WO2006064179A1 - Process and intermediate compounds useful in the preparation of statins - Google Patents

Process and intermediate compounds useful in the preparation of statins Download PDF

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Publication number
WO2006064179A1
WO2006064179A1 PCT/GB2005/004541 GB2005004541W WO2006064179A1 WO 2006064179 A1 WO2006064179 A1 WO 2006064179A1 GB 2005004541 W GB2005004541 W GB 2005004541W WO 2006064179 A1 WO2006064179 A1 WO 2006064179A1
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Prior art keywords
group
optionally substituted
formula
compound
alkyl
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PCT/GB2005/004541
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French (fr)
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David John Moody
Jonathan William Wiffen
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Avecia Pharmaceuticals Limited
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Priority to EP05808835A priority Critical patent/EP1828092A1/en
Priority to US11/721,858 priority patent/US8278467B2/en
Priority to CN2005800479693A priority patent/CN101133010B/en
Priority to JP2007546157A priority patent/JP2008524180A/en
Publication of WO2006064179A1 publication Critical patent/WO2006064179A1/en
Priority to US13/599,606 priority patent/US8519164B2/en
Priority to US13/951,650 priority patent/US8853429B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B41/00—Formation or introduction of functional groups containing oxygen
    • C07B41/08—Formation or introduction of functional groups containing oxygen of carboxyl groups or salts, halides or anhydrides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • 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
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
    • C07D309/10—Oxygen atoms
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

  • the present invention concerns a process and intermediate compounds useful in the preparation of statins.
  • R is a an optionally substituted hydrocarbyl group or an optionally substituted heterocyclic group; provided that R is not a compound of Formula (a):
  • R a represents an alkyl group, such as a Ci -6 alkyl group, and preferably an isopropyl group;
  • R b represents an aryl group, preferably a 4-fluorophenyl group
  • R c represents hydrogen, a protecting group or an alkyl group, such as a C 1-6 alkyl group, and preferably a methyl group;
  • R d represents hydrogen, a protecting group or a SO 2 R 6 group where R e is an alkyl group, such as a Ci -6 alkyl group, and preferably a methyl group, which comprises a) hydroxylating a compound of formu
  • Y represents a halo group, preferably Cl or Br
  • P 1 represents hydrogen or a protecting group
  • any P 1 protecting groups and any additional protecting groups may be removed individually or together and prior to ring opening, during ring opening or after ring opening of the compounds of formula (5) or (6).
  • R is a group selected from
  • R 1 represents hydrogen, a protecting group or an optionally substituted hydrocarbyl group, preferably an alkyl group, such as a C 1-6 alkyl group;
  • R 2 represents an optionally substituted acyl group, preferably an alkanoyl group, such as C ⁇ alkanoyl group, and preferably a -C(O)CH(Me)CH 2 CH 3 or
  • R 3 represents an optionally substituted acyl group, preferably an alkanoyl group, such as C 1-8 alkanoyl group, and preferably a -C(O)CH(Me)CH 2 CH 3 or
  • R 4 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
  • R 5 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a Ci -6 alkyl group, and more preferably a cyclopropyl group;
  • R 6 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
  • R 7 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a C 1-6 alkyl group, and more preferably an isopropyl group;
  • R 8 represents an optionally substituted hydrocarbyl group, or optionally substituted heterocyclic group, preferably an optionally substituted aryl or an optionally substituted aromatic heterocyclic group, more preferably a methyltetrazoyl group;
  • R 9 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
  • R 10 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group, which comprises a) hydroxylating a compound of formula (1):
  • Y represents a halo group, preferably Cl or Br
  • P 1 represents hydrogen or a protecting group
  • R11 and R 12 each independently is an alkyl, aryl, alkoxy or aryloxy group, preferably a phenyl group, to give a compound of formula (5):
  • any P 1 protecting groups and any additional protecting groups may be removed individually or together and prior to ring opening, during ring opening or after ring opening of the compounds of formula (5) or (6).
  • R is as defined above for R 7 , may be obtained by reduction of a compound of Formula (7) or, alternatively a compound of Formula (5) or (6) may be reduced to a corresponding compound of Formula (9) or (10).
  • any P 1 protecting groups and any additional protecting groups may be removed individually or together and prior to ring opening, during ring opening or after ring opening of the compounds of formula (9) or (10).
  • Protecting groups which may be represented by P 1 and P 2 include alcohol protecting groups, examples of which are well known in the art. Particular examples include tetrahydropyranyl, benzyl and methyl groups. Preferred protecting groups are silyl groups, for example triaryl- and especially trialkylsilyl groups. Especially preferred examples are trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenyl groups.
  • Protecting groups which may be represented by P 1 and P 2 may be the same or different. When the protecting groups P 1 and P 2 are different, advantageously this may allow for the selective removal of only P 1 or P 2 .
  • P 1 is a silyl group and P 2 is a methyl group.
  • Protecting groups which may be represented by R 1 include alcohol protecting groups, examples of which are well known in the art.
  • Protecting groups which may be represented by R c and R d include amine protecting groups, examples of which are well known in the art. Particular examples include benzyl groups, carbamates (such as CBZ, Boc, Fmoc), phosphate, thiophosphate, silyl groups and, when R c and R d together are a single protecting group, an imine group.
  • Hydrocarbyl groups which may be represented by R, R 1 and R 3 independently include alkyl, alkenyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups.
  • Alkyl groups which may be represented by R, R a , R c , R d , R 1 and R 4"10 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprising up to 10 branch chain carbon atoms, preferably up to 4 branch chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings.
  • alkyl groups which may be represented by R, R a , R°, R d , R 1 and R 4-10 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups.
  • Alkenyl groups which may be represented by R, R 1 and R 4"10 include C 2-2 o, and preferably C 2-6 alkenyl groups. One or more carbon - carbon double bonds may be present.
  • the alkenyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkenyl groups include vinyl, styryl and indenyl groups.
  • Aryl groups which may be represented by R, R b , R 1 and R 4"10 may contain 1 ring or
  • fused rings which may include cycloalkyl, aryl or heterocyclic rings.
  • aryl groups which may be represented by R 1 , R b and R 4"10 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.
  • Heterocyclic groups which may be represented by R, R 1 and R 4"10 independently include aromatic, saturated and partially unsaturated ring systems and may constitute 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings.
  • the heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P.
  • R, R 1 or R 4"10 represents or comprises a heterocyclic group, preferably attachment is provided through a carbon atom in the R, R 1 or R 4"10 group.
  • heterocyclic groups which may be represented by R, R 1 and R 4"10 include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl, triazoyl and tetrazoyl groups.
