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Title:
PROCESS AND INTERMEDIATE COMPOUNDS USEFUL IN THE PREPARATION OF STATINS
Document Type and Number:
WIPO Patent Application WO/2006/064179
Kind Code:
A1
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.

Inventors:
MOODY DAVID JOHN (GB)
WIFFEN JONATHAN WILLIAM (GB)
Application Number:
PCT/GB2005/004541
Publication Date:
June 22, 2006
Filing Date:
November 28, 2005
Export Citation:
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Assignee:
AVECIA PHARMACEUTICALS LTD (GB)
MOODY DAVID JOHN (GB)
WIFFEN JONATHAN WILLIAM (GB)
International Classes:
C07C51/09; C07C61/29; C07C67/28; C07C69/30; C07D209/12; C07D209/18; C07D215/14; C07D257/04; C07D309/10; C07D405/06
Domestic Patent References:
WO2005079790A12005-09-01
WO2005030758A12005-04-07
WO2005092867A22005-10-06
Foreign References:
US4677211A1987-06-30
US4625039A1986-11-25
US4474971A1984-10-02
US4677211A1987-06-30
US4625039A1986-11-25
US4474971A1984-10-02
Other References:
WADE, PETER A. ET AL: "A Useful Route to Optically Active 4-Oxygenated 4,5-Dihydroisoxazoles", JOURNAL OF ORGANIC CHEMISTRY , 59(24), 7199-200 CODEN: JOCEAH; ISSN: 0022-3263, 1994, XP002365605
SAWAMURA, MASAYA ET AL: "Conversion of alkyl halides into alcohols using a near stoichiometric amount of molecular oxygen. An efficient route to 18O- and 17O-labeled alcohols", SYNLETT , (7), 801-802 CODEN: SYNLES; ISSN: 0936-5214, 1997, XP002365606
ROSEN T ET AL: "SYNTHETIC AND BIOLOGICAL STUDIES OF COMPACTIN AND RELATED COMPOUNDSSYNTHESIS OF THE LACTONE MOIETY OF COMPACTIN", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 49, 19 October 1994 (1994-10-19), pages 3994 - 4003, XP000996454, ISSN: 0022-3263
BECK G ET AL: "Synthesis and Biological Activity of New HMG-CoA Reductase Inhibitors. 1. Lactones of Pyridine- and Pyrimidine-Substituted 3,5-Dihydroxy-6-heptenoic (-heptanoic) Acids", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 33, no. 1, 1990, pages 52 - 60, XP002324910, ISSN: 0022-2623
BARTH M ET AL: "TOWARDS A NEW TYPE OF HMG-COA REDUCTASE INHIBITOR", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 46, no. 19, 1990, pages 6731 - 6740, XP000942264, ISSN: 0040-4020
WADE ET AL.: "A Useful Route to Optically Active 4-Oxygenated 4,5-Dihydroisoxazoles", J. ORG. CHEM., vol. 59, 1994, pages 7199 - 7200
SAWAMURA: "Conversion of Alkyl Halides into Alcohols Using a Near Stoichiometric Amount of Molecular Oxygen: An Efficient Route to 18O- and 170-Labelled Alcohols", SYNLETT, 1997, pages 801 - 802
ROSEN ET AL.: "Synthetic and Biological Studies of Compactin and Related Compounds. 2. Synthesis of the Lactone Moiety of Compactin", J. ORG. CHEM., vol. 49, 1984, pages 3994 - 4003
BECK ET AL.: "Synthesis and Biological Activity of New HMG-CoA Reductase Inhibitors. 1. Lactones of Pyridine- and Pyrimidine-Substituted 3,5-Dihydroxy-6-heptenoic (-heptanoic) Acids", J. MED. CHEM., vol. 33, 1990, pages 52 - 60
BARTH ET AL.: "Towards a New Type of HMG-CoA Reductase Inhibitor", TETRAHEDRON, vol. 46, no. 19, 1990, pages 6731 - 6740
Attorney, Agent or Firm:
Atkinson, Jonathan D. M. (Tower North Central Merrion Way, Leeds LS2 8pa, GB)
Download PDF:
Claims:
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): wherein Ra represents an alkyl group, such as a C16 alkyl group, and preferably an isopropyl group; Rb represents an aryl group, preferably a 4fluorophenyl group; Rc represents hydrogen, a protecting group or an alkyl group, such as a C16 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 C16 alkyl group, and preferably a methyl group, which comprises a) hydroxylating a compound of formula (1): 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): b) oxidising the compound of formula (2) to give a compound of formula (3): 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): d) when W represents OP2, removing any P2 protecting group and oxidising the compound of formula (5) to give a compound of formula (6): and e) subjecting the compound of formula (5) when W represents =O, or compound of formula (6) to ringopening, 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): (7) wherein R is a group selected from and wherein R1 represents hydrogen, a protecting group or an optionally substituted hydrocarbyl group, preferably an alkyl group, such as a