Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/34—One oxygen atom
  • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom

Definitions

• This invention concerns a novel chemical process, and more particularly it concerns a novel chemical process for the manufacture of rosuvastatin and its pharmaceutically acceptable salts, especially rosuvastatin calcium, as well novel intermediates used in said process and processes for the manufacture of the novel intermediates.
• Rosuvastatin and its pharmaceutically acceptable salts are HMG CoA reductase inhibitors and have use in the treatment of, inter alia, hypercholesterolemia and mixed dyslipidemia. Rosuvastatin calcium is marketed under the trademark CRESTORTM.
• European Patent Application, Publication No. (EPA) 0521471 discloses (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5- dihydroxyhept-6-enoic acid (rosuvastatin) and its sodium salt and calcium salt (rosuvastatin calcium, illustrated below) and a process for their preparation.
• Rosuvastatin and its pharmaceutically acceptable salts are obtained therein by condensation of methyl (3R)-3-[(/er/-butyldimethylsilyl)oxy]-5-oxo-6- triphenylphosphoranylidene hexanoate with 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl- N-methanesulfonylamino)-5-pyrimidinecarboxaldhyde, followed by deprotection of the 3- hydroxy group, asymmetric reduction of the 5-oxo group and hydrolysis.
• rosuvastatin and its pharmaceutically acceptable salts are described in WO 00/49014 and WO 04/52867.
• the compound and its pharmaceutically acceptable salts are obtained in WO 00/49104 by reaction of diphenyl [4- (4-fluoropheny)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl] phosphine oxide with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl ⁇ acetate in the presence of a base, followed by removal of protecting groups.
• WO 04/52867 discloses the condensation of l-cyano-(2S)-2-[(tert-butyldimethylsilyl)oxy-4-oxo-5- triphenylphosphoranylidene pentane with 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methanesulfonylamino)-5-pyrimidinecarboxaldhyde, followed by deprotection, asymmetric reduction of the 4-oxo group and hydrolysis.
• WO 03/004450 (Ciba Specialty Chemicals) discloses a process for preparation of heptanoic acid derivatives and their use as intermediates in the synthesis of statin derivatives.
• WO 03/018555 (Ciba Specialty Chemicals) discloses a process for preparation of indole derivatives, such as fluvastatin.
• EP252476 (Warner Lambert) discloses compounds which are HMG CoA reductase inhibitors and a process for their synthesis.
• L is a leaving group and X is a group Z which is N-(methyl)methylsulfonylamino (CHsSO 2 N(CH 3 )-) or X is a group Y which is a group that is capable of conversion into the group Z, with a compound of the formula III,
• A is selected from a group (i) to (vii) below,
• P 1 and P 2 are independently selected from hydrogen and a hydroxy protecting group, or P 1 together with P 2 form a 1,3-dihydroxy protecting group;
• P 3 is hydrogen or a hydroxy protecting group
• P 4 and P 5 are independently selected from hydrogen and a hydroxy protecting group, or P 4 together with P 5 form a 1,3-dihydroxy protecting group, and P 6 and P 7 are independently a hydroxy protecting group; or P 5 together with P 6 form a 1,3-dihydroxy protecting group, and P 4 is hydrogen or a hydroxy protecting group and P 7 is a hydroxy protecting group;
• P 8 is hydrogen or a hydroxy protecting group
• P 9 is hydrogen or a hydroxy protecting group
• P 10 and P 11 are independently selected from hydrogen and a hydroxy protecting group, or
• R 10 together with P 1 1 , or P 11 together with R 4 form a 1,3-dihydroxy protecting group; and unless otherwise stated R 1 , R , R 3 and R are independently carboxy protecting groups;
• A(i) is attached directly to the carbon-carbon double bond of formula III, and the groups A(ii) to A(vii) are attached in a likewise manner. It will be appreciated that tautomeric forms of the groups A are also included within the scope of the present invention. For example, when A is a group (vii) in which P 11 is hydrogen, this may exist in the keto form shown below.
• Suitable palladium catalysts are, for example, those disclosed in J. Am. Chem.
• Particularly suitable palladium catalysts include, for example, those with trialkylphosphine ligands (Pd/P(alkyl) 3 ) , especially bis(tri-tert-butylphosphine)palladium (0).
• Pd/P(alkyl) 3 catalyst wherein the alkyl group is tert-butyl, such as a mixture of Pd2(dba) 3 and P(t-Bu)3, may also be used.
• catalytically effective amount means an amount from 1 mol% to 30 mol%, particularly from 2 mol% to 20 mol%, and more particularly from 5 mol% to 10 mol%, based on the amount of the compound of formula II.
• the compounds of formula II and III are generally reacted together in the ratio of about 1 to 1.
