EP1893585A1

EP1893585A1 - Process for the preparation of n-[4-(4-fluorophenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-n-methylmethanesulfonamide

Info

Publication number: EP1893585A1
Application number: EP06755392A
Authority: EP
Inventors: Arne Grumann; Pekka PIETIKÄINEN; Inese Reine
Original assignee: Fermion Oy
Current assignee: Fermion Oy
Priority date: 2005-06-01
Filing date: 2006-05-31
Publication date: 2008-03-05
Also published as: WO2006128954A1

Abstract

The present invention is directed to a method for the preparation of N-[4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide and its use in the preparation of rosuvastatin or a pharmaceutically acceptable salt thereof.

Description

PROCESS FOR THE PREPARATION OF N-[4-(4-FLUOROPHENYL)-5-

FORMYL-6-ISOPROPYL-PYRIMIDIN-2-YL]-N-

METHYLMETHANESULFONAM1DE

FIELD OF THE INVENTION

The present invention is directed to a method for the preparation of N-[4-(4- fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide having a structure of formula I

and its use in the preparation of rosuvastatin or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

Rosuvastatin is a HMG-CoA reductase inhibitor used as a calcium salt in the treatment of hypercholesterolemia, hyperlipodemia and atherosclerosis. Its chemical name is (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)-pyrimidin-5-yl]-3,5-dihydroxy-6(E)heptenoic acid. Other statins used as lipid-lowering drugs are e.g. simvastatin, atorvastatin, lovastatin and pravastatin.

Rosuvastatin and a process for its preparation is disclosed in US patent no 5,260,440. The preparation process described contains four steps: a) condensation of methyl (3R)-3-[tert-butylmethylsilyl)-oxy]-5-oxo-6-triphenylphosphoranylidene hexanoate with N-[4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N- methylmethanesulfonamide, b) deprotection of the 3-hydroxyl group to give the keto alcohol, c) reduction of 5-oxo to obtain the chiral dihydroxy heptenate, and d) hydrolysis of the dihydroxy heptenate. The starting material N-[4-(4-fluorophenyl)-5- formyl-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (referred later as pyrimidine compound) is prepared from 4-fluorobenzaldehyde, 4-methyl-3-oxo- pentanoic acid ethyl ester and S-methylisothiourea. The preparation of the pyrimidine compound requires eight synthetic steps and involves the use of expensive and hazardous reagents and solvents like 2,3-dichloro-5,6-dicyano-l,4-benzoquinone, m- chloroperoxybenzoic acid, tetrapropylammonium perruthenate, and hexamethylphosphoramide. Also, the pyrimidine compound is obtained only in moderate yield.

The preparation of Ν-4-(4-fluorophenyl)-5-formyl-6-isoproρylpyrirnidin-2- yl]-N-methyl-methanesulfonamide is described also in WO 03/097614. The starting material also in this process is p-fluorobenzaldehyde which is reacted with a keto ester and isothiourea. This process involves also eight reaction steps including several oxidation and reduction steps , some of which involve either hazardous reagents (peracetic acid) or very low reaction temperatures (-70 - -75 ⁰C)

These multistep processes include process and environmentally unfriendly oxidation and reduction steps. Therefore a more convenient and economical process is needed for the preparation of pyrimidine compound used in the preparation of rosuvastatin.

The present inventors have noticed, that the starting material for rosuvastatin, N- [4-(4-fluorophenyl)-5 -formyl-6-isopropylpyrimidin-2-yl] -N-methylmethane- sulfonamide can be prepared economically starting from 2,4,6- trihalogenopyrimidme-5-carbaldehyde, which can be made from 2,4,6- trioxohexahydropyrimidine (barbituric acid) or from 2,4,6-trihalogenopyrirnidine.

SUMMARY OF THE INVENTION

One aspect of the present invention is the process for the preparation of a compound of formula I

comprising the steps:

a) protection of the aldehyde group of the compound of formula II

wherein X is halogen, to obtain a compound of formula III or HI'

wherein Rl is OR5 or SR5 and R2 is OR5 or SR5 or NR5 and R5 is substituted or non substituted alkyl chain and they together form a linear or cyclic aldehyde protecting group and N-R4 is an aldehyde protecting group wherein R4 is e.g. NMe₂, OMe or OBn. b) reaction of a compound of formula in or IH' with a suitable isopropyl metallic compound to obtain a compound of formula IV or IV'

IV

c) reaction of a compound of formula IV or IV' with a 4-fluorophenyl metal compound to obtain a compound of formula V or V

d) nucleophilic displacement at the 2-position with N-methyl methanesulfonamide to obtain a compound of formula VI or VI '

and

e) deprotection the aldehyde group to obtain a compound of formula I.

