Title of Invention	PROCESS AND INTERMEDIATE COMPOUNDS USEFUL IN THE PREPARATION OF STATINS
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 SO2Rc group where Re is an alkyl group, such as a C1-16 alkyl group, and preferably a methyl group.

Title of Invention

PROCESS AND INTERMEDIATE COMPOUNDS USEFUL IN THE PREPARATION OF STATINS

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 SO2Rc group where Re is an alkyl group, such as a C1-16 alkyl group, and preferably a methyl group.

Full Text	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): 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 C1-6 alkyl group, and preferably an sopropyl 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 C1-6 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): 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 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): wherein R is a group selected from 3 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 C1-8 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, 4 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): 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). In step (e), any P1 protecting groups and any additional protecting groups may be 5 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 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). 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 6 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, Rc, Rd, R1 and R4-10 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyI, t-butyl and cyclohexyl groups. Alkenyl groups which may be represented by R, R1 and R4-10 include C2-20, 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, 0, 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 7 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 KO2/18-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 50°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 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 0 to -100°C, preferably -50 to -80°C. Preferably, reagents are added at reduced temperature, such as -30 to -80°C, and then once all reagents are added, the reaction mixture is allowed to warm to 15 to 20°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 R11 and R12 include Chalky! groups, such as methyl and ethyl groups, C8-12aryl groups, such phenyl, tolyl or naphthyl, C1-6alkoy groups, such as ethoxy groups, and C6-12aryloxy groups such as phenoxy groups. Anions which may be represented by X include halide. 8 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: wherein W, P1 and Y are as previously described. Preferred compounds of formula (2) are compounds of formula: 9 wherein W and P1 are as previously described. Preferred compounds of formula (3) are compounds of formula: wherein W and P1 are as previously described. Preferred compounds of formula (5) are of formula: wherein R1, R2, W and P1 are as previously described. Preferred compounds of formula (6) are of formula: wherein R1 and R2 are as previously described. Preferred compounds of formula (7) are of formula: 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: 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. 10 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 40°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; 1H nmr CDCI3 3.6-3.7 (m 2H), 4.1 (m 1H), 1.5-1.6 (m 2H), 4.0 (m 1H), 1.3-1.6 (m 2H), 4.9 (m 1H), 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 80°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; 1H nmr CDCI31.6-2.0 (m 4H), 3.4 & 3.5 (s 3H), 3.6 (m 2H), 3.8 (m 1H), 4.0 (m 1H), 4.5 (m 2H), 4.7 (m 1H), 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 (30g) 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°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 (150mls) and extracted with ethyl acetate (3 x 1500mls). The combined upper organic layer was then washed with water (3 x 1500mls). 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 11 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 1H), 4.0 (m 1H), 4.1 (m 2H), 4.5 (m, 2H), 4.7-4.9 (m 1H), 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 50mls three necked round bottomed flask flushed with dry nitrogen the O- benzyl-chlorolactol methyl acetal acetate (2g) was charged into dry methanol (10mls) containing anhydrous potassium carbonate (1g). The resultant suspension was stirred at 20°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%). 1H nmr CDCI31.4-1.8 (m 4H), 3.4 & 3.5 (s 3H), 3.8 (m 1H), 3.9 (m 1H), 4.0 (m 2H), 4.5 (m 2H), 4.7-4.9 (m 1H), 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 (50mls) was charged to a 1000 mls round bottomed flask purged with dry nitrogen. The hydroxy-O-benzyl- lactol methyl acetal (1.0g,) was dissolved in dichloromethane (50mls) and added to the Dess-Martin periodinane reagent at 20°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 (200mls). The upper organic layer was then washed with water (250mls). 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 nmrCDCI31.6-1.9 (m 4H), 3.3 & 3.5 (s 3H), 3.7 (m 1H), 3.8 (m 1H), 4.4 (m 2H), 4.7-4.9 (m 1H), 7.2-8.1 (m, 5H), 9.6-9.7 (2 xs, 1H). 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: 11 A stirred solution of oxalyl chloride (0.037 cm3, 0.44 mmol) in dichloromethane (4 cm3) under nitrogen was cooled to -78 ºC 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 °C 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 -60°C and then adding 0.2ml of a 2M solution of sodium hexamethyldisilazide. After 20min, a solution of 0.1 g formyl-O-benzyl-lactol methyl acetal in 10ml dry THF at -30°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 20°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 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 wherein R3 represents a -C(O)CH(Me)CH2CH3 or -C(O)C(Me)2CH2CH3 group. Example 5c, R is wherein R4 represents a 4-fluorophenyl group; and R5 a C1-6 alkyl group, and more preferably a cyclopropyl group. Example 5d, R is 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 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. 14 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 1M 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 60°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. 15 WE CLAIM 1. A process for the preparation of a compound of formula (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 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 C1-8 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): 16 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 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): 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 C1-6alkanoyl 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 C1-6alkanoyl 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, which comprises a) hydroxylating a compound of formula (1): wherein Y represents a halo group, preferably Cl or Br; P1 represents hydrogen or 18 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): 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): d) when W represents -OP2, removing any P2 protecting group and oxidising the compound of formula (5) to give a compound of formula (6): 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): 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) 19 and then, when W represents -OP , removing any P 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): which comprises coupling the compound of formula (3): 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 C1-6 alkyl group, and preferably an 20 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 C1-6 alkyl group, and preferably a methyl group. wherein R is a group selected from 5. A process for the preparation of a compound of formula (5): 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 C1-6alkanoyl group, and preferably a -C(O)CH(Me)CH2CH3 or 21 -C(O)C(Me)2CH2CH3 group; R3 represents an optionally substituted acyl group, preferably an alkanoyl group, such as C1-6alkanoyl 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 (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. A compound of formula (5) or (9): wherein R is a an optionally substituted hydrocarbyl group or an optionally substituted heterocyclic group; Z represents (PR11R12)+X- or P(=0)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; 22. 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 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 C1-6 alkyl group, and preferably a methyl group. A compound of formula (5) or (9): 23 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 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 (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. 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 SO2Rc group where Re is an alkyl group, such as a C1-16 alkyl group, and preferably a methyl group.