• reaction is carried out in a suitable solvent such as toluene, diphenyl ether and poly(ethylene glycol), and particularly N,N-dimethylformamide, N- methylpyrrolidone, N,N-dimethylacetamide, or dimethylsulfoxide, and more particularly water and binary mixtures of water and N,N-dimethylformamide and N,N- dimethylacetamide.
• a suitable solvent such as toluene, diphenyl ether and poly(ethylene glycol)
• suitable solvent such as toluene, diphenyl ether and poly(ethylene glycol)
• N,N-dimethylformamide, N- methylpyrrolidone, N,N-dimethylacetamide, or dimethylsulfoxide and more particularly water and binary mixtures of water and N,N-dimethylformamide and N,N- dimethylacetamide.
• reaction is carried out at a temperature in the range 30-110 0 C, particularly 40-80 0 C, more particularly 50-60 0 C.
• Suitable bases for use in the process of the invention include, for example, amine bases, such as ammonia, and particularly bulky tertiary amines such as N- methyldicyclohexylamine, used either stoichiometrically or catalytically with a stoichiometric amount of an inorganic base, such as cesium carbonate.
• amine bases such as ammonia
• bulky tertiary amines such as N- methyldicyclohexylamine
• the reaction may also optionally be carried out in the presence of a tetrabutylammonium salt, such as tetrabutylammonium chloride or tetrabutylammonium tetrafluoroborate.
• a tetrabutylammonium salt such as tetrabutylammonium chloride or tetrabutylammonium tetrafluoroborate.
• a leaving group L referred to hereinbefore or hereinafter includes, for example, chloro, bromo, iodo, -OSO 2 CF 3 , -COCl, -SO 2 Cl and -C(O)O-SO 2 R y wherein R y is aryl (such as phenyl) or substituted aryl (such as tolyl), particularly chloro, bromo, iodo, - OSO 2 CF 3 , and more particularly bromo.
• a group that is capable of conversion into a group Z means that the group Y is selected from any functional group which can be converted, by carrying out one or more synthetic chemical steps, to form the group Z.
• Suitable groups Y which are capable of such conversion, and the synthetic chemical steps that can be used to carry out the conversion of Y into Z, are well known in the art, for example as described in standard works such as Contemporary Heterocyclic Chemistry by George R. Newkome and William W. Paudler, published by John Wiley & Sons, Inc., and Advanced Organic Chemistry by J. March, 4 th and 5 th Editions.
• Typical groups Y and synthetic chemical steps suitable for such conversion are illustrated, for example, in any of Schemes 1 to 5 or in the examples hereinafter, or by analogy therewith.
• a group Y referred to hereinbefore or hereinafter includes, for example, hydroxy, chloro, bromo, iodo, amino, methylamino, benzylamino, methanesulfonylamino, N- benzylmethanesulfonylamino, 11"SO 2 O- wherein R" is (l-6C)alkyl (such as methyl, ethyl or propyl), aryl (such as phenyl) or substituted aryl (such as tolyl), R y C(O)O- wherein R y is (l-6C)alkyl (such as methyl, ethyl or propyl), aryl (such as phenyl) or substituted aryl (such as tolyl).
• Particularly suitable groups Y include, for example, hydroxy, chloro, tosyloxy, amino, methylamino and methylsulfonylamino.
• aryl herein includes, for example, a monocyclic or bicyclic aromatic hydrocarbon group that contains 6-12 atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl and indanyl, particularly phenyl.
• substituted aryl means an aryl group bearing one or more substituents, for example 1 to 3 substituents, more particularly 1 to 2 substituents.
• Suitable substituents include, for example, (l-4C)alkyl (such as methyl, ethyl or propyl), (l-4C)alkoxy (such as methoxy or ethoxy) and halogeno (such as chloro, bromo or iodo).
• hydroxy protecting group and “carboxy protecting group” referred to hereinbefore or hereinafter mean that the hydroxy or carboxy group is protected from reaction by forming a suitable derivative, such as a (l-4C)alkyl ester group.
• a hydroxy protecting group also includes, for example, tetrahydropyranyl, tert-butyl, methoxymethyl or a silyl radical, for example a silyl radical of the formula SiR 3 wherein the R radicals can be the same or different and are selected from (l-6C)alkyl, phenyl and phenyl(l-4C)alkyl, in which latter two groups a phenyl group is unsubstituted or bears a halogeno, (1- 4C)alkoxy or (l-4C)alkyl substituent.
• a group SiR 3 includes trimethylsilyl and tert-butyldimethylsilyl. Examples of suitable means of protection of hydroxy and carboxy groups (as well as means of formation and eventual deprotection), may be found in T. W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Third
• Particular protecting groups hereinbefore or hereinafter for P 1 taken together with P 2 , or P 4 taken together with P 5 , or P 5 taken together with P 6 , to form a 1,3-dihydroxy protecting group include those described in EPA 0319845 and GB 2244705, which are included herein by reference.
• Particularly suitable 1,3-dihydroxy protecting groups include, for example, the groups (a), (b), (c) and (d) illustrated below
• Rw and Rx are independently (l-4C)alkyl, and Ry and Rz are independently (1- 4C)alkyl, or one of Ry and Rz is (l-4C)alkyl and the other is hydrogen, or Ry and Rz taken together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or cycloheptyl ring, and more particularly group (a) in which Ry and Rz are both methyl (i.e. an acetonide protecting group).
• Analogous protecting groups may also be used when P 1 ' together with R 4 forms a 1,3-dihydroxy protecting group.
• R 1 , R 2 , R 3 and R 4 include, for example, (l-4C)alkyl, such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, especially the latter.
• the protecting groups may be removed in any order which allows the compound of formula I to be obtained. It will also be appreciated that protecting groups and conditions for their removal may be chosen which allow for simultaneous removal of more than one protecting group. However it is preferred to carry out a final step under non-acidic conditions to avoid lactonisation of the compound of formula I.
• a suitable pharmaceutically acceptable salt includes, for example, an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example, calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example with methylamine, ethylamine, dimethylamine, trimethylamine , morpholine, diethanolamine, tris(2-hydroxyethyl)amine and tris(hydroxymethyl)methylamine.
• A is a group (ii)
• the asymmetric reduction of the carbonyl group adjacent to the carbon-carbon double bond may be carried out, for example, using diethylmethoxyborane and sodium borohydride.
• the reaction may be carried out, for example, in an alcohol-organic solvent mixture.
• the alcohol may be selected from, for example, methanol, ethanol, propanol and butanol.
• the non-alcoholic organic solvent may be selected from, for example, acetonitrile, diethyl ether, tetrahydrofuran and dimethylformamide.
• a particularly suitable combination of solvents is, for example, methanol and tetrahydrofuran.
• the reaction is generally carried out at a temperature between -100°C to 20 0 C, for example between -85 0 C to -70 0 C, under cooling for 10 minutes to 20 hours, for example 30 minutes to 10 hours.
• the asymmetric hydration of the carbon-carbon double bond may be carried out, for example, using benzyl aldehyde in the presence of a base, such as potassium tert-butoxide or potassium hexamethyldisilazide, in a suitable solvent, such as tetrahydrofuran, and at a temperature in the range of -2O 0 C to +10 0 C, such as about 0 0 C, by analogy with the procedure described in J. Org. Chem., 1993, 58, 2446-2453 which is hereby incorporated herein by reference.
• a base such as potassium tert-butoxide or potassium hexamethyldisilazide
• suitable solvent such as tetrahydrofuran
• the asymmetric hydration of the carbon-carbon double bond may be carried out, for example, using an appropriate alcohol, such as allyl alcohol, in the presence of a base, such as LiOH, or benzyl alcohol in the presence of a base, such as NaOH, followed by reduction using palladium on carbon or palladium hydroxide on carbon under acidic conditions, by analogy with the procedure described in WO 02/05519, which is hereby incorporated herein by reference.
• an appropriate alcohol such as allyl alcohol
• a base such as LiOH
• benzyl alcohol in the presence of a base, such as NaOH
• the asymmetric reduction of the carbon-carbon double bond adjacent to the group COOR 4 may be carried out, for example, using similar conditions to those described above for the asymmetric reduction of the carbonyl group of A(ii).
• variable radicals or groups are as follows. Such values may be used where appropriate with any other of the values, definitions, claims or embodiments defined hereinbefore or hereinafter.
• A is a group (i) wherein P 1 and P 2 together form an acetonide protecting group;
• A is a group (i) wherein P 1 and P 2 are both hydrogen;
• A is a group (ii) wherein P 3 is a hydroxy protecting group
• A is a group (ii) wherein P 3 is hydrogen
• A is a group (iii) wherein P 4 to P 7 are all hydroxy protecting groups
• A is a group (iii) wherein P 4 and P 5 are both hydrogen and P 6 and P 7 are the same or different hydroxy protecting groups (such as (l-4C)alkyl groups, for example methyl or ethyl)
• A is a group (iv) wherein P 8 is a hydroxy protecting group (for example, trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS) or tert- butyldimethylsilyl (TBDMS))
• TMS trimethylsilyl
• TES triethylsilyl
• TDPS tert-butyldiphenylsilyl
• TDMS tert- butyldimethylsilyl
• A is a group (v) wherein P 9 is a hydroxy protecting group
• A is a group (v) wherein P 9 is hydrogen
• A is a group (vii) wherein P 10 is hydrogen and P 11 together with R 4 is a 1,3-dihydroxy protecting group (for example, P 11 together with R 4 is an acetonide protecting group).
• EtOH ethanol
• NBS N-bromosuccinimide
• DMF N,N-dimethylformamide
• TEA triethylamine
• MeCN acetonitrile
• MsCl mesyl chloride
• TsCl tosyl chloride
• OTs tosyloxy
• THF tetrahydrofuran
• IPA isopropanol
• DCM dichloromethane
• a compound of the formula III wherein A is a group (i) may be obtained, for example, as described in Org. Lett., 2003, Vol. 5, No. 23, 4385-4388 or SynLett, 2003, page 215-218, or Tetrahedron Letters, 2002, 43(10), 1851-1854, or by analogy therewith.
• a compound of the formula III wherein A is a group (ii) may be obtained, for example, as disclosed in WO 03/04450 or by analogy therewith, or by analogy with the procedure described in JACS, 2000, page 8837, as follows: a) CH 2 CI 2 , low temp. OS i CI 3 O O chiral catalyst O OH O
• a compound of the formula III wherein A is a group (iii) may be obtained, for example, as follows:
• a compound of the formula III wherein A is a group (iv) may be obtained, for example, as disclosed in Org. Lett., 2004, Vol. 6, No. 20, 3465-3467, or as follows:
• a compound of the formula III wherein A is a group (v) may be obtained as described in SynLett, 2003, page 215-218.
• a compound of the formula III wherein A is a group (vi) may be obtained by analogy with the procedure described in Tetrahedron Lett., 2003, page 8081.
• a compound of the formula III wherein A is a group (vii) may be obtained, for example, as described in Synlett 1999, No. 9, 1435-1437, or by analogy therewith.
• a further aspect of the present invention comprises the manufacture of a compound of the formula I or a pharmaceutically acceptable salt thereof comprising reaction of a compound of the formula II wherein X is N-(methyl)methylsulfonylamino and L is a leaving group, with a compound of the formula III wherein A is a group (i) as set out hereinbefore wherein P 1 and P 2 are independently selected from hydrogen or a hydroxy- protecting group, or P 1 together with P 2 form a 1,3-dihydroxy protecting group (and particularly wherein P 1 and P 2 form together a 1,3-dihydroxy protecting group, and especially wherein P 1 and P 2 complete a group (a) defined herein wherein Ry and Rz are both methyl, i.e.
• R 1 is a carboxy protecting group (such as (l-4C)alkyl and particularly tert-butyl), in the presence of a catalytically effective amount of a palladium catalyst and in the presence of a base as described above; whereafter the protecting groups P 1 , P 2 and R 1 are removed in any order; whereafter when the product is obtained as the free acid, optionally forming a pharmaceutically acceptable salt of the compound of formula I, or when the product is obtained as a pharmaceutically acceptable salt, optionally converting the product to a different pharmaceutically acceptable salt.
• carboxy protecting group such as (l-4C)alkyl and particularly tert-butyl
• a further embodiment of this process comprises wherein a compound of the formula II is used in which X is N-(methyl)methylsulfonylamino and L is bromo.
• a further embodiment comprises wherein the latter compound is obtained from 5-bromo-2- hydroxy-4-(4-fluorophenyl)-6-isopropylpyrimidine, for example, by tosylation (such as by reaction with tosyl chloride) or chlorination (such as by reaction with phosphorus oxychloride), followed by reaction with N-methylmethanesulfonamide under basic conditions (for example in the presence of sodium hydride)).
• a further embodiment comprises wherein the 5-bromo-2-hydroxy-4-(4-fluorophenyl)-6-isopropylpyrimidine is obtained from 2-hydroxy-4-(4-fluorophenyl)-6-isopropylpyrimidine (for example by bromination with N-bromosuccinimide in DMF).
• a further embodiment comprises wherein the 2-hydroxy-4-(4-fluorophenyl)-6-isopropylpyrimidine is obtained from l-(4- fluorophenyl)-4-methylpentane-l,3-dione (for example by reaction with urea under acidic conditions).
• a further embodiment comprises wherein the latter compound is obtained from an (l-4C)alkyl 4-fluorobenzoate (for example by reaction with 3-methyl-2-butanone in the presence of a base, such as potassium tert-butoxide).
• a further embodiment comprises wherein the protecting groups P 1 and P 2 are removed prior to removal of R 1 .
• Conversion of a compound of formula I obtained in the free acid form into a pharmaceutically acceptable salt form may be carried out using any of the procedures well known in the art for the formation of salts from carboxylic acids. Conversion of a compound of the formula I obtained in a salt form may be converted into a different pharmaceutically acceptable salt using any of the procedures will known in the art for the interconversion of salts, for example, conversion of the sodium salt to the calcium salt by treatment with a water soluble calcium salt (such as calcium chloride or calcium acetate) under aqueous conditions (for example as disclosed in EP 521471, WO 00/49014, WO 04/52867 and WO 04/108691).
• a water soluble calcium salt such as calcium chloride or calcium acetate
• a further aspect of the present invention comprises a process for the manufacture of a compound of the formula IV
• R 1 is a carboxy protecting group (such as (l-4C)alkyl and particularly tert-butyl), in the presence of a catalytically effective amount of a palladium catalyst and in the presence of a base as described above.
• a carboxy protecting group such as (l-4C)alkyl and particularly tert-butyl
• a further aspect of the present invention comprises a process for the manufacture of a compound of the formula IV wherein P 1 and P 2 arc independently hydroxy-protecting groups, or P 1 together with P 2 form a 1,3-dihydroxy protecting group, X is a group Y as defined above, and R 1 is a carboxy protecting group, comprising reaction of a compound of the formula II wherein X is a groupY as defined above and L is a leaving group, with a compound of the formula III wherein A is a group (i) as set out hereinbefore wherein P 1 and P 2 are independently hydroxy-protecting groups, or P 1 together with P 2 form a 1,3- dihydroxy protecting group (and particularly wherein P 1 and P 2 form together a 1,3- dihydroxy protecting group, and especially wherein P 1 and P 2 complete a group (a) defined herein wherein Ry and Rz are both methyl, i.e.
• R 1 is a carboxy protecting group (such as (l-4C)alkyl and particularly tert-butyl), in the presence of a catalytically effective amount of a palladium catalyst and in the presence of a base as described above.
• carboxy protecting group such as (l-4C)alkyl and particularly tert-butyl
• a further aspect of the present invention comprises a novel compound of the formula IV wherein X is a group Y as defined herein, P 1 and P 2 are independently hydroxy-protecting groups, or P 1 together with P 2 form a 1,3-dihydroxy protecting group, and R 1 is a carboxy protecting group.
• a compound of the formula IV wherein X is hydroxy, chloro, bromo, iodo, amino, methylamino, benzylamino, N- benzylmethanesulfonylamino, R X SO 2 O- wherein R x is (l-6C)alkyl, aryl or substituted aryl, or R y C(O)O- wherein R y is (l-6C)alkyl, aryl or substituted aryl, and P 1 together with P 2 are independently selected from hydrogen or a hydroxy -protecting group, or P 1 together with P 2 form a 1,3-dihydroxy protecting group and R 1 is (l-4C)alkyl.
• X is hydroxy, P 1 and P 2 taken together form an acetonide (-C(CHs) 2 -) protecting group and R 1 is (l-4C)alkyl, especially tert-butyl;
• X is chloro, P 1 and P 2 taken together form an acetonide (-C(CHs) 2 -) protecting group and R 1 is (l-4C)alkyl, especially tert-butyl; (3) X is amino, P 1 and P 2 taken together form an acetonide (-C(CHs) 2 -) protecting group and R 1 is (l-4C)alkyl, especially tert-butyl;
• X is methylamino
• P 1 and P 2 taken together form an acetonide (-C(CH 3 ) 2 -) protecting group and R 1 is (l-4C)alkyl, especially tert-butyl;
• X is tosyloxy
• P 1 and P 2 taken together form an acetonide (-C(CHs) 2 -) protecting group and R 1 is (1 -4C)alkyl, especially tert-butyl
• a further aspect of the present invention comprises the manufacture of a compound of the formula V
• a further aspect of the present invention comprises the manufacture of a compound of the formula V wherein P 3 is a hydroxy-protecting group, X is a group Y as defined above, and R 2 is a carboxy protecting group, comprising reaction of a compound of the formula II wherein X is the group Y as defined herein and L is a leaving group, with a compound of the formula III in which A is a group (ii) as set out hereinbefore wherein P 3 is a hydroxy-protecting group and R 2 is a carboxy protecting group, in the presence of a catalytically effective amount of a palladium catalyst and in the presence of a base.
• X is R 11 SO 2 O- wherein R x is (l-6C)alkyl (such as methyl, ethyl or propyl), aryl (such as phenyl) or substituted aryl (such as tolyl).
• the compounds of formula V may be converted into a compound of formula I by converting the group Y into the group Z, followed by carrying out in any order the steps of (1) asymmetric reduction of the carbonyl group adjacent to the carbon-carbon double bond; (2) removal of P 3 ; and removal of the carboxy protecting group R 2 , as described herein. In a particular embodiment, the asymmetric reduction is carried out before removal of the protecting groups.
• a further aspect of the present invention comprises novel compounds of the formula V.
• a further aspect of the present invention comprises the manufacture of a compound of the formula VI
• a further aspect of the present invention comprises the manufacture of a compound of the formula VI wherein P 4 , P 5 , P 6 and P 7 are independently hydroxy-protecting groups, or P 4 together with P 5 or P 5 together with P 6 form a 1,3-dihydroxy protecting group, and X is a group Y as defined herein, comprising reaction of a compound of the formula II, wherein X is a group Y as defined above and L is a leaving group, with a compound of the formula III in which A is a group (iii) as set out hereinbefore wherein P 4 , P 5 , P 6 and P 7 are independently hydroxy-protecting groups, or P 4 together with P 5 or P 5 together with P 6 form a 1,3-dihydroxy protecting group, in the presence of a catalytically effective amount of a palladium catalyst and in the presence of a base as described above.
• X is R X SO 2 O- wherein R* is (l-6C)alkyl (such as methyl, ethyl or propyl), aryl (such as phenyl) or substituted aryl (such as tolyl).
• R* is (l-6C)alkyl (such as methyl, ethyl or propyl), aryl (such as phenyl) or substituted aryl (such as tolyl).
• the compounds of formula VI may be converted into a compound of formula I by converting the group Y into the group Z, followed by carrying out in any order the removal of P 4 , P 5 , P 6 and P 7 , as described herein.
• a further aspect of the present invention comprises novel compounds of the formula VI.
• a further aspect of the present invention comprises the manufacture of a compound of the formula VII
• a further aspect of the present invention comprises the manufacture of a compound of the formula VII wherein P 8 is a hydroxy-protecting group, X is a group Y as defined above, and R 3 is a carboxy protecting group comprising reaction of a compound of the formula II wherein X is a group Y and L is a leaving group with a compound of the formula III in which A is a group (iv) as set out hereinbefore wherein P 8 is a hydroxy- protecting group and R 3 is a carboxy protecting group, in the presence of a catalytically effective amount of a palladium catalyst and in the presence of a base.
• X is R 51 SO 2 O- wherein R x is (l-6C)alkyl (such as methyl, ethyl or propyl), aryl (such as phenyl) or substituted aryl (such as tolyl).
• the compounds of formula VII may be converted into a compound of formula I by converting the group Y into the group Z, followed by carrying out in any order the steps of (1) removal of P 8 ; (2) asymmetric hydration of the carbon-carbon double bond adjacent to the ester group COOR 3 ; and (3) removal of R 3 , as described herein. In a particular embodiment, the asymmetric hydration is carried out before P 8 and R 3 are removed.
• a further aspect of the present invention comprises novel compounds of the formula VII.
• a further aspect of the present invention comprises the manufacture of a compound of the formula VIII
• a further aspect of the present invention comprises the manufacture of a compound of the formula VIII wherein P 9 is hydrogen or a hydroxy-protecting group and X is a group Y as defined above, comprising reaction of a compound of the formula II wherein X is a group Y and L is a leaving group with a compound of the formula III in which A is a group (v) as set out hereinbefore wherein P 9 is a hydroxy-protecting group, in the presence of a catalytically effective amount of a palladium catalyst and in the presence of a base.
• X is R X SO 2 O- wherein R x is (l-6C)alkyl (such as methyl, ethyl or propyl), aryl (such as phenyl) or substituted aryl (such as tolyl).
• the compounds of formula VIII may be converted into a compound of formula I by converting the group Y into the group Z, followed by carrying out in any order the steps of (1) removal of the protecting group P 9 if present and (2) ring opening by hydrolysis under basic conditions, as described herein.
• P is a hydroxy protecting group.
• a further aspect of the present invention comprises novel compounds of the formula VIII.
• a further aspect of the present invention comprises the manufacture of a compound of the formula IX
• a further aspect of the present invention comprises the manufacture of a compound of the formula IX wherein X is a group Y as defined above, comprising reaction of a compound of the formula II wherein X is a group Y and L is a leaving group with a compound of the formula III in which A is a group (vi) as set out hereinbefore, in the presence of a catalytically effective amount of a palladium catalyst and in the presence of a base.
• Further separate independent embodiments of this process comprise the manufacture of compounds of the formula IX using a compound of the formula II wherein: (i) X is hydroxy; (ii) X is chloro;
• X is amino; (iv) X is methylamino; (v) methanesulfonylamino; and (vi) X is R X SO 2 O- wherein R x is (l-6C)alkyl (such as methyl, ethyl or propyl), aryl (such as phenyl) or substituted aryl (such as tolyl).
• R x is (l-6C)alkyl (such as methyl, ethyl or propyl), aryl (such as phenyl) or substituted aryl (such as tolyl).