Another aspect of the present invention is the reaction of the the pyrimidine compound of formula I prepared according to the invention to produce rosuvastatin or a pharmaceutically acceptable salt thereof.

Additional objects and advantages of the invention will be set forth in part in the description, which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described below step by step as defined in the summary of the invention.

Step a) from 2,4,6-trihalogenopyrimidme-5-carbaldehyde to 2,4,6- trihalogeno-5-[l,3]dioxolane-2-ylpyrimidine:

The first step is the addition of a suitable group to protect the aldehyde. Suitable protective groups as well as processes for their addition are described in textbooks, e.g. in Greene and Wuts (T. W. Greene and P.G.M. Wuts, Protective groups in organic synthesis, John Wiley & Sons, Inc., 3^rd. ed, New York, 1999), which is incorporated here as a reference, hi the process of the invention the preferable groups used are e.g. acyclic or cyclic acetal, monothioacetal or dithioacetal. If e.g. 1,3-dioxolane (cyclic acetal), is used as a protective group, the process maybe the following: 2,4,6-trihalogenopyrimidine-5-carbaldehyde is dissolved in a suitable organic solvent, which can be e.g. an aromatic hydrocarbon or ethylene glycol or a mixture thereof, or the reagent, like ethylene glycol, may be used as a solvent. Acid catalyst, e.g. Lewis acid or protic acid may be used in the reaction. The mixture is typically reacted at ambient or reflux temperature for the process to complete, and thereafter the product is isolated and purified using the methods known in the art.

Step b) from 2,4,6-trihalogeno-5-[l,3]dioxolane-2-ylpyrimidine to 2,4- dihalogeno-5-[l,3]dioxolane-2-yl-6-isopiOpylpyrimidine:

The product from the previous step is dissolved in a suitable organic solvent, e.g. ethers like tetrahydrofuran, aromatic hydrocarbons like toluene or xylene, aprotic polar solvents like N-methylpyrrolidinone or mixtures thereof may be used. The isopropyl group can be added using an isopropyl metallic compound, such as an isopropyl magnesium halide, e.g. bromide or chloride using transition metal catalysis e.g. Fe, Ni or Cu compounds can be used, preferably Li₂CuCl₄ is used as a catalyst. An aqueous work up and purification as known in the art, such as column chromatography or crystallization may be used to provide the adduct in good purity.

In one aspect of the invention the process may be continued in one pot to step c) without isolation of the intermediate from step b).

Step c) from 2,4-dihalogeno-5-[l,3]dioxolane-2-yl-6-isopropylpyrimidine to

2-halogeno-5-[l,3]dioxolane-2-yl-4-(4-fluorophenyl)-6-isopropylpyrimidine:

Compound of formula IV is reacted with a 4-fluorophenyl metallic compound (4-F-C₆H₄-M) in a suitable solvent, e.g. ethers like tetrahydrofuran, nonpolar hydrocarbons like toluene or xylene, polar double or triple bond containing solvents like acetonitrile, other polar aprotic solvents like N,N-dimethylformamide, and polar protic solvents like alcohols or water or mixtures thereof may be used. Suitable metallic substituents (M) include e.g. alkali metals like Na or MgX wherein X is a halogen, transition metals like ZnX wherein X is a halogen, other metals like SnY₃ wherein Y is aryl or alkyl, or AlY₂ wherein Y is alkyl, metalloids like BY₂ wherein Y is alkyl or aryl, or B(OY)₂ wherein Y is H or alkyl. Non-metallic substituents (M) like Si can also be used in this reaction step. The reaction maybe catalyzed by transition metal catalysts e.g. Fe, Ni, Cu or Pd compounds, preferably Pd(H) or Pd(O) compounds are used. An aqueous work up and purification as known in the art such as column chromatography or crystallization may be used to provide the adduct in good purity.

Step d) from 2-halogeno-5-[l,3]dioxolane-2-yl-4-(4-fluorophenyl)-6- isopropylpyrimidine to N-[5-[ 1 ,3]dioxolane-2-yl-4-(4-fluorophenyl)-6-isopropyl- pyrimidin-2-yl] -N-methylmethane sulfonamide :

A compound of formula V is reacted with N-methylmethanesulfonamide or its anion in a suitable solvent. The anion can be formed with a suitable base, which can be e.g. carbonate, hydroxide, alkoxide, hydride, amidine, or alkylmetal compound. Suitable solvent is dependent on the base used, e.g. ethers, aprotic polar solvents, aromatic or aliphatic hydrocarbons or mixtures thereof can be used. Typical base-solvent combinations include e.g. sodium hydride/N,N-dimethylformamide, potassium tert-butoxide/tetrahydrofuran, l,8-diazabicyclo[5.4.0]undec-7- ene/acetonitrile and n-butyllithiuni/hexane-ether. The product is isolated and optionally purified by a suitable method known in the art.