  • R, R 1 and R 4"10 is a substituted hydrocarbyl group, the substituent(s) should be such so as not to adversely affect the rate or selectivity of any of the reaction steps or the overall process.
  • Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di- hydrocarbylamino, hydrocarbylthio, esters, carbamates, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R 1 above.
  • One or more substituents may be present. Examples of R 1 and R 4'10 groups having more than one substituent present include -CF 3 and -C 2 F 5 .
  • Hyrdoxylation of compounds of formula (1) can be achieved by methods known in the art for displacing a halo group with a hydroxide source.
  • the process comprises contacting the compound of formula (1) with a source of hydroxide.
  • Hydroxide sources include hydroxide salts, especially ammonium or alkali metal hydroxides, particularly lithium, sodium or potassium hydroxide, and various aqueous media such as water in the presence of basic media such as N-methylpryrrolidinone, HMPA, AI 2 O 3 , CaCO 3 , Na 2 CO 3 , K 2 CO 3 or K0 2 /18-crown-6, silver salts such as AgNO 3 or Ag 2 O, or oxidants such perbenzioc acid.
  • a particularly preferred process comprises contacting the compound of formula (1) with 5 molar equivalents of KOH in the presence of dimethylsulfoxide solvent at a temperature of, for example, about 50 0 C.
  • hydroxylation may be achieved by first displacing the halogen with a leaving group such as acetate, triflate or sulphate optionally in the presence of a silver salt, then displacing the leaving group with a hydroxide source.
  • a particularly preferred process comprises contacting the compound of formula (1) with 3 molar equivalents of NaOAc in the presence of dimethylformamide solvent and tetra-n-butylammonium chloride at a temperature of, for example, about 100°C, isolating the acetyl compound and contacting with potassium carbonate in the presence of methanol solvent and at a temperature of, for example, about O 0 C.
  • Oxidation of compounds of formula (2) can be achieved using oxidation systems known in the art for the oxidation of alcohols, especially those known in the art for the oxidation of primary alcohols. Examples include oxidation with Dess-Martin periodinane, bromine, Swern oxidation or various metal based oxidations such as Fetizon reagent, manganate based reagents, and chromate based reagents such as Collins reagent. Swern oxidation is preferred.
  • preferred conditions comprise the use of dimethyl sulphoxide and oxalyl chloride or bromine in a solvent such as dichloromethane or dichlormethane/THF mixtres, at reduced temperature, such as from O to -100°C, preferably -50 to -80°C.
  • a solvent such as dichloromethane or dichlormethane/THF mixtres
  • reagents are added at reduced temperature, such as -30 to -80 0 C, and then once all reagents are added, the reaction mixture is allowed to warm to 15 to 20 0 C.
  • the coupling of the compound of formula (3) with the compound of formula (4) may employ conditions analogous to those given in Bull. Chem. Soc. Japan 1995, 68, 364-372, Tet. Lett. 1992, 33(49), 7525-75226, Tetrahedron 1997, 53(31) 10659-10670 and WO01/85702.
  • the conditions preferably comprise reacting the compounds of formula (3) and (4) in a hydrocarbon solvent, such as THF, toluene or cyclohexane, or mixtures thereof, optionally in the presence of a base, followed by contact with aqueous acid, such as aqueous HCI.
  • Alkyl, aryl, alkoxy or aryloxy groups which may be represented by R 11 and R 12 include C 1-6 alkyl groups, such as methyl and ethyl groups, C 6- i 2 aryl groups, such phenyl, tolyl or naphthyl, C 1-6 alkoy groups, such as ethoxy groups, and C 6- i 2 aryloxy groups such as phenoxy groups.
  • Anions which may be represented by X include halide.
  • the protecting group may be removed to form a hydroxy group by methods known in the art for the removal of the given protecting group.
  • silyl protecting groups may be removed by contact with a source of fluoride ion, such as tetrabutylammonium fluoride.
  • Oxidation of compounds formed by deprotection of compounds wherein W represents -OP 2 may employ conditions known in the art for the oxidation of pyranols to pyranones, and include those given in "Comprehensive Organic Transformations", R. C. Larock, 2 nd Ed (1999) p 1670, published by Wiley VCH, incorporated herein by reference.
  • Preferred oxidation systems include Ag 2 CO 3 /Celite, especially Celite J2, bromine or Swern.
  • (6) may employ conditions known in the art for ring opening of a pyranone.
  • the ring is opened by contact with a base, such as sodium hydroxide.
  • a base such as sodium hydroxide.
  • polar solvents are employed, for example methanol, acetonitrile, tetrahydrofuran or mixtures thereof.
  • Remaining protecting groups may be removed by methods known in the art for the removal of the given protecting group.
  • silyl protecting groups may be removed by contact with a source of fluoride ion, such as tetrabutylammonium fluoride.
  • Reduction of the compounds of formula (5), (6) or (7) may employ conditions known in the art for the reduction of double bonds. For example, hydrogenation using hydrogen gas in the present of transition metals or transition metal catalysts such as hydrogen in the presence of group VIII metal or metal catalyst, especially Ru, Rh, Pd, Ir or Pt metals or metal based catalysts.
  • Preferred compounds of formula (1) are compounds of formula:
  • Preferred compounds of formula (2) are compounds of formula:
  • Preferred compounds of formula (3) are compounds of formula:
  • R 1 and R 2 are as previously described.
  • Preferred compounds of formula (7) are of formula:
  • R 1 and R 2 are as previously described.
  • the black solution was then diluted with water (15OmIs) and extracted with ethyl acetate (3 x 150OmIs). The combined upper organic layer was then washed with water (3 x 150OmIs). The aqueous portion showed no product content at this point. The layers were then separated, dried, (Na 2 SO 4 ) and the solvent removed in vacuo to yield a black flowing oil (31 g, 95%) containing a mixture of anomers.
  • nmr CDCI 3 1.4-1.8 (m 4H), 2.0- 2.1 ( duplicate s, 3H), 3.4 & 3.5 (s 3H), 3.8 (m 1 H), 4.0 (m 1 H), 4.1 (m 2H), 4.5 (m, 2H), 4.7-4.9 (m 1 H), 7.2-7.3 (m, 5H); 13 C nmr CDCI 3 20.8; 30-35; 55&56; 57&64; 66&68; 69&72; 70&71 ; 98&99; 127-128 & 138; 170.5; m/z 293, 262, 221 , 203, 156, 91 and 43.