Full Text

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):

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 C1-6 alkyl group, and preferably an
sopropyl 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 C1-6 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):
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 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):

wherein
R is a group selected from
3

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 C1-8 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,
4

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):

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).
In step (e), any P1 protecting groups and any additional protecting groups may be
5

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 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).

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
6

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, Rc, Rd, R1 and R4-10 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyI, t-butyl
and cyclohexyl groups.
Alkenyl groups which may be represented by R, R1 and R4-10 include C2-20, 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, 0, 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
7

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 KO2/18-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 50°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 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 0 to -100°C, preferably -50 to -80°C. Preferably, reagents are added at reduced
temperature, such as -30 to -80°C, and then once all reagents are added, the reaction
mixture is allowed to warm to 15 to 20°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 R11 and R12
include Chalky! groups, such as methyl and ethyl groups, C8-12aryl groups, such phenyl,
tolyl or naphthyl, C1-6alkoy groups, such as ethoxy groups, and C6-12aryloxy groups such
as phenoxy groups.
Anions which may be represented by X include halide.
8

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:

wherein W, P1 and Y are as previously described.
Preferred compounds of formula (2) are compounds of formula:

9

wherein W and P1 are as previously described.
Preferred compounds of formula (3) are compounds of formula:

wherein W and P1 are as previously described.
Preferred compounds of formula (5) are of formula:

wherein R1, R2, W and P1 are as previously described.
Preferred compounds of formula (6) are of formula:

wherein R1 and R2 are as previously described.
Preferred compounds of formula (7) are of formula:
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:

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.
10

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 40°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;
1H nmr CDCI3 3.6-3.7 (m 2H), 4.1 (m 1H), 1.5-1.6 (m 2H), 4.0 (m 1H), 1.3-1.6 (m 2H), 4.9
(m 1H), 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 80°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; 1H nmr CDCI31.6-2.0 (m 4H), 3.4 & 3.5
(s 3H), 3.6 (m 2H), 3.8 (m 1H), 4.0 (m 1H), 4.5 (m 2H), 4.7 (m 1H), 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 (30g) 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°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 (150mls) and extracted with ethyl
acetate (3 x 1500mls). The combined upper organic layer was then washed with water (3
x 1500mls). 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
11