Step e) from N-[5-[l,3]dioxolane-2-yl-4-(4-fluorophenyi)-6-isopropyl- pyrimidin-2-yl]-N-methylmethane sulfonamide to N-[4-(4-fluorophenyl)-5-formyl-6- isopropyl pyrimidin-2-yl]-N-methylmethanesulfonamide:

Aldehyde protection made in step a) is removed by a suitable method known in the art to obtain a compound of formula I.

The steps of the process can be performed also in a different order, which is also included in the scope of the invention. The addition of the isopropyl- fluorobenzyl- and methylmethanesulfonamide groups can be carried out in any order.

Compound of formula I can be further reacted, e.g. as described in US 5,260,440 to obtain rosuvastatin, and further to a pharmaceutically acceptable salt as desired. Also other possible reactions to make rosuvastatin from the compound of formula I prepared according to the present invention are included in the scope of the present invention.

The starting compound of formula II can be made starting from barbituric acid or from 2,4,6-trihalogeno pyrimidine, which are commercially available compounds. 2,4,6-trichloropyrimidine-5-carbaldehyde can be made from barbituric acid in one pot reaction e.g. in the following way.

Barbituric acid is reacted with suitable chlorinating and formylating agents in a suitable solvent to obtain 2,4,6-trichloropyrimidine-5-carbaldehyde. Suitable solvents may be e.g. polar aprotic or aromatic hydrocarbons like toluene or xylene, chlorinated hydrocarbons like 1,2-dichloroethane or chlorobenzene. Possible chlorinating agents include but are not limited to POCl₃, SOCl₂, PCl₃, PCl₅, COCl₂, or (COCl)₂ and as formylating agent e.g. formamides like ΛζiV-dimethylformamide, iV-methylformanilide, iV-formylpiperidine, N-formylmoφholine or other amides like Aζ JV-dimethylacetamide, N-methylpyrrolidone, N,N, dimethylbenzamide may be used. Reaction temperature and time depend on the solvent used, e.g. reflux temperature may be used. Remaining halogenating agent is removed and the resulting 2,4,6-trichloropyrimidine-5-carbaldehyde may be isolated and purified by methods known in the art.

Compound of formula II may also be made in two steps comprising chlorination using the chlorinating agents as mentioned above and formylation separately by some method known in the art, or it may be obtained by formylation of commercially available halogenated compound of formula II by some methods known in the art, e.g. using n-butyllithium/ N,iV-dmiethylformamide, lithium diisopropylamide/ethylformate, and hexamethylenetetramine.

Chlorinated compound of formula II is the preferred compound used, but also other halogens can be used. e.g. bromo-compound may be made using e.g. PBr₃ as a halogenating agent.

The following examples merely illustrate the invention and they are not to be construed as limiting.

EXAMPLES

Reference example

2,4,6-Trichloropyrimidine-5-carbaldehyde

Dry DMF (33 ml) was added drop-wise to a cooled (10-15 ⁰C) phosphorus oxychloride (315 ml). Then barbituric acid (45 g) was added at once upon effective stirring. The suspension was left overnight at room temperature after which it was heated at 50 ⁰C for 6 h and at 90 ⁰C for 20 h. Remainder OfPOCl₃ was evaporated and the residue was poured on crushed ice (700 g) and water (400 ml). Light yellow precipitate was filtered, the solid washed with water, and dried. Crude product was dissolved in dichloromethane (500 ml) and an insoluble material was filtered off. Evaporation of solvent afforded 57.4 g (74%) of 2,4,6-trichloropyrimidine-5- carbaldehyde , m.p. 129-130 ⁰C.

Example 1.

2,4,6-Trichloro-5 -[1,3] dioxolane-2-ylpyrimidine To the solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (10.0 g) in dry benzene (200 ml) were added ethylene glycol (8.0 ml) andp-toluenesulfonic acid (0.15 g). The mixture was refluxed for 20 h, the warm benzene layer was decanted and the residue was washed with warm benzene (2x50 ml). Combined benzene solution was evaporated, water (30 ml) was added and the suspension formed was neutralized with 9% NaHCO₃. The precipitate was filtered to afford 10.3 g (85%) of 2,4,6-trichloro-5- [l,3]dioxolane-2-ylpyrimidine, m.p. 161-162 ⁰C.

¹H NMR (CDCl₃) δ: 3.94-4.42 (4H, m, OCH₂), 6.30 ppm (IH, s, OCH).

Example 2. 2,4-Dichloro-5-[l,3]dioxolane-2-yl-6-isopropylpyrimidine To the cooled solution of dioxolanylpyrimidine (5.0 g) in THF (75 ml) were successively added 20 ml of Li₂CuCl₄/THF (10 mol-%, prepared from 265 mg of CuCl₂ and 167mg of LiCl) and 33 ml of isopropyl magnesium bromide in THF (0.72 M)). The reaction mixture was stirred overnight at room temperature and then poured into a mixture of 10% NH₄Cl and ice. After separation of organic phase the water phase was extracted with ethyl acetate (2x50 ml). Combined organic extract was washed with saturated NaCl solution (50 ml), dried, and evaporated under reduced pressure. The residue was subjected to column chromatography (silica gel, eluent: acetone-petroleum ether) to obtain 2.18 g (42%) of 2,4-dichloro-5-[l,3]dioxolane-2- yl-6-isopropylpyrimidine , m.p. 91-92 ⁰C. ¹H NMR (CDCl₃) δ: 1.25 (6H, d, J= 6.6 Hz, CH(CH₃J₂), 3.48 (IH, septet, J= 6.6 Hz,_CH(CH₃)₂) 4.00-4.28 (4H, m, OCH₂), 6.18 ppm (IH, s, OCH). ¹³C NMR (CDCl₃) δ: 21.7, 32.0, 65.3, 100.1, 123.1, 160.2, 162.5, and 181.6 ppm.

Example 3 2,4-Dichloro-5-[ 1 ,3]dioxolane-2-yl-6-isopropylpyrimidine

To the cooled (ca. -20 ⁰C) solution of dioxolanylpyrimidine (10.0 g) in dry NMP (250 ml) was added drop wise an isopropylmagnesium chloride solution in THF (2 M, 23.6 ml) under stirring. After stirring for 1 h at -20 ⁰C, 10 % NH₄Cl solution saturated with NaCl (150 ml) was added. The suspension was extracted with ethyl acetate (2x300 ml), then 100 ml of saturated NaCl was added to the aqueous phase and extraction with ethyl acetate (7x100 ml) was continued. After evaporation of the organic extracts the oily residue was treated with water (100 ml) under cooling. Formed precipitate was filtered to afford 9.5 g (yield 84%, assay 93%) of 2,4- dichloro-5-[l,3]dioxolane-2-yl-6-isopropylpyrimidine.

Example 4 2-Chloro-5-[l,3]dioxolane-2-yl-4-(4-fluorophenyl)-6-isopropylpyrimidine

4-Fluorobromobenzene (0.27 ml) dissolved in THF (10 ml) was cooled to -70 ⁰C. n- BuLi (2.5 M in hexane, 1.0 ml) was added at -70 ⁰C and the reaction mixture was stirred at this temperature for 30 min. Then a solution of dry ZnCl₂ (0.37 g) in THF (5 ml) was added drop-wise maintaining the temperature below -60 ⁰C. The temperature of resulting reaction mixture was allowed to rise to room temperature within 1 h. This organozinc solution was added to a mixture of 2,4-dichloro-5- [l,3]dioxolane-2-yl-6-isopropylpyrimidine (0.5 g) and Pd(PPh₃)₄ (1 mol-%, 13 mg) in THF (15 ml). The reaction mixture was heated at 55-60 ⁰C for 4.5 h. After cooling it was poured in 10% NH₄Cl — ice mixture. The organic layer was separated and aqueous phase was extracted with ethyl acetate (2x20 ml). The combined organic extract was washed with 10% aq EDTA (15 ml) and saturated NaCl solution, and evaporated. The residue was chromatographed on silica gel column (eluent: CHCl₃- petroleum ether) to obtain 0.25 g (41%) of 2-chloro-5-[l,3]dioxolane-2-yl-4-(4- fluorophenyl)-6-isopropylpyrimidine m.p. 135-137 ⁰C. ¹H NMR (CDCl₃) δ: 1.32 (6H, d, J= 6.6 Hz, CH(CH₃J₂), 3.53 (IH, septet, J= 6.6

Hz, CH(CH₃)₂) 3.90-4.18 (4H, m, OCH₂), 5.72 (IH, s, OCH), 7.15 (2H, t, J= 8.8 Hz, 3',5'-H), 7.60 ppm (2H, dd, J_H-H= 8.8 Hz, J_H-F= 5.4 Hz, 2',6'-H).