  • nmr CDCI 3 1.4-1.8 (m 4H), 3.4 & 3.5 (s 3H), 3.8 (m 1 H), 3.9 (m 1 H), 4.0 (m 2H), 4.5 (m 2H), 4.7-4.9 (m 1 H), 7.2-7.3 (m, 5H); 13 C nmr CDCI 3 30-38; 55&56; 65&66; 65&69; 70&71 ; 72&73; 99&100; 128 & 140; m/z 252, 221 , 189, 163, 114 and 91.
  • the hydroxy-O-benzyl- lactol methyl acetal (1.Og 1 ) was dissolved in dichloromethane (5OmIs) and added to the Dess-Martin periodinane reagent at 2O 0 C. The reaction mixture was then stirred at room temperature for 30 minutes. The reaction was monitored by tic. The reaction mixture was then diluted with diethyl ether (500 mis) to precipitate the excess reagent. The suspension was then washed with 10% aqueous sodium hydroxide (20OmIs). The upper organic layer was then washed with water (25OmIs). The upper organic layer was then separated, dried (Na 2 SO 4 ) and the solvent removed in vacuo to yield a dark flowing oil as a mixture of anomers (0.8g).
  • a Swern oxidation can be carried out as illustrated by the following example: A stirred solution of oxalyl chloride (0.037 cm 3 , 0.44 mmol) in dichloromethane (4 cm 3 ) under nitrogen was cooled to -78 "C and DMSO was added in one portion. A solution of the alcohol (100 mg, 0.40 mmol) in dichloromethane (1 cm 3 ) was added to the reaction mixture and the reaction mixture stirred at -78 0 C for 5 min. Triethylamine (0.272 cm 3 , 19.8 mmol) was added and the resulting solution was stirred at -78 ° C for 25 min and used immediately without isolation or purification. TIc r f 0.40 ethyl acetate:hexane (1 :1) orange spot with 2,4-dinitrophenylhydrazine stain
  • R 1 represents hydrogen, a protecting group or a C 1-6 alkyl group
  • R 2 represents a -C(O)CH(Me)CH 2 CH 3 or -C(O)C(Me) 2 CH 2 CH 3 group.
  • R 3 represents a -C(O)CH(Me)CH 2 CH 3 or -C(O)C(Me) 2 CH 2 CH 3 group.
  • R 4 represents a 4-fluorophenyl group
  • R 5 a Ci -6 alkyl group, and more preferably a cyclopropyl group.
  • R 6 represents a 4-fluorophenyl group
  • R 7 represents a C 1-6 alkyl group, and more preferably an isopropyl group.
  • R 8 represents a methyltetrazoyl group
  • R 9 represents a 4-fluorophenyl group
  • R 10 a 4-fluorophenyl group.
  • the substituted-ethenyl-OH-lactol methyl acetal may be obtained by reaction of the substituted-ethenyl-O-benzyl-lactol methyl acetal of Example 5(a-e) with TMSI.
  • the substituted-ethenyl-OH-lactol may be obtained by treatment of the substituted- ethenyl-OH-lactol methyl acetal of Example 6(a-e) with 0.1 N HCI in methanol.
  • the lactone may be obtained by adding the substituted-ethenyl-OH-lactol of
  • Example 7(a-e) (35mg, 0.065mmol) in dichloromethane (0.5ml) to Dess-Martin periodinane (30mg, 0,07mmol) and stirring at room temperature for 2.5 hours.
  • the reaction is partitioned between 1 M sodium hydroxide and diethyl ether. The phases are then separated and the organic volume reduced in vaccuo to afford the crude product oil.
  • Example 9 Preparation of hydroxy-acid (hydrolysis of Lactone), a compound of Formula 7
  • the lactone of Example 8(a-e) (1.1g) may be ring opened by dissolving in ethanol

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  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

There is provides a process for the preparation of a compound of formula (7): wherein R is an optionally substituted hydrocarbyl group or an optionally substituted heterocyclic group; provides that R is not a compound of Formula (a): wherein Ra represents an alkyl group, such as a C1-16 alkyl group, and preferably an isopropyl group; Rb represents an aryl group, preferably a 4-fluorophenyl group; Rc represents hydrogen, a protecting group or an alkyl group, such as a C1-16 alkyl group, and preferably a methyl group; and Rd represents hydrogen, a protecting group or a SO2Re group where Re is an alkyl group, such as a C1-16 alkyl group, and preferably a methyl group.

Description

PROCESS AND INTERMEDIATE COMPOUNDS USEFUL IN THE PREPARATION OF
STATINS
The present invention concerns a process and intermediate compounds useful in the preparation of statins.
According to the present invention there is provide a process for the preparation of a compound of formula (7):
OH OH O
R OH
(7) wherein
R is a an optionally substituted hydrocarbyl group or an optionally substituted heterocyclic group; provided that R is not a compound of Formula (a):
Figure imgf000002_0001
wherein
Ra represents an alkyl group, such as a Ci-6 alkyl group, and preferably an isopropyl group;
Rb represents an aryl group, preferably a 4-fluorophenyl group;
Rc represents hydrogen, a protecting group or an alkyl group, such as a C1-6 alkyl group, and preferably a methyl group; and
Rd represents hydrogen, a protecting group or a SO2R6 group where Re is an alkyl group, such as a Ci-6 alkyl group, and preferably a methyl group, which comprises a) hydroxylating a compound of formu
Figure imgf000002_0002
wherein Y represents a halo group, preferably Cl or Br; P1 represents hydrogen or a protecting group, and W represents =0 or -OP2, in which P2 represents hydrogen or a protecting group, to give a compound of formula (2):
Figure imgf000003_0001
b) oxidising the compound of formula (2) to give a compound of formula (3):
Figure imgf000003_0002
c) coupling the compound of formula (3) with a compound of formula (4):
wherein Z represents (PR11R12)+X" or P(=O)R11R12 in which X is an anion and R11 and R12 each independently is an alkyl, aryl, alkoxy or aryloxy group, preferably a phenyl group, to give a compound of formula (5):
Figure imgf000003_0003
d) when W represents -OP2, removing any P2 protecting group and oxidising the compound of formula (5) to give a compound of formula (6):
Figure imgf000003_0004
and e) subjecting the compound of formula (5) when W represents =0, or compound of formula (6) to ring-opening, removal of any P1 protecting groups, and optionally removing any additional protecting groups to give a compound of formula (7). In step (e), any P1 protecting groups and any additional protecting groups may be removed individually or together and prior to ring opening, during ring opening or after ring opening of the compounds of formula (5) or (6).
Preferably, there is provided a process for the preparation of a compound of formula (7):
OH OH o R-^^v^^OH
(7) wherein R is a group selected from
Figure imgf000004_0001
or
and wherein
R1 represents hydrogen, a protecting group or an optionally substituted hydrocarbyl group, preferably an alkyl group, such as a C1-6 alkyl group;
R2 represents an optionally substituted acyl group, preferably an alkanoyl group, such as C^alkanoyl group, and preferably a -C(O)CH(Me)CH2CH3 or
-C(O)C(Me)2CH2CH3 group;
R3 represents an optionally substituted acyl group, preferably an alkanoyl group, such as C1-8alkanoyl group, and preferably a -C(O)CH(Me)CH2CH3 or
-C(O)C(Me)2CH2CH3 group;
R4 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
R5 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a Ci-6 alkyl group, and more preferably a cyclopropyl group;
R6 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
R7 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a C1-6 alkyl group, and more preferably an isopropyl group;
R8 represents an optionally substituted hydrocarbyl group, or optionally substituted heterocyclic group, preferably an optionally substituted aryl or an optionally substituted aromatic heterocyclic group, more preferably a methyltetrazoyl group;
R9 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
R10 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group, which comprises a) hydroxylating a compound of formula (1):
Figure imgf000005_0001
wherein Y represents a halo group, preferably Cl or Br; P1 represents hydrogen or a protecting group, and W represents =0 or -OP2, in which P2 represents hydrogen or a protecting group, to give a compound of formula (2):
Figure imgf000005_0002
b) oxidising the compound of formula (2) to give a compound of formula (3):
Figure imgf000005_0003
c) coupling the compound of formula (3) with a compound of formula (4):
wherein Z represents :_ .
Figure imgf000005_0004
in w..Uhiic-Uh1 X v ! is,-. a .-.*n, a n-n.;i^onn
Figure imgf000005_0005
D R11 and R12 each independently is an alkyl, aryl, alkoxy or aryloxy group, preferably a phenyl group, to give a compound of formula (5):
Figure imgf000005_0006
d) when W represents -OP2, removing any P2 protecting group and oxidising the compound of formula (5) to give a compound of formula (6):
Figure imgf000005_0007
and e) subjecting the compound of formula (5) when W represents =0, or compound of formula (6) to ring-opening, removal of any P1 protecting groups, and optionally removing any additional protecting groups to give a compound of formula (7).
In step (e), any P1 protecting groups and any additional protecting groups may be removed individually or together and prior to ring opening, during ring opening or after ring opening of the compounds of formula (5) or (6). Further, compounds of formula (8):
Figure imgf000006_0001
wherein R is as defined above for R7, may be obtained by reduction of a compound of Formula (7) or, alternatively a compound of Formula (5) or (6) may be reduced to a corresponding compound of Formula (9) or (10).
Figure imgf000006_0002
(9) (10) and then the compound of formula (9) when W represents -OP2 may be converted to a compound of formula (10) by removing any P2 protecting group and oxidising the compound of formula (9) to give a compound of formula (10), and then the compound of formula (9), when W represents =0, or a compound of formula (10) may be ring-opened, any P1 protecting groups, and optionally removing any additional protecting groups to give a compound of formula (8). Any P1 protecting groups and any additional protecting groups may be removed individually or together and prior to ring opening, during ring opening or after ring opening of the compounds of formula (9) or (10).
Protecting groups which may be represented by P1 and P2 include alcohol protecting groups, examples of which are well known in the art. Particular examples include tetrahydropyranyl, benzyl and methyl groups. Preferred protecting groups are silyl groups, for example triaryl- and especially trialkylsilyl groups. Especially preferred examples are trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenyl groups.
Protecting groups which may be represented by P1 and P2 may be the same or different. When the protecting groups P1 and P2 are different, advantageously this may allow for the selective removal of only P1 or P2. Preferably, when the protecting groups P1 and P2 are different, P1 is a silyl group and P2 is a methyl group.
Protecting groups which may be represented by R1 include alcohol protecting groups, examples of which are well known in the art. Protecting groups which may be represented by Rc and Rd include amine protecting groups, examples of which are well known in the art. Particular examples include benzyl groups, carbamates (such as CBZ, Boc, Fmoc), phosphate, thiophosphate, silyl groups and, when Rc and Rd together are a single protecting group, an imine group.
Hydrocarbyl groups which may be represented by R, R1 and R3 independently include alkyl, alkenyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups.
Alkyl groups which may be represented by R, Ra, Rc, Rd, R1 and R4"10 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprising up to 10 branch chain carbon atoms, preferably up to 4 branch chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R, Ra, R°, Rd, R1 and R4-10 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups.
Alkenyl groups which may be represented by R, R1 and R4"10 include C2-2o, and preferably C2-6 alkenyl groups. One or more carbon - carbon double bonds may be present. The alkenyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkenyl groups include vinyl, styryl and indenyl groups. Aryl groups which may be represented by R, Rb, R1 and R4"10 may contain 1 ring or
2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R1, Rb and R4"10 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups. Heterocyclic groups which may be represented by R, R1 and R4"10 independently include aromatic, saturated and partially unsaturated ring systems and may constitute 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. When any of R, R1 or R4"10 represents or comprises a heterocyclic group, preferably attachment is provided through a carbon atom in the R, R1 or R4"10 group. Examples of heterocyclic groups which may be represented by R, R1 and R4"10 include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl, triazoyl and tetrazoyl groups. When any of R, R1 and R4"10 is a substituted hydrocarbyl group, the substituent(s) should be such so as not to adversely affect the rate or selectivity of any of the reaction steps or the overall process. Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di- hydrocarbylamino, hydrocarbylthio, esters, carbamates, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R1 above. One or more substituents may be present. Examples of R1 and R4'10 groups having more than one substituent present include -CF3 and -C2F5.
Hyrdoxylation of compounds of formula (1) can be achieved by methods known in the art for displacing a halo group with a hydroxide source. Preferably, the process comprises contacting the compound of formula (1) with a source of hydroxide. Hydroxide sources include hydroxide salts, especially ammonium or alkali metal hydroxides, particularly lithium, sodium or potassium hydroxide, and various aqueous media such as water in the presence of basic media such as N-methylpryrrolidinone, HMPA, AI2O3, CaCO3, Na2CO3, K2CO3 or K02/18-crown-6, silver salts such as AgNO3 or Ag2O, or oxidants such perbenzioc acid. A particularly preferred process comprises contacting the compound of formula (1) with 5 molar equivalents of KOH in the presence of dimethylsulfoxide solvent at a temperature of, for example, about 500C.