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 1H), 4.0 (m 1H), 4.1 (m 2H), 4.5 (m, 2H),
4.7-4.9 (m 1H), 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 50mls three necked round bottomed flask flushed with dry nitrogen the O-
benzyl-chlorolactol methyl acetal acetate (2g) was charged into dry methanol (10mls)
containing anhydrous potassium carbonate (1g). The resultant suspension was stirred at
20°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%). 1H nmr CDCI31.4-1.8 (m 4H), 3.4 & 3.5 (s
3H), 3.8 (m 1H), 3.9 (m 1H), 4.0 (m 2H), 4.5 (m 2H), 4.7-4.9 (m 1H), 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 (50mls) was charged
to a 1000 mls round bottomed flask purged with dry nitrogen. The hydroxy-O-benzyl-
lactol methyl acetal (1.0g,) was dissolved in dichloromethane (50mls) and added to the
Dess-Martin periodinane reagent at 20°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 (200mls). The upper organic layer
was then washed with water (250mls). 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 nmrCDCI31.6-1.9 (m 4H), 3.3 & 3.5 (s 3H), 3.7 (m 1H), 3.8 (m 1H), 4.4 (m 2H), 4.7-4.9
(m 1H), 7.2-8.1 (m, 5H), 9.6-9.7 (2 xs, 1H).
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:
11

A stirred solution of oxalyl chloride (0.037 cm3, 0.44 mmol) in dichloromethane (4 cm3)
under nitrogen was cooled to -78 ºC 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 °C 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 -60°C and then
adding 0.2ml of a 2M solution of sodium hexamethyldisilazide. After 20min, a solution of
0.1 g formyl-O-benzyl-lactol methyl acetal in 10ml dry THF at -30°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 20°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 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

wherein R3 represents a -C(O)CH(Me)CH2CH3 or -C(O)C(Me)2CH2CH3 group.
Example 5c, R is

wherein R4 represents a 4-fluorophenyl group; and R5 a C1-6 alkyl group, and more
preferably a cyclopropyl group.
Example 5d, R is

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

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.
14

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 1M 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 60°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.
15

WE CLAIM
1. A process for the preparation of a compound of formula (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 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 C1-8 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):
16

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 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):

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 C1-6alkanoyl 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 C1-6alkanoyl 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,
which comprises
a) hydroxylating a compound of formula (1):

wherein Y represents a halo group, preferably Cl or Br; P1 represents hydrogen or
18

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):
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):

d) when W represents -OP2, removing any P2 protecting group and oxidising the
compound of formula (5) to give a compound of formula (6):

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):

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)
19

and then, when W represents -OP , removing any P 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):

which comprises coupling the compound of formula (3):

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 C1-6 alkyl group, and preferably an
20

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 C1-6 alkyl group, and preferably a methyl group.

wherein
R is a group selected from

5. A process for the preparation of a compound of formula (5):
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 C1-6alkanoyl group, and preferably a -C(O)CH(Me)CH2CH3 or
21

-C(O)C(Me)2CH2CH3 group;
R3 represents an optionally substituted acyl group, preferably an alkanoyl group,
such as C1-6alkanoyl 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 (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.
A compound of formula (5) or (9):

wherein
R is a an optionally substituted hydrocarbyl group or an optionally substituted
heterocyclic group;
Z represents (PR11R12)+X- or P(=0)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;
22.

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 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 C1-6 alkyl group, and preferably a methyl group.
A compound of formula (5) or (9):

23

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 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 (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.

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 SO2Rc group where Re is an alkyl group, such as a C1-16
alkyl group, and preferably a methyl group.

PROCESS AND INTERMEDIATE COMPOUNDS USEFUL IN THE PREPARATION OF STATINS

Documents:

Inventors:

PCT Conventions: