WO1993002089A1 - Ketophosphanate coupling procedure - Google Patents

Ketophosphanate coupling procedure Download PDF

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Publication number
WO1993002089A1
WO1993002089A1 PCT/GB1992/001290 GB9201290W WO9302089A1 WO 1993002089 A1 WO1993002089 A1 WO 1993002089A1 GB 9201290 W GB9201290 W GB 9201290W WO 9302089 A1 WO9302089 A1 WO 9302089A1
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group
general formula
alkyl
methyl
hydroxy
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PCT/GB1992/001290
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French (fr)
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Alan Hornsby Davidson
Christopher Mark Blackwell
Christopher Norman Lewis
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British Bio-Technology Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates primarily to novel synthetic procedures of compounds which are useful intermediates in the synthesis of a range of mevinic acids.
  • HMG-CoA 3-hydroxy -3- methylglutaryl coenzyme A reductase
  • EP-A-0251625 discloses compounds of structure
  • R 1 is a group of formula CH 2 OH, CH 2 OCOR 3 , CO 2 R 4 or CONR 6 R 7 wherein R 3 , R 4 , R 6 , and R 7 can cover a range of alkyl, alkoxy or aryl groups, and the dotted lines represent single or double bonds.
  • the compounds disclosed have been generally obtained by fermentation of a suitable microorganism, or derived chemically from compounds obtained from such fermentations.
  • a procedure based totally on chemical synthesis would have significant advantages over a fermentation procedure on grounds of flexibility, yield, ease of purification and hence cost.
  • ketophosphonate reagent corresponding to the substituted ethyl tetrahydropyran moiety:
  • WO-A-9100280 discloses the total synthesis of a group of HMG-CoA reductase inhibiting mevinic acids.
  • the document describes the synthesis of (1S,2S,4aR,6S,8S,8aS,4 , R,6'R)-6'- ⁇ 2-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]- 6-[(E)-prop-1-enyl]-1-napthalenyl) ethyl ⁇ -tetrahydro-4'- hydroxy-2H-pyran-2'-one which has the structure:
  • Z is a bulky organic substituent
  • Y is a hydroxy, alkylsiloxy, a hydroxy function protected by a suitable protecting group, -CN, a halogen, oxo, or CO 2 R group;
  • X is a hydroxy, alkylsiloxy, -CN, a CO 2 R group, a hydroxymethyl or an alkylsiloxymethyl group, or a hydroxy function, hydroxymethyl function or carboxyl function protected by a suitable protecting group; and R is C 1-8 alkyl, C 3-8 cyclcalkyl, C 3-8 cycloalkylC 1-8 alkyl, C 2-8 alkenyl or a C 1-8 alkyl substituted phenyl group; the process comprising reacting a compound of general formula II
  • a weak hydroxylic base such as lithium hydroxide or a Group I or Group II carbonate, in a suitable solvent.
  • C 1-8 alkyl refers to straight chain or branched chain hydrocarbon groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.
  • C 2-8 alkenyl refers to straight chain or branched chain. hydrocarbon groups having from two to eight carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2- butenyl and 2-methyl-2- propenyl.
  • C2 -8 alkynyl refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable. This term would include for example, propynyl, butynyl and pentynyl.
  • C1 -8 alkoxy refers to straight chain or branched chain alkoxy groups having from one to eight carbon atoms. Illustrative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy and hexoxy.
  • hydroxy C 1-8 alkyl refers to straight chain or branched chain alkyl groups having from one to eight carbon atoms and carrying a hydroxy group.
  • alkoxy groups are hydroxyethyl and hydroxyn-propyl.
  • C 3-8 cycloalkyl refers to an alicyclic group having from 3 to 8 carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 4-8 cycloalkenyl refers to an alicyclic group having from 4 to 8 carbon atoms and having in addition one or more double bonds IIlustrative of such cycloalkenyl groups are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • halogen or its abbreviation "halo" means fluoro, chloro, bromo or iodo.
  • substituted alkyl refers to a straight or branched chain hydrocarbon group of one to three carbon atoms substituted with one or more aryl groups. Illustrative of such groups are benzyl and diphenyl methyl.
  • alkylsiloxy refers to a siloxy group substituted with from one to three alkyl groups, each alkyl group independently being straight or branched and having from one to eight carbon atoms. Illustrative of such groups are trimethylsiloxy, triisopropylsiloxy and t-butyldimethylsiloxy.
  • suitable protecting group refers to a group temporarily attached to a reactive centre in a multi-functional molecule.
  • the protecting group should ideally be able to be introduced specifically at the group to be protected, should be stable throughout all subsequent reaction conditions involving manipulations at other reactive sites, and be able to be removed under conditions that do not affect other reactive sites.
  • Z comprises two or more 5 or 6 membered rings either fused together or joined together via a single bond or via a single carbon bridge, each ring being independently saturated, unsaturated or aromatic, and each ring optionally containing one or more heteroatoms, and, in addition, optionally carrying one or more side chains each independently selected from a C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, hydroxy C 1-8 alkyl, hydroxy, halogen, OCOR or CO 2 R group.
  • Z containing two or more 5 or 6 membered saturated rings fused together include decahydronaphthalenyl, and [4,3,0] bicyclononyl.
  • Z containing two or more 5 or 6 membered rings fused together each ring being independently saturated, unsaturated or aromatic, include octahydronapthalenyl, hexahydronapthalenyl, benzocyclohexyl, benzocyclopentyl, and benzocyclohexenyl.
  • Z containing two or more 5 or 6 membered rings fused together, each ring being independently saturated, unsaturated or aromatic, and each optionally containing one or more heteroatoms include benzimidazolyl, quinolinyl and isoquinolinyl.
  • Z containing two or more 5 or 6 membered rings joined via a single bond each ring being independently saturated, unsaturated or aromatic,and each optionally containing one or more heteroatoms include cyclohexylbenzyl, biphenyl, phenylpyridyl and phenyl pyrazolyl.
  • Z containing two or more 5 or 6 membered rings joined via a single carbon bridge each ring being independently saturated, unsaturated or aromatic,and each optionally containing one or more heteroatoms include 2,2-diphenylvinyl.
  • the coupling reaction may be performed at a temperature between 20°C and 40°C.
  • the reaction temperature is preferably room temperature.
  • a further advantage of the invention is that base sensitive moieties of the substrate, reagent or product, or base labile protecting groups on the substrate, reagent or product, are stable under the reaction conditions.
  • the nature of the solvent of a given reaction is important, for example on grounds of solubility of substrate, reagents and products, or for ease of working up the reaction products.
  • the reaction of the invention is particularly adaptable since it may be carried out in either a water miscible solvent, for preference t-butanol or isopropanol, or a water immiscible solvent, for preference diethyl ether.
  • the solvent will be chosen according to the reactants and products in each case.
  • Lithium hydroxide and caesium carbonate have been found to be particularly effective bases for use in the coupling reaction. It is preferable to carry out the reaction in an aprotic solvent such as diethyl ether if lithium hydroxide is used as a base but when the base is caesium carbonate, the reaction proceeds more efficiently in a protic solvent such as t-butanol.
  • aprotic solvent such as diethyl ether
  • caesium carbonate may be used without drying, and lithium hydroxide may be used as the commercially available monohydrate.
  • the coupling reaction may be carried out with a ratio of compound of formula III:base of from 0.9:1 to 1.5:1 and it is preferred that the ratio is 1:1.
  • the ratio of compound of formula II: compound formula III may be from 0.5:1 to 1:1.
  • reaction is especially suitable for the preparation of a compound of general formula I
  • R 3 represents a hydrogen atom, COC 1-8 alkyl, COC 3-8 cycloalkyl, COC 3-8 cycloalkylC 1-8 alkyl, COC 2-8 alkenyl, COC 1- 6 alkyl substituted phenyl group, or a suitable protecting group;
  • R 4 represents a hydrogen atom, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, or a C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl group substituted with a substituted phenyl group, or a hydroxy C 1-8 alkyl group, or a hydroxy group, alkylsiloxy group or a hydroxy group protected by a suitable protecting group;
  • R 5 represents a hydrogen atom or a C 1-8 alkyl group
  • R 6 represents a hydrogen atom, or a methyl or ethyl group; each of a, b,and c, is independently a single or double bond except that when a and c are double bonds then b is a single bond.
  • Y is hydroxy or alkylsiloxy; and X is a CO 2 R C 1-8 alkyl group.
  • Examples of compounds of general formula III are: methyl (R)-3-[(tert-butyldimethylsilyl)oxy]-6- (dimethoxyphosphonyl)-5-oxohexanoate; and methyl (R)-3-[triisopropylsilyloxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate.
  • Compounds of general formula II which are suitable for use in the coupling reaction include:
  • R 3 , R 4 , R 5 and R 6 are as defined in general formula IV;
  • R 7 represents a hydrogen atom or a substituent R 8 or M
  • R 8 represents a C 1-5 alkyl group, or a C 1-5 alkyl group substituted with a group chosen from substituted phenyl, dimethylamino and acetylamino;
  • M represents a cation capable of forming a pharmaceutically acceptable salt
  • Preferred compounds which can be made by this method are:

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Compounds of general formula (I), wherein Z is a bulky organic substituent; Y is a hydroxy, alkylsiloxy or a hydroxy function protected by a suitable protecting group, -CN, a halogen, oxo, or a CO2R group; X is a hydroxy, alkylsiloxy, -CN, a CO2R group, a hydroxymethyl or an alkylsiloxymethyl group, or a hydroxy function, hydroxymethyl function or carboxyl function protected by a suitable protecting group; R is C1-8 alkyl, C3-8 cycloalkyl, C3-8 cycloalkylC1-8 alkyl, C2-8 alkenyl or a C1-8 alkyl substituted phenyl group; may be prepared in good yield and with minimal side reactions by reacting a compound of general formula (II), wherein Z is as defined as in general formula (I), with a compound of general formula (III), wherein X and Y are as defined in general formula (I); in the presence of a weak hydroxylic base such as lithium hydroxide (but excluding strong bases such a sodium hydroxide or potassium hydroxide), or a Group (I) or Group (II) carbonate, in a substantially anhydrous solvent. The reaction is useful for the preparation of mevinic acid derivatives which are HMG-CoA reductase inhibitors and avoids the low temperatures necessary in prior art methods.

Description

Ketophosphanate coupling procedure
This invention relates primarily to novel synthetic procedures of compounds which are useful intermediates in the synthesis of a range of mevinic acids.
A number of mevinic acids have been reported to be potent inhibitors of the enzyme 3-hydroxy -3- methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in the biosynthesis of cholesterol in mammals including man, and as such are useful in the treatment of hypercholesterolaemia and hyperlipidaemia.
Thus W F Hoffman et al (J. Med. Chem., 29, 849-852 (1986)) have reported the synthesis and testing of a compound now known as simvastatin, having the structure
Figure imgf000003_0001
EP-A-0251625 (Inamine) discloses compounds of structure
Figure imgf000004_0001
where R is similar to the corresponding group in the compounds described above, R1 is a group of formula CH2OH, CH2OCOR3, CO2R4or CONR6R7 wherein R3, R4, R6, and R7 can cover a range of alkyl, alkoxy or aryl groups, and the dotted lines represent single or double bonds.
The compounds disclosed have been generally obtained by fermentation of a suitable microorganism, or derived chemically from compounds obtained from such fermentations. However, a procedure based totally on chemical synthesis would have significant advantages over a fermentation procedure on grounds of flexibility, yield, ease of purification and hence cost.
Accordingly, Heathcock and Rosen disclosed in US 4,950,775 the total synthesis of compactin, which also possesses HMG-CoA reductase inhibitory activity, and which has the structure
Figure imgf000005_0001
The synthetic procedure disclosed therein involved a key step involving a Horner Wadsworth Emmons coupling between an aldehyde, corresponding to the decalin portion of the target compound:
Figure imgf000005_0002
and a ketophosphonate reagent corresponding to the substituted ethyl tetrahydropyran moiety:
Figure imgf000005_0003
Similarly, WO-A-9100280 discloses the total synthesis of a group of HMG-CoA reductase inhibiting mevinic acids. In particular the document describes the synthesis of (1S,2S,4aR,6S,8S,8aS,4,R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]- 6-[(E)-prop-1-enyl]-1-napthalenyl) ethyl}-tetrahydro-4'- hydroxy-2H-pyran-2'-one which has the structure:
Figure imgf000006_0001
The synthetic procedure disclosed in WO-A-9100280 also utilised as a key step a Horner Wadsworth Emmons coupling between an aldehyde, corresponding to the decalin portion of the target compound:
Figure imgf000006_0002
and a ketophosphonate:
Figure imgf000006_0003
Horner Wadsworth Emmons couplings have also been described in the art, a typical description being contained in Synthesis, Commun, 884, (1979) wherein simple aldehydes, such as benzaldehydes, were converted in good yield to alkenes in the presence of sodium or potassium hydroxide in a solvent such as tetrahydrofuran or dichloromethane:H2O by treatment with a reagent such as
(CH3O)2P(O) CN
Figure imgf000007_0001
With more complex substrates and reagents, however, lower yields were obtained.
Similarly, in both US 4,950,775 and WO-A-9100280 only moderate yields of product were obtained at this step. The reaction conditions described therein involved using lithium salts of strong bases, such as lithium hexamethyldisilazide, or lithium salts such as lithium chloride in the presence of bases of moderate strength, such as DBU, to catalyse the coupling. It was found that side reactions occurred, including beta- elimination reactions involving reagent and product, and epimerisation of the starting aldehyde. Moreover, these side products were difficult to remove, thus lowering the isolated yields still further and adversely affecting the economic advantages of the totally synthetic route referred to above.
Therefore, although the prior art and the work disclosed in US 4,950,775 and WO-A-9100280 are pioneering, there is still room for further improvement in the synthetic methodology used, net laast to enable coupling of large, bulky substrates and reagents and in particular those containing a variety of reactive centres capable of side reactions and especially those labile under basic conditions, in order to optimise yield and facilitate recovery of products.
It has now been found that other conditions and reactants may be used to expedite such couplings to prepare, inter alia intermediates of mevinic acids in high yield.
According to a first aspect of the invention there is provided a process for the preparation of a compound of general formula I
Figure imgf000008_0001
wherein Z is a bulky organic substituent;
Y is a hydroxy, alkylsiloxy, a hydroxy function protected by a suitable protecting group, -CN, a halogen, oxo, or CO2R group;
X is a hydroxy, alkylsiloxy, -CN, a CO2R group, a hydroxymethyl or an alkylsiloxymethyl group, or a hydroxy function, hydroxymethyl function or carboxyl function protected by a suitable protecting group; and R is C1-8 alkyl, C3-8 cyclcalkyl, C3-8 cycloalkylC1-8 alkyl, C2-8 alkenyl or a C1-8 alkyl substituted phenyl group; the process comprising reacting a compound of general formula II
Figure imgf000009_0001
wherein Z is as defined as in general formula I, with a compound of general formula III
Figure imgf000009_0002
wherein X and Y are as defined in general formula I;
in the presence of a weak hydroxylic base such as lithium hydroxide or a Group I or Group II carbonate, in a suitable solvent.
As used herein the term "C1-8 alkyl" refers to straight chain or branched chain hydrocarbon groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.
As used herein the term "C2-8 alkenyl" refers to straight chain or branched chain. hydrocarbon groups having from two to eight carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2- butenyl and 2-methyl-2- propenyl.
As used herein the term "C2-8 alkynyl" refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable. This term would include for example, propynyl, butynyl and pentynyl. As used herein the term "C1-8 alkoxy" refers to straight chain or branched chain alkoxy groups having from one to eight carbon atoms. Illustrative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy and hexoxy.
As used herein the term "hydroxy C1-8alkyl" refers to straight chain or branched chain alkyl groups having from one to eight carbon atoms and carrying a hydroxy group. Illustrative of such alkoxy groups are hydroxyethyl and hydroxyn-propyl.
As used herein, the term "C3-8 cycloalkyl" refers to an alicyclic group having from 3 to 8 carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term "C4-8 cycloalkenyl" refers to an alicyclic group having from 4 to 8 carbon atoms and having in addition one or more double bonds IIlustrative of such cycloalkenyl groups are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
As used herein the term "halogen" or its abbreviation "halo" means fluoro, chloro, bromo or iodo.
As used herein the term "substituted alkyl" refers to a straight or branched chain hydrocarbon group of one to three carbon atoms substituted with one or more aryl groups. Illustrative of such groups are benzyl and diphenyl methyl. As used herein, the term "alkylsiloxy" refers to a siloxy group substituted with from one to three alkyl groups, each alkyl group independently being straight or branched and having from one to eight carbon atoms. Illustrative of such groups are trimethylsiloxy, triisopropylsiloxy and t-butyldimethylsiloxy.
As used herein the term "suitable protecting group" refers to a group temporarily attached to a reactive centre in a multi-functional molecule. The protecting group should ideally be able to be introduced specifically at the group to be protected, should be stable throughout all subsequent reaction conditions involving manipulations at other reactive sites, and be able to be removed under conditions that do not affect other reactive sites. For a good review of protecting groups, see "Protective Groups in Organic Synthesis", Greene, T W Ed., John Wiley and Sons, 1981.
Preferably, Z comprises two or more 5 or 6 membered rings either fused together or joined together via a single bond or via a single carbon bridge, each ring being independently saturated, unsaturated or aromatic, and each ring optionally containing one or more heteroatoms, and, in addition, optionally carrying one or more side chains each independently selected from a C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkoxy, hydroxy C1-8alkyl, hydroxy, halogen, OCOR or CO2R group. Examples of Z containing two or more 5 or 6 membered saturated rings fused together include decahydronaphthalenyl, and [4,3,0] bicyclononyl.
Examples of Z containing two or more 5 or 6 membered rings fused together, each ring being independently saturated, unsaturated or aromatic, include octahydronapthalenyl, hexahydronapthalenyl, benzocyclohexyl, benzocyclopentyl, and benzocyclohexenyl. Examples of Z containing two or more 5 or 6 membered rings fused together, each ring being independently saturated, unsaturated or aromatic, and each optionally containing one or more heteroatoms include benzimidazolyl, quinolinyl and isoquinolinyl.
Examples of Z containing two or more 5 or 6 membered rings joined via a single bond, each ring being independently saturated, unsaturated or aromatic,and each optionally containing one or more heteroatoms include cyclohexylbenzyl, biphenyl, phenylpyridyl and phenyl pyrazolyl.
Examples of Z containing two or more 5 or 6 membered rings joined via a single carbon bridge, each ring being independently saturated, unsaturated or aromatic,and each optionally containing one or more heteroatoms include 2,2-diphenylvinyl.
One advantage of the invention is that the coupling reaction may be performed at a temperature between 20°C and 40°C. The reaction temperature is preferably room temperature. Clearly therefore, this is an advantage since, with the coupling reaction used previously, it was often necessary to use temperatures as low as -70°C which, of course presents great problems if the reaction is to be used on a large scale.
Furthermore, using the process of the invention, it is possible to obtain the product in yields of 80-90% whereas with previous methods, yields were, at the most, about 66% and were often a great deal lower than this. The invention represents, in this respect, a significant improvement over prior art methods. A further advantage of the invention is that base sensitive moieties of the substrate, reagent or product, or base labile protecting groups on the substrate, reagent or product, are stable under the reaction conditions.
It will be appreciated by those skilled in the art that the nature of the solvent of a given reaction is important, for example on grounds of solubility of substrate, reagents and products, or for ease of working up the reaction products. The reaction of the invention is particularly adaptable since it may be carried out in either a water miscible solvent, for preference t-butanol or isopropanol, or a water immiscible solvent, for preference diethyl ether. The solvent will be chosen according to the reactants and products in each case.
Lithium hydroxide and caesium carbonate have been found to be particularly effective bases for use in the coupling reaction. It is preferable to carry out the reaction in an aprotic solvent such as diethyl ether if lithium hydroxide is used as a base but when the base is caesium carbonate, the reaction proceeds more efficiently in a protic solvent such as t-butanol.
Although it is preferable to use previously dried solvents for the coupling reaction, the reaction itself is unaffected by small amounts of water. Thus caesium carbonate may be used without drying, and lithium hydroxide may be used as the commercially available monohydrate.
The coupling reaction may be carried out with a ratio of compound of formula III:base of from 0.9:1 to 1.5:1 and it is preferred that the ratio is 1:1. The ratio of compound of formula II: compound formula III may be from 0.5:1 to 1:1.
The reaction is especially suitable for the preparation of a compound of general formula I
Figure imgf000014_0001
wherein X and Y are as defined above and Z is a fused ring system of general formula IV
Figure imgf000015_0001
wherein
R3 represents a hydrogen atom, COC1-8 alkyl, COC3-8 cycloalkyl, COC3-8 cycloalkylC1-8 alkyl, COC2-8 alkenyl, COC1- 6 alkyl substituted phenyl group, or a suitable protecting group;
R4 represents a hydrogen atom, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl group, or a C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl group substituted with a substituted phenyl group, or a hydroxy C1-8 alkyl group, or a hydroxy group, alkylsiloxy group or a hydroxy group protected by a suitable protecting group;
R5 represents a hydrogen atom or a C1-8 alkyl group;
R6 represents a hydrogen atom, or a methyl or ethyl group; each of a, b,and c, is independently a single or double bond except that when a and c are double bonds then b is a single bond.
These compounds of general formula I are mevinic acid derivatives which, as has been discussed, are potent inhibitors of HMG-CoA reductase.
It is particularly preferred to use the method of the invention to prepare compounds of general formula I wherein:
Y is hydroxy or alkylsiloxy; and X is a CO2R C1-8 alkyl group.
Examples of compounds of general formula III are: methyl (R)-3-[(tert-butyldimethylsilyl)oxy]-6- (dimethoxyphosphonyl)-5-oxohexanoate; and methyl (R)-3-[triisopropylsilyloxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate. Compounds of general formula II which are suitable for use in the coupling reaction include:
{(1S, 2S, 4aR, 6S, 8S, 8aS)-1,2,4a,5,6,7,8,8a-octahydro- 2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]- 6-[(E)- prop-1-enyl]naphthalene-1-carbaldehyde);
{(1S, 2S, 4aR, 6S, 8S, 8aS)-1,2,4a,5,6,7,8,8a-octahydro- 2,6-dimethyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)- prop-1-enyl]naphthalene-1-carbaldehyde};
{(1S,2S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2-methyl-8-[(2"- (S)-methyl-1"-oxobutyl)oxy]naphthalene-1-carbaldehyde};
{(1S,2S,4aR,6S,8S,8aS)-1,2,4a,5,6,7,8,8a-octahydro-2,6- dimethyl-8-[(2"-(S)-methy1-1"-oxobutyl)oxy]naphthalene- 1-carbaldehyde);
{ (1S,2S,4aR,6R,8S,8aS)-6-(t-butyldiphenylsiloxy)- 1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-(S)-methyl-
1"-oxobutyl)oxy]-naphthalene-1-carbaldehyde);
{(1S,2S,6S,8S,8aS)-1,2,6,7,3,8a-hexahydro-2,6-dimethyl8- [(2",2"-dimethy1-1"-oxobutyl)oxy]naphthalene-1- carbaldehyde};
{(1S,2S,6S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2,6- dimethyl- 8-[(2"-(S)-methyl-1"-oxobutyl)oxy]naphthalene1- carbaldehyde); or
1-benzyl-2-phenyl-4-isopropylimidazole-5-carbaldehyde.
Compounds of general formulae II and III are known in the art or can be prepared by methods analogous to those in the art.
In a second aspect of the invention there is provided a process for the preparation of a methyl (1S,2S, 4aR,6S,8S,8aS,3,R)-7'-(1,2,4a,5,6,7,8,8a-octahydro- 2- methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop- 1-enyl]-1-naphthalenyl)-3'-trialkylsilyl- oxy-5'- oxohept-6'-enoate, the method comprising reacting a methyl (R) -3-[ (trialkylsilyl)oxy]-6- (dimethoxyphosphonyl)-5-oxohexanoate and either lithium hydroxide or caesium carbonate in a substantially anhydrous solvent.
In a further aspect of the invention, there is provided a process for the preparation of compounds of general formulae V and VI
Figure imgf000018_0001
wherein:
R3, R4, R5 and R6 are as defined in general formula IV;
R7 represents a hydrogen atom or a substituent R8 or M;
R8 represents a C1-5 alkyl group, or a C1-5 alkyl group substituted with a group chosen from substituted phenyl, dimethylamino and acetylamino;
M represents a cation capable of forming a pharmaceutically acceptable salt;
Q represents C=O or CHOH; and each of a, b, c, and d is independently a single or double bond except that when a and c are double bonds then b is a single bond; the process comprising preparing a compound of general formula I by the process of the invention and subsequently converting the compound of general formula I to a compound of general formula V or VI by any suitable method.
A suitable method for this conversion is described in WO- A-9100280.
Preferred compounds which can be made by this method are:
(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8, 8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]- 6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'- hydroxy-2H-pyran-2'-one; and
(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8, 8a- octahydro-2,6-dimethyl-8-[(2",2"-dimethyl-1"-oxobutyl)- oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl)- tetrahydro-4'-hydroxy-2H-pyran-2'-one.
The following examples, which are for the purposes of illustration only, show the synthesis of a compound of general formula I from a compound of general formula II and a compound of general formula III using two alternative routes. Organic solutions were dried over anhydrous magnesium sulphate. Ether refers to diethyl ether. NMR spectra aquired at 250MHz (proton) or 62.9MHz (carbon) in deuteriochloroform unless noted otherwise. Coupling constants are given in Hertz.
Example l
Methyl (1S,2S,4aR,6S,8S,8aS,3,R)-7'-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]6- [ (E) -prop-1-enyl ] -1-naphthalenyl ) -3 , -t-butyldimethylsilyl-oxy-5 ' -oxohept-6 '-enoate.
Figure imgf000020_0001
USING LITHIUM HYDROXIDE
A mixture of methyl (R)-3-[(tert-butyldimethylsilyl) oxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate (241 mg, 0.63 mmol) and lithium hydroxide monohydrate (26.5 mg, 0.63 mmol) in anhydrous ether (3 mL) was stirred at room temperature under argon for 35 minutes. The aldehyde
{(1S,2S,4aR,6S,8S,8aS)-1,2,4a,5,6,7,8,8a- octahydro-2- methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-
1-enyl]naphthalene-1-carbaldehyde) (131 mg, 0.40 mmol) in ether (3 mL) was added and the resulting solution stirred for 7 days. The solution was then diluted with more ether
(10 mL), washed with ammonium chloride solution (3 mL) and brine (2 mL). Column chromatography eluting with hexane:ethyl acetate (12:1) gave the unreacted starting aldehyde (12 mg) followed by the required enone (193 mg,
82%; 92% with respect to unrecovered aldehyde). delta H 6.77 (1H, dd, J = 17.5 and 10), 6.01 (1H, d, J = 17.5), 5.75 (1H, ddq, J = 15, 7.5 and 2.5), 5.65 (1H, dq, J = 10.5 and 2.5), 5.50 - 5.30 (2H, m), 4.95 (1H, m), 4.62 (1H, m), 3.68 (3H, s), m.83 (1H, dd, J = 17.5 and 5), 2.74 (1H, dd, J = 17.5 and 5), 2.65 - 2.2 (6H, m), 2.05 - 1.2 (10H, m), 1.14 (3H, s), 1.12 (3H, s), 0.95 (3H, d, J = 7.5), 0.88 - 0.72 (12H, m), 0.08 (3H, s), 0.03 (3H, s)
delta C 195.77 175.15, 170.05, 147.05, 134.46, 130.73, 130.54, 129.51, 121.68, 68.77, 64.55, 49.99, 46.09, 41.33, 41.23, 41.11, 41.01, 40.03, 35.70, 34.53, 34.44, 34.00, 31.56, 29.31, 24.30, 23.23, 23.05, 16.47, 15.03, 7.77, -6.13, -6.47 Using the above method with 7.0 g of aldehyde (21 mmol), 11.29 g of keto-phosphonate (6a) (29.5 mmol) and 1.24 g of lithium hydroxide gave 0.92 g of recovered aldehyde and 9.45 (76%; 88% with respect to unrecovered aldehyde) of enone.
Example 2
Methyl (1S,2S,4aR,6S,8S,8aS,3'R)-7'-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]6- [(E)-prop-1-enyl]-1-naphthalenyl)-3'-triisopropyl-silyl- oxy-5'-oxohept-6'-enoate.
Figure imgf000022_0001
Using the method of Example 1 with 25 mg of aldehyde (0.075 mmol), methyl (R)-3-[triisopropyl- silyloxy]-6- (dimethoxyphosphonyl)-5-oxohexanoate (35 mg, 0.083 mmol) and lithium hydroxide (3.5 mg, 0.083 mmol) gave a 60% yield of enone after 4 days.
Example 3
Methyl (1S,2S,4aR,6S,8S,8aS,3,R)-7'-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethγl-1"-oxobutyl)oxy]6- [(E)-prop-1-enyl]-1-naphthalenyl)-3'-t-butyldimethyl- silyl-oxy-5'-oxohept-6'-enoate
Figure imgf000023_0001
USING CAESIUM CARBONATE tert-Butanol (14 mL) was added to a mixture of methyl (R)-3-[(tert-butyldimethylsilyl)oxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate (1.26 g, 3.30 mmol) and caesium carbonate (1.07 g, 3.28 mmol) and the resulting solution stirred at room temperature for 40 minutes under argon. A solution of the aldehyde (l.Og, 3.01mmol) in t- butanol (6 mL) was added and the reaction stirred for 4 days. The resulting dark yellow solution was diluted with ether (40 mL) and washed with ammonium chloride solution
(20 mL). The aqueous layer was extracted with more ether
(2 x 20 mL) and the combined organic layers washed with brine (2 x 15 mL), dried and evaporated to give a dark yellow solid. Chromatography on silica eluting with firstly dichloromethane gave unreacted aldehyde (220 mg), and then with hexane: ethyl acetate (4:1) gave the desired enone as a pale yellow solid (930 mg, 53%; 68% with respect to unrecovered aldehyde). Example 4
Methyl ( 3 ,R) - (E) -7 ' - (l-benzyl-2-phenyl-4-isopropyl- imidazol-5-yl) -3 'tert-butyldimethylsilyloxy-S'-oxohepte'- enoate
Figure imgf000024_0001
A mixture of the methyl (R)-3-[(tert-butyldimethyl- silyl)oxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate (369 mg; 0.97 mmol) and lithium hydroxide monohydrate (40 mg; 0.97 mmol) in ether (5 mL) was stirred under argon for 30 minutes at room temperature. A solution of 1- benzyl-2- phenyl-4-isopropylimidazole-5-carbaldehyde (184 mg; 0.60 mmol in ether (5 mL) was added and stirring continued for 5 days after which time the reaction was diluted with ether (10 mL). The organic solution was washed with ammonium chloride solution (10 mL) and brine (5 mL), dried and evaporated to an orange semi-solid. Chromatography on silica eluting with hexane-ethyl acetate (4:1) gave the product (116mg, 34%; 89% with respect to recovered aldehyde). deltah 7.55 - 7.23 (9H m), 7.1 - 7.05 (2H m), 6.27 (1H d J = 16), 5.3 (2H s), 4.55 (1H m), 3.65 (3H m), 3.27 (1H m), 2.70 (1H dd J = 15 and 6), 2.62 (1H J = 15 and 6), 2.52 (dd J = 14.7 and 5.5), 2.42 (dd J = 14.7 and 5.5), 1.41 (3H s), 1.38, (3H s), 0.81 (9H s), 0.03 (3H s), -0.03
(3H s). deltaC 195.83, 170.07, 153.61, 150.00, 135.20, 128.56, 128.09, 127.84, 127.59, 127.37, 127.28, 126.47, 124.18, 122.27, 121.04, 65.00,50.04, 47.46, 47.26, 41.11, 25.95,
24.27, 20.78, 16.46, -6.41.
From the above Examples, it can be seen that the coupling reaction of the invention can be carried out at room temperature and it is not necessary to use the extreme conditions which were essential for prior art coupling reactions.

Claims

1. A process for the preparation of a compound of general formula I
Figure imgf000026_0001
wherein
Z is a bulky organic substituent;
Y is a hydroxy, alkylsiloxy or a hydroxy function protected by a suitable protecting group, -CN, a halogen, oxo, or a CO2R group;
X is a hydroxy, alkylsiloxy, -CN, a CO2R group, a hydroxymethyl or an alkylsiloxymethyl group, or a hydroxy function, hydroxymethyl function or carboxyl function protected by a suitable protecting group;
R is C1-8 alkyl, C3-8 cycloalkyl, C3-8 cycloalkylC1-8 alkyl, C2-8 alkenyl or a C1-8 alkyl substituted phenyl group; the process comprising reacting a compound of general formula II
Figure imgf000027_0001
wherein Z is as defined as in general formula I, with a compound of general formula III
Figure imgf000027_0002
wherein X and Y are as defined in general formula I; in the presence of a weak hydroxylic base such as lithium hydroxide or a Group I or Group II carbonate, in a suitable solvent.
2. A process as claimed in claim 1, wherein Z comprises two or more 5 or 6 membered rings either fused together or joined together via a single bond or via a single carbon bridge, each ring being independently saturated, unsaturated or aromatic, and each ring optionally containing one or more heteroatoms, and, in addition, optionally carrying one or more side chains each independently selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkoxy, hydroxy C1-8alkyl, hydroxy, halogen, OCOR or a CO2R group.
3. A process as claimed in claim 1 or claim 2 wherein the reaction is carried out at a temperature of from 20°C to 40°C.
4. A process as claimed in claim 3, wherein the reaction is carried out at room temperature.
5 A process as claimed in any one of claims 1 to 4 wherein the solvent is aprotic, for example diethyl ether.
6. A process as claimed in any one of claims 1 to 4 wherein the solvent is protic, for example t-butanol or isopropanol.
7. A process as claimed in any one of claims 1 to 6 wherein the base is lithium hydroxide or caesium carbonate.
8. A process as claimed in any one of claims 1 to 7 wherein the ratio of the compound of formula III:base is from 0.9:1 to 1.5:1.
9. A process as claimed in any one of claims 1 to 8 wherein the ratio of compound of formula II:compound of formula III is from 0.5:1 to 1:1.
10. A process as claimed in any one of claims 1 to 9, wherein Z is a fused ring system of general formula IV
Figure imgf000029_0001
wherein
R3 represents a hydrogen atom, COC1-8 alkyl, COC3-8 cycloalkyl, COC3-8 cycloalkylC1-8 alkyl, COC2-8 alkenyl, COC1- 6 alkyl substituted phenyl group, or a a suitable protecting group;
R4 represents a hydrogen atom, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl group, or a C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl group substituted with a substituted phenyl group, or a hydroxy C1-8 alkyl group, or a hydroxy group, alkylsiloxy group or a hydroxy group protected by a suitable protecting group;
R5 represents a hydrogen atom or a C1-8 alkyl group;
R6 represents a hydrogen atom, or a methyl or ethyl group; each of a, b,and c, is independently a single or double bond except that when a and c are double bonds then b is a single bond.
11. A process as claimed in any one of claims 1 to 10 wherein:
Y is hydroxy or alkylsiloxy; and X is a CO2 C1-8 alkyl group.
12. A process as claimed in any preceding claim, wherein the compound of general formula III is
Methyl (R)-3-[(tert-butyldimethylsilyl)oxy]-6- (dimethoxyphosphonyl)-5-oxonexanoate; or
Methyl (R)-3-[triisopropylsilyloxy]-6-(dimethoxy- phosphonyl)-5-oxohexanoate.
13. A process as claimed in any preceding claim wherein the compound of general formula II is {(1S, 2S, 4aR, 6S, 8S, 8aS)-1,2,4a,5,6,7,8,8a-octahydro- 2-methyl-8-[(2",2"-dimethy1-1"-oxobutyl)oxy]- 6-[(E)- prop-1-enyl]naphthalene-1-carbaldehyde};
{(1S, 2S, 4aR, 6S, 8S, 8aS) -1,2,4a,5, 6,7,8, 8a- octahydro- 2,6-dimethyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)- prop-1-enyl]naphthalene-1-carbaldehyde};
{(1S,2S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2-methyl-8-[(2"- (S)-methy1-1"-oxobutyl)oxy]naphthalene-1-carbaldehyde};
{(1S,2S,4aR,6S,8S,8aS)-1,2,4a,5,6,7,8,8a-octahydro-2,6- dimethyl-8-[(2"-(S)-methyl-1"-oxobutyl)oxy]naphthalene- 1-carbaldehyde); {(1S,2S,4aR,6R,8S,8aS)-6-(t-butyldimethylsiloxy)-
1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-(S)-methyl- 1"-oxobutyl)oxy]-naphthalene-1-carbaldehyde);
{(1S,2S,6S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2,6-dimethyl8- [(2",2"-dimethy1-1"-oxobutyl)oxy]naphthalene-1- carbaldehyde};
{(1S,2S,6S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2,6-dimethyl- 8-[(2"-(S)-methyl-1"-oxobutyl)oxy]naphthalenel- carbaldehyde); or 1-benzyl-2-phenyl-4-isopropylimidazole-5-carbaldehyde. 13. A process for the preparation of a methyl (1S,2S,
4aR,6S,8S,8aS,3,R)-7'-(1,2,4a,5,6,7,8,8a-octahydro- 2- methyl-8-[(2",2"-dimethy1-1"-oxobutyl)oxy]-6-[(E)-prop- 1-enyl]-1-naphthalenyl)-3'-trialkylsilyloxy-5'-oxohept- 6'-enoate, the method comprising reacting a
methyl (R)-3-[(trialkylsilyl)oxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate with {(1S,2S,4aR,6S,8S,8aS)- 1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2",2"-dimethyl- 1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl] naphthalene-1- carbaldehyde} and either lithium hydroxide or caesium carbonate in a substantially anhydrous solvent.
14. A process for the preparation of a compound of general formula V or VI
Figure imgf000032_0001
wherein
R3, R4, R5 and R6 are as defined in general formula IV;
R7 represents a hydrogen atom or a substituent R8 or M; R8 represents a C1-5 alkyl group, or a C1-5 alkyl group substituted with a group chosen from substituted phenyl, dimethylamino and acetylamino;
M represents a cation capable of forming a pharmaceutically acceptable salt;
Q represents C=O or CHOH; and each of a, b, c, and d is independently a single or double bond except that when a and c are double bonds then b is a single bond; the process comprising preparing a compound of general formula I by a process as claimed in anyone of claims 1 to 11 and subsequently converting the compound of general formula I to a compound of general formula V or VI by any suitable method. 16. A process as claimed in claim 15 for the preparation of:
(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]- 6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'- hydroxy-2H-pyran-2'-one; or
(1S,2S,4aR,6S,8S,8aS,4,R,6,R)-6'-{2-(1,2,4a,5,6,7,8,8a- octahydro-2,6-dimethyl-8-[(2",2"-dimethyl-1"-oxobutyl)- oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}- tetrahydro-4'-hydroxy-2H-pyran-2'-one.
PCT/GB1992/001290 1991-07-22 1992-07-15 Ketophosphanate coupling procedure WO1993002089A1 (en)

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