C16 alkyl group; R2 represents an optionally substituted acyl group, preferably an alkanoyl group, such as Ci8alkanoyl 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 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 4fluorophenyl group; R5 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a Ci6 alkyl group, and more preferably a cyclopropyl group; R6 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4fluorophenyl group; R7 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a C16 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 4fluorophenyl group; R10 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4fluorophenyl group, which comprises a) hydroxylating a compound of formula (1 ): 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): b) oxidising the compound of formula (2) to give a compound of formula (3): 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): d) when W represents OP2, removing any P2 protecting group and oxidising the compound of formula (5) to give a compound of formula (6): and e) subjecting the compound of formula (5) when W represents =0, or compound of formula (6) to ringopening, 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) (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 ringopening, 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): which comprises coupling the compound of formula (3): 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): wherein Ra represents an alkyl group, such as a C16 alkyl group, and preferably an isopropyl group; Rb represents an aryl group, preferably a 4fluorophenyl group; Rc represents hydrogen, a protecting group or an alkyl group, such as a C16 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 Ci6 alkyl group, and preferably a methyl group.
5. A process for the preparation of a compound of formula (5): which comprises coupling the compound of formula (3): with a compound of formula (4): R ^z wherein R is a group selected from and wherein R1 represents hydrogen, a protecting group or an optionally substituted hydrocarbyl group, preferably an alkyl group, such as a C16 alkyl group; R2 represents an optionally substituted acyl group, preferably an alkanoyl group, such as C18alkanoyl 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 C18alkanoyl 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 4fluorophenyl group; R5 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a C16 alkyl group, and more preferably a cyclopropyl group; R6 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4fluorophenyl group; R7 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a Ci6 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 4fluorophenyl group; R10 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4fluorophenyl 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): (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): wherein Ra represents an alkyl group, such as a Ci6 alkyl group, and preferably an isopropyl group; Rb represents an aryl group, preferably a 4fluorophenyl group; Rc represents hydrogen, a protecting group or an alkyl group, such as a C16 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 Ci6 alkyl group, and preferably a methyl group.
7. A compound of formula (5) or (9): wherein R is a group selected from and wherein R1 represents hydrogen, a protecting group or an optionally substituted hydrocarbyl group, preferably an alkyl group, such as a C16 alkyl group; R2 represents an optionally substituted acyl group, preferably an alkanoyl group, such as C18alkanoyl 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 Ci8alkanoyl 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 4fluorophenyl group; R5 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a C16 alkyl group, and more preferably a cyclopropyl group; R6 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4fluorophenyl group; R7 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted alkyl group, such as a C16 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 4fluorophenyl group; R10 represents an optionally substituted hydrocarbyl group, preferably an optionally substituted aryl group, more preferably a 4fluorophenyl 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.
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):

wherein

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; and

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

wherein Y represents a halo group, preferably Cl or Br; P 1 represents hydrogen or a protecting group, and W represents =0 or -OP 2 , in which P 2 represents hydrogen or a protecting group, to give a compound of formula (2):

b) oxidising the compound of formula (2) to give a compound of formula (3):

c) coupling the compound of formula (3) with a compound of formula (4):

wherein Z represents (PR 11 R 12 ) + X " or P(=O)R 11 R 12 in which X is an anion and R 11 and R 12 each independently is an alkyl, aryl, alkoxy or aryloxy group, preferably a phenyl group, to give a compound of formula (5):

d) when W represents -OP 2 , removing any P 2 protecting group and oxidising the compound of formula (5) to give a compound of formula (6):

and e) subjecting the compound of formula (5) when W represents =0, or compound of formula (6) to ring-opening, removal of any P 1 protecting groups, and optionally removing any additional protecting groups to give a compound of formula (7). In step (e), 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).

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

or

and wherein

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

-C(O)C(Me) 2 CH 2 CH 3 group;

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

-C(O)C(Me) 2 CH 2 CH 3 group;

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):

wherein Y represents a halo group, preferably Cl or Br; P 1 represents hydrogen or a protecting group, and W represents =0 or -OP 2 , in which P 2 represents hydrogen or a protecting group, to give a compound of formula (2):

b) oxidising the compound of formula (2) to give a compound of formula (3):

c) coupling the compound of formula (3) with a compound of formula (4):

wherein Z represents :_ . in w..Uhiic-Uh 1 X v ! is,-. a .-.*n, a n -n.;i^o n n D 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):

d) when W represents -OP 2 , removing any P 2 protecting group and oxidising the compound of formula (5) to give a compound of formula (6):

and e) subjecting the compound of formula (5) when W represents =0, or compound of formula (6) to ring-opening, removal of any P 1 protecting groups, and optionally removing any additional protecting groups to give a compound of formula (7).

In step (e), 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). Further, compounds of formula (8):

wherein 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).

(9) (10) and then the compound of formula (9) when W represents -OP 2 may be converted to a compound of formula (10) by removing any P 2 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 P 1 protecting groups, and optionally removing any additional protecting groups to give a compound of formula (8). 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 . Preferably, when the protecting groups P 1 and P 2 are different, 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. Examples of 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

2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of 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. When any of 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. Examples of 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. When any of 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. 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, 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.

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 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. 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 -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.

Z preferably is P(=O)R 11 R 12 where R 7 and R 8 each independently is an alkyl, aryl, alkoxy or aryloxy group, preferably a phenyl group.

When W represents OP 2 , 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 -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.

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:

wherein W, P 1 and Y are as previously described. Preferred compounds of formula (2) are compounds of formula:

wherein W and P 1 are as previously described.

Preferred compounds of formula (3) are compounds of formula:

wherein W and P 1 are as previously described. Preferred compounds of formula (5) are of formula:

wherein R 1 , R 2 , W and P 1 are as previously described. Preferred compounds of formula (6) are of formula:

wherein R 1 and R 2 are as previously described.

Preferred compounds of formula (7) are of formula:

OH OH O

wherein R 1 and R 2 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:

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 OP 2 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, P 1 = H and W = -OP 2 , in which P 2 = Me.

Crude chlorolactol (15g) was dissolved in methanol (150ml) and heated to 4O 0 C 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; 1 H nmr CDCI 3 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); 13 C nmr CDCI 3 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, P 1 = Bn and W = -OP 2 , in which P 2 = 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 8O 0 C 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 ; 1 H nmr CDCI 3 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); 13 C nmr CDCI 3 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 P 1 - Bn and W = -OP 2 , in which P 2 = 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 100 0 C 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, (Na 2 SO 4 ) and the solvent removed in vacuo to yield a black

flowing oil (31 g, 95%) containing a mixture of anomers. 1 H 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.

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 2O 0 C 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%). 1 H 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.

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 P 1 = Bn and W = -OP 2 , in which P 2 = 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.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).

1 H nmr CDCI 3 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).

13 C nmr CDCI 3 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 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

Example 5 - Preparation of a compound of Formula 5 where P 1 = Bz and W = -OP 2 , in which P 2 = 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 -60 0 C 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 -30 0 C 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 2O 0 C. 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

wherein R 1 represents hydrogen, a protecting group or a C 1-6 alkyl group; and R 2 represents a -C(O)CH(Me)CH 2 CH 3 or -C(O)C(Me) 2 CH 2 CH 3 group.

Example 5b, R is

wherein R 3 represents a -C(O)CH(Me)CH 2 CH 3 or -C(O)C(Me) 2 CH 2 CH 3 group.

Example 5c, R is

wherein R 4 represents a 4-fluorophenyl group; and R 5 a Ci -6 alkyl group, and more preferably a cyclopropyl group.

Example 5d, R is

wherein R 6 represents a 4-fluorophenyl group; and R 7 represents a C 1-6 alkyl group, and more preferably an isopropyl group.

Example 5e, R is

wherein R 8 represents a methyltetrazoyl group; R 9 represents a 4-fluorophenyl group; and R 10 a 4-fluorophenyl group.

Example 6 - Preparation of a compound of Formula 5 where P 1 = H and W = -OP 2 , in which P 2 = 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 P 1 = H and W = -OP 2 , in which P 2 = 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 P 1 =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 6O 0 C 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.