the present invention relates to the method that selectivity prepares fluvastatin sodium (I-Na), this fluvastatin sodium salt is used for the low-density lipoprotein white level of reducing total cholesterol level and blood plasma.
Background technology
Having a special problem in the preparation Compound I is 3, and the formation of 5-dihydroxyl side chain, reaction need to form cis-stereoisomer, promptly form 3R, 5S/3S, and 5R-enantiomorph, unwanted trans-isomer(ide) only allow to exist with very low concentration.According to the American Pharmacopeia draft (Pharmacopeial Forum, (Pharmacopeial Previews, Pharmacopeial Forum) VOL.25, No.4,8420-8426), contained trans-isomer content should not surpass 0.8% in the medical compounds fluvastatin sodium.
The preparation method of existing known fluvastatin of document and sodium salt thereof.Public publication " tetrahedron wall bulletin " Vol.28, No.2,155-188, disclose in people's such as K.-M.Chen the document, the fluvastatin methyl ester can be by mixing (E)-7-[3-(4-fluorophenyl)-1-sec.-propyl-2-indoles]-5-hydroxyl-3-oxo-6-Methylheptanoate (II-Me) mixes with methoxyl group diethyl borine, uses the product of sodium borohydride reduction gained then.Utilize the reaction of this method after 5 hours the products therefrom yield reach 90%, and the ratio of suitable/trans isomer is 98:2, but process choice is lower, need be further purified the primary reaction product.
European patent EP-A-0363934 has disclosed a kind of similar method, but done improvement a little, wherein 5-hydroxyl-3-oxo-6-heptanoate derivative I I-R and previously prepared methoxyl group diethyl borine and sodium borohydride carry out reduction reaction, react in tetrahydrofuran (THF)/methanol mixed solvent.According to the instruction of the document, change reinforced order, wherein increased the selectivity that borane compound (with K.-M.Chen, Vol.28, No.2,155-188, the method that discloses in " tetrahedron wall bulletin " is relatively) then can improve reduction reaction greatly.But this method only when adopting the tert-butyl ester (II-tert-Bu) selectivity of gained just can accept.But adopt tertiary butyl ester then to have many serious problems, as the removal problem of butyl alcohol-tert after the fluvastatin sodium saponification.And adopt methyl ester (II-Me), and although there are some advantages in industrial production, the gained total recovery only is 80%, trans-isomer(ide) is up to more than 1%.Therefore, the reacting final product that EP-A-0363934 discloses need carry out steric isomer and separate before being used as active ingredient in pharmaceutical, to remove trans-isomer(ide).
Because the amount of handling in the large-scale commercial production is very big, the separation of steric isomer is also very difficult.Recrystallization and chromatographic separation then can increase the consumption of solvent, and be not only uneconomical, says also unreasonable from ecological angle.
The inventor furthers investigate the synthesis technique of fluvastatin, the inventor is surprised to find, by improving synthetic route, formula (III) compound below using is as synthetic intermediate, can highly-selective preparation obtain suitable-(E)-7-[3-(4-fluorophenyl)-1-sec.-propyl-2-indoles]-3,5-dihydroxyl-6-enanthic acid (fluvastatin, I) and pharmaceutically acceptable ester and salt, the gained compound need not to carry out the separation of steric isomer, promptly can be used as active ingredient in pharmaceutical.Finished the present invention thus.
Summary of the invention
The midbody compound that the purpose of this invention is to provide a kind of preparation fluvastatin medicine of following general formula (III):
Wherein R is the alkyl of H or C1-C6, the preferable methyl or the tertiary butyl; R
1Be hydrogen or hydroxyl protecting group R
2, R wherein
2Preferred TMS (TMS-), tert-butyl diphenyl silylation (TBDPS-) or tertiary butyl dimethylsilyl (TBS-), most preferably TBS-protecting group;
Another object of the present invention has provided the method for a kind of preparation formula (III) compound;
Another object of the present invention has provided the purposes that formula (III) compound is used to prepare cis fluvastatin medicine;
Another object of the present invention has provided the midbody compound of the formula (IV) of a kind of preparation formula (III) compound:
Wherein R is the alkyl of H or C1-C6, the preferable methyl or the tertiary butyl; R
1Be hydrogen or hydroxyl protecting group R
2, R wherein
2Preferred TMS (TMS-), tert-butyl diphenyl silylation (TBDPS-) or tertiary butyl dimethylsilyl (TBS-), most preferably TBS-protecting group; R
3Be the alkyl of C1-C6, preferable methyl.
The synthetic method that known production fluvastatin adopts in the existing document, products therefrom then can not directly be used as active ingredient in pharmaceutical, and all these methods all are with (E)-7-[3-(4-fluorophenyl)-1-sec.-propyl-2-indoles]-5-hydroxyl-3-oxo-6-enanthic acid (II) or its ester (II-R) are starting raw material.Surprisingly, the present invention adopts (E)-7-[3-(4-fluorophenyl)-1-sec.-propyl-2-indoles]-3-hydroxyl-5-oxo-when 6-heptanoate (III-R) conduct prepares the intermediate of cis fluvastatin, its stereoselectivity is then improved greatly, products therefrom then can directly be used as active ingredient in pharmaceutical, and need not to carry out the separation of suitable/trans isomer.Even adopt the methyl ester (III-Me) that many advantages are arranged in industrial production, the gained selectivity still reaches the medicine requirement.And, to compare with existing document, the yield of method of the present invention improves, and the reaction times then shortens.
The starting raw material 3-hydroxyl of selective reduction among the present invention-5-oxo-6-heptanoate (III-R) then can obtain by the similar reaction of Wittig or Wittig, by aldehyde and 6-position have the capronate coupling of functional group, the latter can be activated in drone salt or carbanion.And by asymmetric 3 protected 1, the chainpropagation of 5-pentanedioic acid mono alkyl ester for example by using methyl phosphorodithioate, can obtain suitable 3 protected 3-hydroxyl-5-oxo-capronates with 6-position phosphorus functional group.Among the present invention, can get 6-phosphorus-Nei drone salt of 3-hydroxyl-5-oxo-caproic acid or other group of 6-phosphorus-carbanion and be suitable for too.Because protection is 3-hydroxyl functional base, each blocking group that is suitable for is all available.According to the present invention, silicon ether, as TMS-(TMS-), TBDPS-(tert-butyl diphenyl silylation-) or TBS-(tertiary butyl dimethylsilyl) ether are preferably made the protecting group of 3-hydroxyl, most preferably the TBS-protecting group.
Asymmetric 3 protected 1,5-pentanedioic acid mono alkyl ester, as the monomethyl ester, can be by 1 of 3 protections, the 5-Pyroglutaric acid carries out alcoholysis reaction with corresponding alkyl alcohol (as methyl alcohol) and obtains.
6 bit function bases of caproic acid derivative are preferably phosphonium salt, and it can be activated into corresponding drone salt, by Wittig reaction and aldehyde coupling.Another preferred aspect of the present invention is that 6 bit function bases of caproic acid derivative are phosphoric acid ester, and it can be become the phosphoric acid salt carbanion by deprotonation, and can be by Horner-Wadsworth-Emmons reaction and aldehyde coupling.Another particularly preferred aspect of the present invention is that 6 bit function bases are phosphate dialkyl ester (formula (IV) compounds), suc as formula (IV-TBS) compound.
Behind the chain lengthening, the free acid functional group is protected, preferably protects with ester.Particularly preferably be by in Anhydrous potassium carbonate, reacting with methyl iodide.
The activation of 6 phosphorus functional groups of 3 protected 3-hydroxyl-5-oxo caproic acid derivatives then can be adopted suitable alkali, as alkaline carbonate, and alkalimetal hydride or alkali metal alcoholate.Most preferably can adopt golden alkali to belong to carbonate, as adopting Anhydrous potassium carbonate.
3-hydroxyl-5-oxo-caproic acid derivative (IV) can be undertaken by the method for existing document with [3-(4-fluorophenyl)-1-sec.-propyl-2-indoles]-coupling of aldehyde (F1) and the deprotection of 3-hydroxyl functional base.Under the situation that adopts the silylation protecting group, preferably adopt to add the fluorochemical deprotection.The one side that the present invention is good especially, deprotection are to be undertaken by adding ammonium bifluoride.
(the E)-7-[3-of above-mentioned technology gained (4-fluorophenyl)-1-sec.-propyl-2-indoles]-Stereoselective reduction of 3-hydroxyl-5-oxo-6-heptanoic alkyl ester (III) is by III-R being mixed with the alkoxyl group Dialkylborane, forming borane complexes.The alkoxyl group Dialkylborane can be ready raw material, also can come by suitable method preparation with trialkylborane.Preferably trialkylborane obtains with a kind of pure prepared in reaction under air catalysis.This optimum method is that the solution of trialkylborane and methyl alcohol generates dialkyl group methoxyl group borine under air effect; Another optimum method is before 3-hydroxyl-5-oxo-compound adds, and prepares methoxyl group diethyl borine with the tetrahydrofuran solution of air catalysis boron triethyl and methyl alcohol.
In next step, this boron compound can be by adding the reductive agent reduction, and particularly appropriate solvent is mixture pure and ether, preferably tetrahydrofuran (THF) in these reactions.Among the present invention, preferably reduction reaction is carried out in the mixture of tetrahydrofuran (THF) and the alcohol (linear or be with side chain) that contains 1-4 carbon, particularly preferably is the mixture of methyl alcohol and tetrahydrofuran (THF).The alkoxyl group Dialkylborane can directly add also can react generation in device.About reductive agent, each appropriate reductant all can be used, and in the present invention, the most preferred reductive agent of application is a sodium borohydride.
This (E)-7-[3-that obtains with the selective reduction of aforesaid method high-cis (4-fluorophenyl)-1-sec.-propyl-2-indoles]-3,5-dihydroxyl-6-heptanoic alkyl ester (I-R), can be converted into suitable acid form (Fluvastatin, I).In addition, also can be converted into the form of acceptable salt on the pharmacology with alkali.Most preferably obtain fluvastatin sodium (I-Na) with the sodium hydroxide saponification
Formula of the present invention (III) compound is a new compound, this compound is the synthetic cis of selectivity-(E)-7-[3-(4-fluorophenyl)-1-sec.-propyl-2-indoles]-3,5-dihydroxyl-6-enanthic acid (fluvastatin, I) and the important intermediate of pharmacologically acceptable salt or ester, use formula of the present invention (III) compound can highly-selective preparation to obtain formula (I) compound of above-mentioned cis, the gained compound need not to carry out the separation of steric isomer, promptly can be used as active ingredient in pharmaceutical.Formula of the present invention (III) compound can be by Wittig reaction or its similar prepared in reaction, and preferably the side chain compound by formula (IV) obtains by 3-(4-the fluorophenyl)-1-sec.-propyl-2-aldehyde radical-benzazolyl compounds prepared in reaction under alkaline condition with formula (F1):
R wherein, R
1And R
3Definition the same.
Formula of the present invention (IV) compound is a new compound, is the important intermediate compound of preparation formula (III) compound, and it constitutes another aspect of the present invention.
Formula of the present invention (IV) compound can carry out esterification with formula RX compound by following formula (S-3) compound and prepare under alkaline condition:
R wherein, R
1And R
3What define is the same, and X is a leavings group, preferred I, Br, Cl, or tosic acid ester group.
Formula (S-3) compound can obtain with methyl acid phosphate dialkyl prepared in reaction in the presence of alkali by following formula (S-2) compound:
R wherein
1And R
3Define the same; Methyl acid phosphate dialkyl preferable methyl chlorooxon; Alkali preferred alkyl lithium compound, most preferably butyl lithium compounds.
Formula (S-2) compound can pass through following 3-tertiary butyl dimethyl Si base-1, and the alcoholysis of 5-Pyroglutaric acid (S-1) compound prepares:
Formula of the present invention (III) compound is the synthetic cis of selectivity-(E)-7-[3-(4-fluorophenyl)-1-sec.-propyl-2-indoles]-3, the important intermediate of 5-dihydroxyl-6-enanthic acid (fluvastatin) and pharmacologically acceptable salt or ester, use formula of the present invention (III) compound highly-selective preparation to obtain above-mentioned cis-compound, this is another importance of the present invention, the gained compound need not to carry out the separation of steric isomer, promptly can be used as active ingredient in pharmaceutical.
Formula of the present invention (III) compound can prepare cis-(E)-7-[3-(4-fluorophenyl)-1-sec.-propyl-2-indoles through the following steps]-3,5-dihydroxyl-6-enanthic acid (fluvastatin) and pharmacologically acceptable salt or ester.
(1). side chain 3-position protected hydroxyl deprotection under acidic conditions of following formula (III-1) compound is obtained formula (III-R) compound:
And/or
(2). in the presence of alkoxyl group dialkyl group boron, obtain formula (I-R) compound of cis with reductive agent reduction-type (III-R) compound:
Wherein, the alkoxyl group Dialkylborane can be ready raw material, also can come by suitable method preparation with trialkylborane.Preferably trialkylborane obtains with a kind of pure prepared in reaction under air catalysis, and preferred method is that the solution of trialkylborane and methyl alcohol generates dialkyl group methoxyl group borine under air effect; Another preferred method is before 3-hydroxyl-5-oxo-compound adds, and prepares methoxyl group diethyl borine with the tetrahydrofuran solution of air catalysis boron triethyl and methyl alcohol; With
(3). (in the presence of sodium hydroxide, potassium hydroxide or calcium hydroxide) hydrolyzing type (I-R) compound obtains corresponding acid or salt under alkaline condition, as sodium salt:
Cis fluvastatin or its sodium salt compound of the prepared gained that the present invention discloses can directly be used as active ingredient in pharmaceutical, and need not to remove unwanted enantiomer.Adopt technology of the present invention, the suitable/inverted stereo selectivity of products therefrom can reach 99.2/0.8 at least, 99.5/0.5 preferably, and the ratio that particularly preferably is cis-isomeride is 99.8%.
Further specify the present invention below by embodiment.The preparation method who it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, and the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.
Concrete embodiment
Embodiment 1:3-tertiary butyl dimethyl Si base-1,5-monomethyl glutarate (S-2-TBS)
Under the nitrogen protection, with 18kg3-tertiary butyl dimethyl Si base-1,5-Pyroglutaric acid (S1) is dissolved in the 90L anhydrous methanol, and reflux is after 24 hours, and TLC checks, during no raw material, is concentrated into the dried 20.0kg of obtaining mono-methyl.
Embodiment 2:3-tertiary butyl dimethyl Si base-6,6-dimethoxy phosphino--5-oxo-caproic acid (S-3-TBS)
Nitrogen protection under-78 ℃, was added drop-wise to 168.6L n-Butyl Lithium/ether in the solution of 35.9kg methyl-phosphoric acid dimethyl ester/THF in 15 minutes, after adding ,-78 ℃ of stirring reactions 30 minutes.Again 20.0kg S-2-TBS/THF solution was added dropwise to wherein in 5 minutes, after 3 hours, be added dropwise to the saturated ammonium chloride solution stopped reaction in-78 ℃ of stirring insulations, use the 2N hcl acidifying, ethyl acetate extraction, layering, water layer is carried once with ethyl acetate is counter, merges organic layer, wash secondary with saturated common salt, anhydrous sodium sulfate drying filters, and is concentrated into dried 27.6kg S-3-TBS.
Embodiment 3:3-tertiary butyl dimethyl Si base-6,6-dimethoxy phosphino--5-oxo-methyl caproate (IV-TBS)
27.6kg S-3-TBS is dissolved in the 220L acetone, adds 53.3kg methyl iodide and 10.4kg salt of wormwood then successively, stirring at room reaction 24h hour (TLC inspection) adds the entry termination reaction.With ethyl acetate extraction twice, merge organic layer, with the saturated common salt washing once, anhydrous sodium sulfate drying spends the night, and is concentrated into dried 24.7kg IV-TBS.
Embodiment 4:(E)-7-[3-(4-fluorophenyl)-1-sec.-propyl-2-indoles]-3-tertiary butyl dimethyl Si base-5-oxo-methyl caproate (III-TBS)
Under the nitrogen protection, 24.7kg IV-TBS, 8.9kg salt of wormwood and 15.1kg F1 put in the dehydrated alcohol of 150L, about 24 hours of stirring reaction (HPLC follows the tracks of reaction).After reaction finishes, adding ethyl acetate and saturated aqueous common salt stirs, layering, water layer is carried once with ethyl acetate is counter, merges organic layer, saturated common salt washing secondary, anhydrous sodium sulfate drying spends the night, organic phase is concentrated into dried, uses ethyl acetate: normal hexane=1:5 crystallization obtains compound 18.2kg III-TBS.
Embodiment 5:(E)-7-[3-(4-fluorophenyl)-1-sec.-propyl-2-indoles]-3-hydroxyl-5-oxo-methyl caproate (III-Me)
Under nitrogen protection; 18.2kg III-TBS is dissolved with acetate; drop into 3.9kg hydrofluoric acid ammonium; react 24 hours (HPLC follows the tracks of reaction process); reaction adds entry and ethyl acetate extraction layering after finishing, and organic layer washes with water once; saturated sodium bicarbonate aqueous solution is washed till PH〉7, washing once with the saturated common salt aqueous solution.Anhydrous sodium sulfate drying filters, and is concentrated into driedly, obtains III-Me 12.2kg with the normal hexane crystallization.
Embodiment 6:(E)-and 7-[3-(4-fluorophenyl)-1-sec.-propyl-2-indoles]-3,5-dihydroxyl-methyl caproate (I-Me)
Under whipped state, 45.2kg triethyl-boron/tetrahydrofuran solution joins in 120L tetrahydrofuran (THF) and the 44L absolute methanol solution.Blasted air 2 minutes, and stirred after 30 minutes, drop into 12.2kg III-Me, stir and made its dissolving in 30 minutes.Be cooled to-78～-80 ℃ then and add the 1.5kg sodium borohydride down.After reaction finishes, be added dropwise to ethyl acetate and saturated sodium bicarbonate aqueous solution.Extract layering, water layer is carried once with ethyl acetate is counter.Merge organic layer, behind twice of saturated common salt water washing organic layer, anhydrous sodium sulfate drying is more than 12 hours, filtering and concentrating.
With enriched material, add dissolve with methanol and be heated to 50 ℃, stir after 60 minutes, concentrating under reduced pressure is gone out methyl alcohol.So repeatable operation is four times.Add the anhydrous diethyl ether reflux, crystallisation by cooling gets 10.4kgI-Me.
Embodiment 7: fluvastatin sodium salt (I-Na)
10.4kg I-Me is put in the mixing solutions of 50L dehydrated alcohol and 24.6L aqueous sodium hydroxide solution (1.0N), stirring reaction is after 30 minutes, and the HPLC trace analysis after raw material reaction is complete, is evaporated to dried.Add the deionized water stirring and dissolving, add anhydrous diethyl ether and extract layering, after water layer was taken out 30 minutes in advance with vacuum, aqueous solution freeze-drying was to fluvastatin finished product 10.0kg.(wherein suitable/anti-hydroxyl isomer proportion: 99.6:0.08)
Claims (17)
1. a selectivity prepares midbody compound formula (III) compound of fluvastatin:
Wherein R is H or C
1-C
6Alkyl; R
1Be H or R
2, R wherein
2It is hydroxyl protecting group.
2. according to the compound of claim 1, R wherein
2Be selected from TMS, tert-butyl diphenyl silylation or tertiary butyl dimethylsilyl.
3. according to the compound of claim 2, wherein R is H, methyl or the tertiary butyl; R
1Be H or tertiary butyl dimethylsilyl.
4. according to the preparation method of formula (III) compound of one of claim 1-3, this method is that the 3-(4-fluorophenyl) of the side chain compound of formula (IV) and formula (F1)-1-sec.-propyl-2-aldehyde radical-benzazolyl compounds prepared in reaction under alkaline condition is obtained formula (III) compound:
Wherein, radicals R and R
1Definition is as claim 1～3 as described in each, wherein R
3Be C
1-C
6Alkyl.
5. the preparation method of a formula (IV) compound,
Wherein R is H or C
1-C
6Alkyl, R
1Be H or R
2, R wherein
2Be hydroxyl protecting group, R
3Be C
1-C
6Alkyl;
This method comprises:
(1) for R be the formula IV compound of H, i.e. formula (S-3) compound reacts following formula (S-2) compound with the methyl acid phosphate dialkyl in the presence of alkali:
(2) be C for R
1-C
6The formula IV compound of alkyl, i.e. formula (IV ') compound makes formula (S-3) compound carry out esterification with formula RX compound under alkaline condition:
Wherein X is a leavings group.
6. according to the preparation method of formula (IV) compound of claim 5, its Chinese style (S-2) compound reacts with methyl-phosphoric acid dimethyl ester in the presence of alkyl lithium compounds.
7. according to the preparation method of claim 6, wherein R is a methyl, R
1Be tertiary butyl dimethylsilyl, X is I, Br, Cl, or tosic acid ester group.
8. according to the preparation method of claim 7, wherein alkyl lithium compounds is a butyllithium.
9. the formula of one of claim 1-3 (III) compound is used to prepare the purposes of fluvastatin compound.
10. according to the purposes of claim 9, this purposes realizes by following method:
(1). side chain 3-position protected hydroxyl deprotection under acidic conditions of following formula (III-1) compound is obtained formula (III-R) compound:
Wherein R and R
2Definition as claim 1～3 as described in each;
(2). in the presence of alkoxyl group dialkyl group boron, obtain formula (I-R) compound of cis with reductive agent reduction-type (III-R) compound:
With
(3). hydrolyzing type under alkaline condition (I-R) compound obtains corresponding acid or salt.
11. according to the purposes of claim 10, wherein the salt that obtains in step (3) is sodium salt.
12. according to the purposes of claim 10, wherein step (2) Chinese style (III-R) compound forms borane complexes with the reaction of alkoxyl group dialkyl group boron earlier, and then is reduced the agent reduction.
13. according to the purposes of claim 12, wherein the alkoxyl group dialkyl group boron in the step (2) is prepared through oxidation on the spot by trialkylborane.
14. according to the purposes of one of claim 10-13, alkoxyl group dialkyl group boron, formula (III-R) compound and reductive agent add in order.
15. according to the purposes of claim 14, wherein R is a methyl, R
2It is tertiary butyl dimethylsilyl.
16. according to the purposes of claim 15, wherein alkoxyl group dialkyl group boron is methoxyl group diethyl boron, reductive agent is a sodium borohydride.
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| CN101215297B (en) * | 2008-01-14 | 2011-09-14 | 湖南师范大学 | Statin-diphosphonic acid conjugates, preparation method and application thereof |
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Non-Patent Citations (4)
| Title |
|---|
| HMG-CoA Reductase Inhibitors:Synthesis,andBiological Activity ofTETRAHYDROINDAZOLE-Substituted3,S-Dihyroxy-6-heptenoic. Peter J.Connolly,et al.J.Med Chem,Vol.36 No.23. 1993 |
| HMG-CoA Reductase Inhibitors:Synthesis,andBiological Activity ofTETRAHYDROINDAZOLE-Substituted3,S-Dihyroxy-6-heptenoic. Peter J.Connolly,et al.J.Med Chem,Vol.36 No.23. 1993 * |
| Total Synthesis and Biological Evaluation of StructuralAnalogues of Compactinand Dihydromevinolin. Clayton H.Heathcock,et al.J.Med Chem,Vol.30 No.10. 1987 |
| Total Synthesis and Biological Evaluation of StructuralAnalogues of Compactinand Dihydromevinolin. Clayton H.Heathcock,et al.J.Med Chem,Vol.30 No.10. 1987 * |
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