• the compounds of formula IX may be converted into a compound of formula I by converting the group Y into the group Z, followed by carrying out in any order the steps of as (1) asymmetric hydration of the ring carbon-carbon double bond and (2) hydrolysis under basic conditions, as described herein. In a particular embodiment, the asymmetric hydration is carried out prior to hydrolysis.
• a further aspect of the present invention comprises novel compounds of the formula IX.
• a further aspect of the present invention comprises the manufacture of a compound of the formula X
• X wherein P 10 and P 11 are independently selected from hydrogen and a hydroxy protecting group, or P 10 together with P 11 , or P 11 together with R 4 , form a 1,3-dihydroxy protecting group;
• X is the group Z as defined herein; and
• R 4 is a carboxy protecting group comprising reaction of a compound of the formula II as defined above, wherein X is the group Z as defined herein and L is a leaving group, with a compound of the formula III in which A is a group (vii) as set out hereinbefore wherein P 10 and P 11 are independently selected from hydrogen and a hydroxy protecting group, or P 10 together with P 11 form a 1,3-dihydroxy protecting group, in the presence of a catalytically effective amount of a palladium catalyst and in the presence of a base as described above.
• a further aspect of the present invention comprises the manufacture of a compound of the formula X wherein P 10 and P 11 are independently selected from hydrogen and a hydroxy protecting group, or P 10 together with P 11 , or P 11 together with R 4 , form a 1,3- dihydroxy protecting group;
• X is the group Y as defined herein; and
• R 4 is a carboxy protecting group, comprising reaction of a compound of the formula II, wherein X is a group Y as defined above and L is a leaving group, with a compound of the formula III in which A is a group (vii) as set out hereinbefore wherein P and P are independently selected from hydrogen and a hydroxy protecting group, or P 10 together with P 11 , or P 11 together with R 4 , form a 1,3-dihydroxy protecting group, in the presence of a catalytically effective amount of a palladium catalyst and in the presence of a base.
• Further separate independent embodiments of this process comprise the manufacture of compounds of the formula X using a compound of the
• X is R 11 SO 2 O- wherein R x is (l-6C)alkyl (such as methyl, ethyl or propyl), aryl
• the compounds of formula X may be converted into a compound of formula I by converting the group Y into the group Z, followed by carrying out in any order the steps of (1) asymmetric reduction of the carbon- carbon adjacent to the group COOR 4 ; (2) removal of the protecting groups, as described herein.
• P 1 ' is hydrogen.
• a further aspect of the present invention comprises novel compounds of the formula X.
• Further independent embodiments of the invention comprise any of the processes described above wherein the starting material of formula II is obtained from a compound of the formula XI.
• a further aspect of the present invention comprises novel compounds of the formula II.
• Particular novel compounds of formula II include, for example,
• a further aspect of the present invention comprises novel starting materials for obtaining compounds of the formula II including, for example, 2-hydroxy-4-(4- fluorophenyl)-6-isopropylpyrimidine (formula XI).
• a still further aspect of the invention comprises a process for the production of 2- hydroxy-4-(4-fluorophenyl)-6-isopropylpyrimidine said process comprising a) reaction of ethyl-4-fluorobenzoate with 3-methyl-2-butanone in toluene to give l-(4- fluorophenyl)-4-methylpentane-l,3-dione as a solution in toluene; and b) reaction of said solution in toluene with urea and hydrogen chloride in isopropanol.
• the above process which starts from simple starting materials, efficiently avoids the need to isolate the intermediate l-(4-fluorophenyl)-4-methylpcntane- 1,3-dione because toluene is present as a solvent in both steps.
• the second step is generally carried out at elevated temperatures, for example at about 80°. Suitable conditions for carrying out this process are as illustrated in the accompanying examples.
• Example 1 The invention is further illustrated, but not limited by, the following Examples.
• Example 1 The invention is further illustrated, but not limited by, the following Examples.
• BEM white solid
• the compound BEM can then be converted into rosuvastatin calcium as described in International Patent Application, Publication No. WO 00/49014 (incorporated herein in full by reference) as follows:- A mixture of BEM (5.0 g) and acetonitrile (35 ml) was stirred under an inert atmosphere at 40 0 C. 0.02M hydrochloric acid (9.5 ml) was added over 30 minutes to the resultant solution, maintaining the temperature at 35°C to 42 0 C. The mixture was stirred at 40 0 C for 3 hours then cooled to 25°C. l.OM sodium hydroxide solution (9.5 ml) was added with stirring at 25°C and the mixture was stirred for an additional one hour at 25°C.
• the compound BEM may be converted into rosuvastatin calcium as described in International Patent Application WO 04/108691 (incorporated herein in full by reference) as follows: BEM (20.Og) was dissolved in acetonitrile (140ml) at 4O 0 C, then cooled to 35 0 C before gradual addition of hydrochloric acid (0.02M, 35ml) at 35 0 C. The resulting solution was stirred at 35°C until the reaction was complete then cooled to 25 0 C. Sodium hydroxide (1.0M, 38ml) was added at 25 0 C and the resulting mixture stirred at this temperature until the reaction was complete. Aqueous hydrochloric acid (IM) was added to adjust the pH of the solution to pH9.
• the solution was distilled under reduced pressure (52mBar, ⁇ 40°C) until approximately 100ml of acetonitrile/water had been removed. Water (100ml) was added and distillation continued until a further 100ml of acetonitrile/water had been removed. The resulting mixture was filtered through a filter pad, the filter washed with water (30ml) and the filtrates heated to 4O 0 C before addition of a solution of calcium chloride dihydrate (3.07g) in water (29.5ml) over 20min, maintaining the reaction mixture at 38-41°C.
• BEM (20.Og) was dissolved in acetonitrile (140ml) at 40 0 C, then cooled to 35°C before gradual addition of hydrochloric acid (0.02M, 35ml) at 35 0 C. The resulting solution was stirred at 35°C until the reaction was complete then cooled to 25 0 C. Further acetonitrile (8 ml) was added before sodium hydroxide (1.0M, 38ml) was added at 25 0 C and the resulting mixture stirred at this temperature until the reaction was complete. Aqueous hydrochloric acid (0.1M) was added to adjust the pH of the solution to approximately pH10.5.
• This solution was heated to 40 0 C before addition of a solution of calcium chloride di-hydrate (3.05g) in water (29.5ml) over 20min, maintaining the reaction mixture at 38-41°C.
• the reaction mixture was stirred for a further 15 min at 4O 0 C, then cooled to 2O 0 C and stirred at this temperature for a further 15min.
• N-Bromosuccinimide (3.504 g, 19.69 mmoles) was added to suspension of 4-(4- fluorophenyl)-6-isopropylpyrimidin-2-ol (4.573 g, 19.69 mmoles) in DMF (30 mL) at - 8.5°C. The mixture was stirred for 10 minutes and the reaction mixture was allowed to warm to ambient temperature. The mixture was stirred for 4 hours and then diluted with ethyl acetate (80 mL), toluene (20 mL), and water (100 mL). The organic phase was separated, and the aqueous phase extracted with 4:1 ethyl acetate/toluene (2 x 100 mL).
• the resulting suspension was cooled to -7°C and N-methylmethanesulfonamide (2.585 g, 22.5 mmoles) was added, washed in with DMF (10 mL). The mixture was stirred for 17.5 hours, then diluted with ethyl acetate (80 mL), toluene (100 mL), and water (120 mL). The organic phase was separated, and the aqueous phase was extracted with a mixture of ethyl acetate (20 mL) and toluene (30 mL). The organic phases were combined, washed with water (2 x 40 mL) and then brine (20 mL), and dried over anhydrous magnesium sulphate.
• N-methylmethanesulfonamide 2.585 g, 22.5 mmoles
• the reactor used for this experiment was thoroughly dried by carrying out a toluene distillation prior to use.
• Fresh toluene (100 mL) and potassium tert-butoxide (7.50 g, 64.8 mmol) were charged to the vessel and stirred to form a slurry.
• the mixture was cooled to - 9°C and 3-methyl-2-butanone (3.63 g, 41.7 mmol) added.
• the mixture was warmed to - 5°C and stirred for 30mins.
• Ethyl-4-fluorobenzoate (6.25 g, 36.8 mmol) was dissolved in toluene (4 mL) and added via a syringe followed by a small toluene (ImI) line wash.
• the mixture was stirred for 10 minutes at 0 0 C, warmed to 10 0 C, and then stirred at this temperature overnight.
• the mobile slurry was warmed to 25°C and acetic acid (4.4 mL) added, followed by water (37.5 mL).
• the mixture was stirred thoroughly for 5 minutes and then allowed to stand.
• the lower phase was run off and discarded.
• a 5% sodium bicarbonate solution (16 mL) was charged to the upper phase, stirred for 5 minutes and then allowed to stand.
• the lower aqueous layer was run off and the upper organic phase washed twice with water (5 mL).
• the aqueous layer was separated off and re-extracted with butyl acetate (250 mL) by stirring at 60 0 C for 15 mins.
• the organic layers were combined and 1 M aqueous NaOH (330 mL) added. This mixture was stirred at 60 0 C for 20 minutes, then the lower aqueous phase separated off.
• the organic layer was concentrated in vacuo to 20% original volume, then allowed to cool and crystallize.
• the crude solid was isolated by filtration (50.5 g slightly damp), and this material recrystallized from methanol (500 mL), filtered and dried at 50 0 C to constant weight to give the title compound (30.54 g, 38% yield) as a white crystalline solid.

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