Alternatively, hydroxylation may be achieved by first displacing the halogen with a leaving group such as acetate, triflate or sulphate optionally in the presence of a silver salt, then displacing the leaving group with a hydroxide source. A particularly preferred process comprises contacting the compound of formula (1) with 3 molar equivalents of NaOAc in the presence of dimethylformamide solvent and tetra-n-butylammonium chloride at a temperature of, for example, about 100°C, isolating the acetyl compound and contacting with potassium carbonate in the presence of methanol solvent and at a temperature of, for example, about O0C.
Oxidation of compounds of formula (2) can be achieved using oxidation systems known in the art for the oxidation of alcohols, especially those known in the art for the oxidation of primary alcohols. Examples include oxidation with Dess-Martin periodinane, bromine, Swern oxidation or various metal based oxidations such as Fetizon reagent, manganate based reagents, and chromate based reagents such as Collins reagent. Swern oxidation is preferred. When Swern oxidation is employed, preferred conditions comprise the use of dimethyl sulphoxide and oxalyl chloride or bromine in a solvent such as dichloromethane or dichlormethane/THF mixtres, at reduced temperature, such as from O to -100°C, preferably -50 to -80°C. Preferably, reagents are added at reduced temperature, such as -30 to -800C, and then once all reagents are added, the reaction mixture is allowed to warm to 15 to 200C.
The coupling of the compound of formula (3) with the compound of formula (4) may employ conditions analogous to those given in Bull. Chem. Soc. Japan 1995, 68, 364-372, Tet. Lett. 1992, 33(49), 7525-75226, Tetrahedron 1997, 53(31) 10659-10670 and WO01/85702. The conditions preferably comprise reacting the compounds of formula (3) and (4) in a hydrocarbon solvent, such as THF, toluene or cyclohexane, or mixtures thereof, optionally in the presence of a base, followed by contact with aqueous acid, such as aqueous HCI. Alkyl, aryl, alkoxy or aryloxy groups which may be represented by R11 and R12 include C1-6alkyl groups, such as methyl and ethyl groups, C6-i2aryl groups, such phenyl, tolyl or naphthyl, C1-6alkoy groups, such as ethoxy groups, and C6-i2aryloxy groups such as phenoxy groups.
Anions which may be represented by X include halide. Z preferably is P(=O)R11R12 where R7 and R8 each independently is an alkyl, aryl, alkoxy or aryloxy group, preferably a phenyl group.
When W represents OP2, the protecting group may be removed to form a hydroxy group by methods known in the art for the removal of the given protecting group. For example, silyl protecting groups may be removed by contact with a source of fluoride ion, such as tetrabutylammonium fluoride.
Oxidation of compounds formed by deprotection of compounds wherein W represents -OP2 may employ conditions known in the art for the oxidation of pyranols to pyranones, and include those given in "Comprehensive Organic Transformations", R. C. Larock, 2nd Ed (1999) p 1670, published by Wiley VCH, incorporated herein by reference. Preferred oxidation systems include Ag2CO3/Celite, especially Celite J2, bromine or Swern.
Ring opening of the compounds of formula (5), when W represent =0 or formula
(6) may employ conditions known in the art for ring opening of a pyranone. Preferably, the ring is opened by contact with a base, such as sodium hydroxide. Conveniently, polar solvents are employed, for example methanol, acetonitrile, tetrahydrofuran or mixtures thereof.
Remaining protecting groups may be removed by methods known in the art for the removal of the given protecting group. For example, silyl protecting groups may be removed by contact with a source of fluoride ion, such as tetrabutylammonium fluoride.
It will also be recognised that compounds of formulae (2), (3) and (5) may also be subjected to oxidation (when W represents -OH) or deprotection and oxidation (when W represents (-O-protecting group) to form the corresponding compound wherein W represents =0. Reduction of the compounds of formula (5), (6) or (7) may employ conditions known in the art for the reduction of double bonds. For example, hydrogenation using hydrogen gas in the present of transition metals or transition metal catalysts such as hydrogen in the presence of group VIII metal or metal catalyst, especially Ru, Rh, Pd, Ir or Pt metals or metal based catalysts. Preferred compounds of formula (1) are compounds of formula:
Figure imgf000009_0001
wherein W, P1 and Y are as previously described. Preferred compounds of formula (2) are compounds of formula:
Figure imgf000009_0002
wherein W and P1 are as previously described.
Preferred compounds of formula (3) are compounds of formula:
Figure imgf000010_0001
wherein W and P1 are as previously described. Preferred compounds of formula (5) are of formula:
Figure imgf000010_0002
wherein R1, R2, W and P1 are as previously described. Preferred compounds of formula (6) are of formula:
Figure imgf000010_0003
wherein R1 and R2 are as previously described.
Preferred compounds of formula (7) are of formula:
OH OH O
wherein R1 and R2 are as previously described.
Compounds of formula (7) are advantageously converted to pharmaceutically acceptable salts, especially their calcium salts.
Compounds of formula (4) are advantageously prepared by analogy to the methods given in Bull. Chem. Soc. Japan 1995, 68, 364-372, Tet. Lett. 1992, 33(49), 7525-75226, Tetrahedron 1997, 53(31) 10659-10670, WO00/49014 and WO01/85702. Particularly preferred compounds of formula (4) are compounds of formula:
Figure imgf000010_0004
Compounds of formula (1 ) are advantageously prepared by enzyme catalysed condensation of acetaldehyde and 2-haloacetaldehyde, for example using the method given in US patent 5,795,749.
Compounds of formula (5) and (9) when W is OP2 are further aspects of the present invention.
The invention is illustrated by the following examples. Example 1 - Preparation of Chlorolactol methyl acetal ((2S,4R)-2-(chloromethyl)-6- methoxytetrahydro-2H-pyran-4-ol), a compound of Formula 1 where Y = Cl, P1 = H and W = -OP2, in which P2 = Me.
Crude chlorolactol (15g) was dissolved in methanol (150ml) and heated to 4O0C for 2 hours in the presence of 0.1ml sulphuric acid. The solvent was removed by rotary evaporation to afford the product as a dark brown flowing oil. The product was dissolved in DCM and washed with sodium bicarbonate solution. The solvent was removed by rotary evaporation to afford the product as a dark brown flowing oil, which was purified by column chromatography (16.1g) containing a mixture of anomers m/z 179, 149 and 113; 1H nmr CDCI3 3.6-3.7 (m 2H), 4.1 (m 1 H), 1.5-1.6 (m 2H), 4.0 (m 1 H), 1.3-1.6 (m 2H), 4.9
(m 1 H), 3.3 & 3.5 (s 3H); 13C nmr CDCI3 32, 36, 45, 55&56, 64, 65, 94.
Example 2 - Preparation of O-benzyl-chlorolactol methyl acetal ((2S,4R)-4- (benzyloxy)-2-(chloromethyl)-6-methoxytetrahydro-2H-pyran), a compound of Formula 1 where Y = Cl, P1 = Bn and W = -OP2, in which P2 = Me.
Chlorolactol methyl acetal (1g) was dissolved in THF (5ml) and charged to sodium hydride (0.33g 60% in mineral oil) in THF (5ml) at room temperature. Benzyl bromide (1.9g) was added dropwise and the mass heated to 8O0C for 2 hours. Methanol (2ml) was added and the mass was partitioned between DCM/ water, and was then washed with water. The organic phase was dried and the solvent was removed by rotary evaporation to afford an orange flowing oil (2.1g), containing a mixture of anomers containing a mixture of anomers. m/z 270; 238; 203; 132; 91 ; 1H nmr CDCI3 1.6-2.0 (m 4H), 3.4 & 3.5 (s 3H), 3.6 (m 2H), 3.8 (m 1 H), 4.0 (m 1 H), 4.5 (m 2H), 4.7 (m 1 H), 7.3-7.5 (m 5H); 13C nmr CDCI3 32&33, 46, 55&56, 58, 66, 74, 96&98, 128-131.
Example 3 - Preparation of Hydroxy-O-benzyl-lactol methyl acetal ([(2R,4R)-4- (benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl]methanol), a compound of Formula 2 where P1 - Bn and W = -OP2, in which P2 = Me.
Preparation of the Acetate Intermediate:
To a 3-litre three necked round bottomed flask flushed with dry nitrogen the O- benzyl-chlorolactol methyl acetal (3Og) was charged into dry N-methyl pyrollidinone
(756mls). Anhydrous tetrabutylammonium acetate (102.57g) was also charged to the solution. The reaction mixture was then heated at 1000C for 24 hours. The reaction mixture was sampled at routine intervals and directly analysed by tic and gc/ms.
The black solution was then diluted with water (15OmIs) and extracted with ethyl acetate (3 x 150OmIs). The combined upper organic layer was then washed with water (3 x 150OmIs). The aqueous portion showed no product content at this point. The layers were then separated, dried, (Na2SO4) and the solvent removed in vacuo to yield a black flowing oil (31 g, 95%) containing a mixture of anomers. 1H nmr CDCI31.4-1.8 (m 4H), 2.0- 2.1 ( duplicate s, 3H), 3.4 & 3.5 (s 3H), 3.8 (m 1 H), 4.0 (m 1 H), 4.1 (m 2H), 4.5 (m, 2H), 4.7-4.9 (m 1 H), 7.2-7.3 (m, 5H); 13C nmr CDCI3 20.8; 30-35; 55&56; 57&64; 66&68; 69&72; 70&71 ; 98&99; 127-128 & 138; 170.5; m/z 293, 262, 221 , 203, 156, 91 and 43.
Preparation of the Alcohol from the Acetate Intermediate:
To a 5OmIs three necked round bottomed flask flushed with dry nitrogen the O- benzyl-chlorolactol methyl acetal acetate (2g) was charged into dry methanol (1OmIs) containing anhydrous potassium carbonate (1g). The resultant suspension was stirred at 2O0C for 30 minutes. G.C./M.S. showed complete conversion of acetate to alcohol. The solid was filtered off and the solvent removed in vacuo to yield a brown flowing oil containing a mixture of anomers (1.6g, 93%). 1H nmr CDCI3 1.4-1.8 (m 4H), 3.4 & 3.5 (s 3H), 3.8 (m 1 H), 3.9 (m 1 H), 4.0 (m 2H), 4.5 (m 2H), 4.7-4.9 (m 1 H), 7.2-7.3 (m, 5H); 13C nmr CDCI3 30-38; 55&56; 65&66; 65&69; 70&71 ; 72&73; 99&100; 128 & 140; m/z 252, 221 , 189, 163, 114 and 91.
Example 4 - Preparation of formyl-O-benzyl-lactol methyl acetal (2S,4R)-4« (benzyloxy)-6-methoxytetrahydro-2H-pyran-2-carbaldehyde a compound of Formula 3 where P1 = Bn and W = -OP2, in which P2 = Me. Dess-Martin periodinane reagent (1.91g) in dichloromethane (5OmIs) was charged to a 1000 mis round bottomed flask purged with dry nitrogen. The hydroxy-O-benzyl- lactol methyl acetal (1.Og1) was dissolved in dichloromethane (5OmIs) and added to the Dess-Martin periodinane reagent at 2O0C. The reaction mixture was then stirred at room temperature for 30 minutes. The reaction was monitored by tic. The reaction mixture was then diluted with diethyl ether (500 mis) to precipitate the excess reagent. The suspension was then washed with 10% aqueous sodium hydroxide (20OmIs). The upper organic layer was then washed with water (25OmIs). The upper organic layer was then separated, dried (Na2SO4) and the solvent removed in vacuo to yield a dark flowing oil as a mixture of anomers (0.8g).
1H nmr CDCI3 1.6-1.9 (m 4H), 3.3 & 3.5 (s 3H), 3.7 (m 1 H), 3.8 (m 1 H), 4.4 (m 2H), 4.7-4.9 (m 1 H), 7.2-8.1 (m, 5H), 9.6-9.7 (2 x s, 1 H).
13C nmr CDCI3 30-38; 55&56; 65&66; 65&69; 70&71 ; 99&100; 128 & 140; 201.
m/z 250, 221, 189, 163, 143, 117 and 91.
Alternatively, a Swern oxidation can be carried out as illustrated by the following example: A stirred solution of oxalyl chloride (0.037 cm3, 0.44 mmol) in dichloromethane (4 cm3) under nitrogen was cooled to -78 "C and DMSO was added in one portion. A solution of the alcohol (100 mg, 0.40 mmol) in dichloromethane (1 cm3) was added to the reaction mixture and the reaction mixture stirred at -78 0C for 5 min. Triethylamine (0.272 cm3, 19.8 mmol) was added and the resulting solution was stirred at -78 °C for 25 min and used immediately without isolation or purification. TIc rf 0.40 ethyl acetate:hexane (1 :1) orange spot with 2,4-dinitrophenylhydrazine stain
Example 5 - Preparation of a compound of Formula 5 where P1 = Bz and W = -OP2, in which P2 = Me.
The compound of Formula 5 may be obtained by first dissolving 0.21 g of the compound of formula 4 wherein Z=PO(Ph)2 in 10ml dry THF, cooling to -600C and then adding 0.2ml of a 2M solution of sodium hexamethyldisilazide. After 20min, a solution of 0.1g formyl-O-benzyl-lactol methyl acetal in 10ml dry THF at -300C is added. The reaction mixture is then maintained at this temperature for 8 hours and monitored by tic. The reaction mixture is allowed to slowly warm up to 2O0C. Glacial acetic (5mls) acid is then charged to quench the reaction. Water (5mls) is also charged to the mixture. The solvent is then removed in vacuo and reconstituted with toluene (15mls) and water (15mls). The upper organic layer is then separated and the aqueous layer is then washed with ethyl acetate (15 mis). The combined organics are then dried and the solvent removed in vacuo to yield an oil containing a mixture of isomers, that can be purified by chromatography. Example 5a, R is
Figure imgf000013_0001
wherein R1 represents hydrogen, a protecting group or a C1-6 alkyl group; and R2 represents a -C(O)CH(Me)CH2CH3 or -C(O)C(Me)2CH2CH3 group.
Example 5b, R is
Figure imgf000014_0001
wherein R3 represents a -C(O)CH(Me)CH2CH3 or -C(O)C(Me)2CH2CH3 group.
Example 5c, R is
Figure imgf000014_0002
wherein R4 represents a 4-fluorophenyl group; and R5 a Ci-6 alkyl group, and more preferably a cyclopropyl group.
Example 5d, R is
Figure imgf000014_0003
wherein R6 represents a 4-fluorophenyl group; and R7 represents a C1-6 alkyl group, and more preferably an isopropyl group.
Example 5e, R is
Figure imgf000014_0004
wherein R8 represents a methyltetrazoyl group; R9 represents a 4-fluorophenyl group; and R10 a 4-fluorophenyl group.
Example 6 - Preparation of a compound of Formula 5 where P1 = H and W = -OP2, in which P2 = Me.
The substituted-ethenyl-OH-lactol methyl acetal may be obtained by reaction of the substituted-ethenyl-O-benzyl-lactol methyl acetal of Example 5(a-e) with TMSI. Example 7 - Preparation of a compound of Formula 5 where P1 = H and W = -OP2, in which P2 = H
The substituted-ethenyl-OH-lactol may be obtained by treatment of the substituted- ethenyl-OH-lactol methyl acetal of Example 6(a-e) with 0.1 N HCI in methanol.
Example 8 - Preparation of Lactone, a compound of Formula 6 where P1=H
The lactone may be obtained by adding the substituted-ethenyl-OH-lactol of
Example 7(a-e) (35mg, 0.065mmol) in dichloromethane (0.5ml) to Dess-Martin periodinane (30mg, 0,07mmol) and stirring at room temperature for 2.5 hours. The reaction is partitioned between 1 M sodium hydroxide and diethyl ether. The phases are then separated and the organic volume reduced in vaccuo to afford the crude product oil.
Example 9 - Preparation of hydroxy-acid (hydrolysis of Lactone), a compound of Formula 7 The lactone of Example 8(a-e) (1.1g) may be ring opened by dissolving in ethanol
(10ml), addition of water (2ml) and Ca(OH)2 (0.15g) and warming the suspension to 6O0C for 3 hours. A further 10ml of warm water is added, before the mixture is allowed to cool slowly to room temperature. The precipitate formed is filtered and dried to give the calcium salt of the hydroxy-acid. The material was identical to an authentic sample by mixed melting point, NMR and mass spectrometry.

Claims

1. A process for the preparation of a compound of formula (7):
OH OH O
(7) wherein
R is a an optionally substituted hydrocarbyl group or an optionally substituted heterocyclic group; provided that R is not a compound of Formula (a):
Figure imgf000016_0001
wherein
Ra represents an alkyl group, such as a C1-6 alkyl group, and preferably an isopropyl group;
Rb represents an aryl group, preferably a 4-fluorophenyl group;
Rc represents hydrogen, a protecting group or an alkyl group, such as a C1-6 alkyl group, and preferably a methyl group; and
Rd represents hydrogen, a protecting group or a SO2R8 group where Re is an alkyl group, such as a C1-6 alkyl group, and preferably a methyl group, which comprises a) hydroxylating a compound of formula (1):
Figure imgf000016_0002
wherein Y represents a halo group, preferably Cl or Br; P1 represents hydrogen or a protecting group, and W represents =0 or -OP2, in which P2 represents hydrogen or a protecting group, to give a compound of formula (2):
Figure imgf000016_0003
b) oxidising the compound of formula (2) to give a compound of formula (3):
Figure imgf000017_0001
c) coupling the compound of formula (3) with a compound of formula (4):
wherein Z represents (PR11R12)+X' or P(=O)R11R12 in which X is an anion and R11 and R12 each independently is an alkyl, aryl, alkoxy or aryloxy group, preferably a phenyl group, to give a compound of formula (5):
Figure imgf000017_0002
d) when W represents -OP2, removing any P2 protecting group and oxidising the compound of formula (5) to give a compound of formula (6):
Figure imgf000017_0003
and e) subjecting the compound of formula (5) when W represents =O, or compound of formula (6) to ring-opening, removal of any P1 protecting groups, and optionally removing any additional protecting groups to give a compound of formula (7).
2. A process for the preparation of a compound of formula (7):
Figure imgf000017_0004
(7) wherein R is a group selected from
Figure imgf000017_0005
Figure imgf000018_0001
and wherein
R1 represents hydrogen, a protecting group or an optionally substituted hydrocarbyl group, preferably an alkyl group, such as a C1-6 alkyl group;
R2 represents an optionally substituted acyl group, preferably an alkanoyl group, such as Ci-8alkanoyl group, and preferably a -C(O)CH(Me)CH2CH3 or
-C(O)C(Me)2CH2CH3 group;
R3 represents an optionally substituted acyl group, preferably an alkanoyl group, such as
Figure imgf000018_0002
group, and preferably a -C(O)CH(Me)CH2CH3 or
-C(O)C(Me)2CH2CH3 group;
R4 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
R5 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a Ci-6 alkyl group, and more preferably a cyclopropyl group;
R6 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
R7 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a C1-6 alkyl group, and more preferably an isopropyl group;
R8 represents an optionally substituted hydrocarbyl group, or optionally substituted heterocyclic group, preferably an optionally substituted aryl or an optionally substituted aromatic heterocyclic group, more preferably a methyltetrazoyl group; R9 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
R10 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group, which comprises a) hydroxylating a compound of formula (1 ):
Figure imgf000018_0003
wherein Y represents a halo group, preferably Cl or Br; P1 represents hydrogen or a protecting group, and W represents =0 or -OP2, in which P2 represents hydrogen or a protecting group, to give a compound of formula (2):
Figure imgf000019_0001
b) oxidising the compound of formula (2) to give a compound of formula (3):
Figure imgf000019_0002
c) coupling the compound of formula (3) with a compound of formula (4):
wherein Z represents (PR11R12)+X" or P(=O)R11R12 in which X is an anion and R11 and R12 each independently is an alkyl, aryl, alkoxy or aryloxy group, preferably a phenyl group, to give a compound of formula (5):
Figure imgf000019_0003
d) when W represents -OP2, removing any P2 protecting group and oxidising the compound of formula (5) to give a compound of formula (6):
Figure imgf000019_0004
and e) subjecting the compound of formula (5) when W represents =0, or compound of formula (6) to ring-opening, removal of any P1 protecting groups, and optionally removing any additional protecting groups to give a compound of formula (7).
3. A process for the preparation of a compound of Formula (8) wherein either: (i) a compound of Formula (7), prepared according to Claim 1 or 2, is hydrogenated to give a compound of formula (8), or
(ii) a compound of formula (5) or (6), prepared according to steps (a) to (c) or (a) to (d) of Claim 1 or 2, is hydrogentated to give a compound of formula (9) or (10)
Figure imgf000020_0001
(9) (10) and then, when W represents -OP2, removing any P2 protecting group and oxidising the compound of formula (9) to give a compound of formula (10); and subjecting the compound of formula (9) when W represents =0, or compound of formula (10) to ring-opening, removal of any P1 protecting groups, and optionally removing any additional protecting groups to give a compound of formula (8).
4. A process for the preparation of a compound of formula (5):
Figure imgf000020_0002
which comprises coupling the compound of formula (3):
Figure imgf000020_0003
with a compound of formula (4):
R^^z wherein
R is a an optionally substituted hydrocarbyl group or an optionally substituted heterocyclic group;
Z represents (PR11R12)+X" or P(=O)R11R12 in which X is an anion and R11 and R12 each independently is an alkyl, aryl, alkoxy or aryloxy group, preferably a phenyl group;
P2 represents hydrogen or a protecting group; and
W represents =0 or -OP2, in which P2 represents hydrogen or a protecting group; provided that R is not a compound of Formula (a):
Figure imgf000020_0004
wherein
Ra represents an alkyl group, such as a C1-6 alkyl group, and preferably an isopropyl group;
Rb represents an aryl group, preferably a 4-fluorophenyl group;
Rc represents hydrogen, a protecting group or an alkyl group, such as a C1-6 alkyl group, and preferably a methyl group; and
Rd represents hydrogen, a protecting group or a SO2Re group where Re is an alkyl group, such as a Ci-6 alkyl group, and preferably a methyl group.
5. A process for the preparation of a compound of formula (5):
Figure imgf000021_0001
which comprises coupling the compound of formula (3):
Figure imgf000021_0002
with a compound of formula (4):
R ^z wherein R is a group selected from
Figure imgf000021_0003
and wherein
R1 represents hydrogen, a protecting group or an optionally substituted hydrocarbyl group, preferably an alkyl group, such as a C1-6 alkyl group;
R2 represents an optionally substituted acyl group, preferably an alkanoyl group, such as C1-8alkanoyl group, and preferably a -C(O)CH(Me)CH2CH3 or -C(O)C(Me)2CH2CH3 group;
R3 represents an optionally substituted acyl group, preferably an alkanoyl group, such as C1-8alkanoyl group, and preferably a -C(O)CH(Me)CH2CH3 or
-C(O)C(Me)2CH2CH3 group; R4 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
R5 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a C1-6 alkyl group, and more preferably a cyclopropyl group; R6 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
R7 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a Ci-6 alkyl group, and more preferably an isopropyl group; R8 represents an optionally substituted hydrocarbyl group, or optionally substituted heterocyclic group, preferably an optionally substituted aryl or an optionally substituted aromatic heterocyclic group, more preferably a methyltetrazoyl group;
R9 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group; R10 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
Z represents (PR11R12)+X" or P(=O)R11R12 in which X is an anion and R11 and R12 each independently is an alkyl, aryl, alkoxy or aryloxy group, preferably a phenyl group; P2 represents hydrogen or a protecting group; and
W represents =0 or -OP2, in which P2 represents hydrogen or a protecting group.
6. A compound of formula (5) or (9):
Figure imgf000022_0001
(5) (9) wherein
R is a an optionally substituted hydrocarbyl group or an optionally substituted heterocyclic group;
Z represents (PR11R12)+X" or P(=O)R11R12 in which X is an anion and R11 and R12 each independently is an alkyl, aryl, alkoxy or aryloxy group, preferably a phenyl group; P2 represents hydrogen or a protecting group; and
W represents =0 or -OP2, in which P2 represents hydrogen or a protecting group; provided that R is not a compound of Formula (a):
Figure imgf000023_0001
wherein
Ra represents an alkyl group, such as a Ci-6 alkyl group, and preferably an isopropyl group;
Rb represents an aryl group, preferably a 4-fluorophenyl group;
Rc represents hydrogen, a protecting group or an alkyl group, such as a C1-6 alkyl group, and preferably a methyl group; and
Rd represents hydrogen, a protecting group or a SO2R6 group where Re is an alkyl group, such as a Ci-6 alkyl group, and preferably a methyl group.
7. A compound of formula (5) or (9):
Figure imgf000023_0002
wherein
R is a group selected from
Figure imgf000023_0003
and wherein R1 represents hydrogen, a protecting group or an optionally substituted hydrocarbyl group, preferably an alkyl group, such as a C1-6 alkyl group;
R2 represents an optionally substituted acyl group, preferably an alkanoyl group, such as C1-8alkanoyl group, and preferably a -C(O)CH(Me)CH2CH3 or -C(O)C(Me)2CH2CH3 group;
R3 represents an optionally substituted acyl group, preferably an alkanoyl group, such as Ci-8alkanoyl group, and preferably a -C(O)CH(Me)CH2CH3 or
-C(O)C(Me)2CH2CH3 group;
R4 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
R5 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a C1-6 alkyl group, and more preferably a cyclopropyl group;
R6 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
R7 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a C1-6 alkyl group, and more preferably an isopropyl group;
R8 represents an optionally substituted hydrocarbyl group, or optionally substituted heterocyclic group, preferably an optionally substituted aryl or an optionally substituted aromatic heterocyclic group, more preferably a methyltetrazoyl group;
R9 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
R10 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4-fluorophenyl group;
Z represents (PR11R12pC or P(=O)R11R12 in which X is an anion and R11 and R12 each independently is an alkyl, aryl, alkoxy or aryloxy group, preferably a phenyl group;
P2 represents hydrogen or a protecting group; and W represents =0 or -OP2, in which P2 represents hydrogen or a protecting group.
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