Example 5. 2-Chloro-5-[l,3]dioxolane-2-yl-4-(4-fluorophenyl)-6-isopropylpyrimidine A solution of KOH (4.18 g) in water (250 ml) was added to a mixture of 2,4- dichloro-5-[l,3]dioxolane-2-yl-6-isopropylpyrimidine (9.5 g) and 4- fluorophenylboronic acid (5.1 g) in acetonitrile (250 ml). Palladium acetate (0.19 g) was added and the resulting mixture was stirred under reflux for 8 h. The reaction mixture was cooled and extracted with ethyl acetate (total 500 ml). Organic extract was washed with saturated NaCl (150 ml), dried (MgSO₄), treated with charcoal (1.5 g), filtered, and evaporated to dryness. The residue was treated with hot methanol (50 ml) and cooled to -10⁰C to afford crystals, which were filtered and washed with cold methanol to afford 7.84 g (yield 73%, assay 99%) of 2-chloro-5-[l,3]dioxolane-2-yl- 4-(4-fluorophenyl)-6-isopropylpyrimidine.

Example 6. N-[5-[ 1 ,3]Dioxolane-2-yl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N- methylmethanesulfonamide

Sodium hydride (60% suspension in oil, 3.31 g) was added to a solution of N- methylmethanesulfonamide (9.03 g) in dry DMF (80 ml) and stirred for 20 min at room temperature. Then a solution of 2-Chloro-5-[l,3]dioxolane-2-yl-4-(4- fluorophenyl)-6-isopropylpyrimidine (22.4 g) in dry DMF (110 ml) was added. The reaction mixture was stirred at 100 ⁰C for 5 h. After cooling to room temperature the reaction mixture was poured on crushed ice (800 g). Formed precipitate was filtered and washed with water to afford after drying 27.2 g (99%) of N-[5-[l,3]dioxolane-2- yl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl] -N-methylmethanesulfonamide as a white solid, m.p. 155-157 ⁰C.

¹H NMR (CDCl₃) δ: 1.28 (6H, d, J= 6.6 Hz, CH(CH₃)₂), 3.50 (IH, septet, overlapped, CH(CH₃)₂), 3.48 (3H, s) and 3.54 (3H, s) NCH₃ and SO₂CH₃, 3.81-4.21 (4H, m, OCH₂), 5.72 (IH, s, OCH), 7.12 (2H, t, J= 8.8 Hz, 3',5'-H), 7.61 (2H, dd, JH-H= 8.8 Hz, JH-F= 5.4 Hz, 2',6'-H).

Example 7.

N-[4-(4-Fluorophenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-N- methylmethanesulfonamide

Sulfonamide (32.9 g) was suspended in 80% aqueous acetic acid (210 ml) and heated with stirring at 60-70 ⁰C for 10 min. The mixture was cooled and filtered to afford 27.1 g (93%) of N-[4-(4-Fluoroρhenyl)-5-formyl-6-isoρropyl-ρyrimidin-2-yl]-N- methylmethanesulfonamide, m.p. 176-178 ⁰C. The product could be further purified by crystallization from methanol, m.p. 179-180 ⁰C, assay 98.5 %. ¹H NMR (CDCl₃) δ: 1.32 (6H, d, J= 6.6 Hz₅ CH(CH₃)₂), 3.52 (3H, s, CH₃), 3.62 (3H, s, CH₃), 4.01 (IH, septet, J= 6.6 Hz, CH(CH₃)₂), 7.21 (2H, t, J= 8.8 Hz, 2',6'- H), 7.62 (2H, dd, J_H-_H = 8.8 Hz, J_H-F = 5.6 Hz, 3',5'-H), 9.84 ppm (IH, s, CHO). C₁₆H₁₈FN₃O₃S (MW 351.40) Found, (%): C 54.83, H 4.99, N 12.02

Calculated, (%): C 54.69, H 5.16, N 11.96

Claims

. The process for the preparation of a compound of formula I

comprising the steps:

a) protection of the aldehyde group of the compound of formula II

wherein X is halogen, to obtain a compound of formula m

wherein Rl and R2 together form a linear or cyclic aldehyde protecting group;

b) reaction of a compound of formula DI with a suitable isopropyl metallic compound to obtain a compound of formula IV

c) reaction of a compound of formula FV with a 4-fluorophenyl metal compound to obtain a compound of formula V

d) nucleophilic displacement at the 2-position with N-methyl methanesulfonamide to obtain a compound of formula VI

and

e) deprotection the aldehyde group to obtain a compound of formula I.

2. The process for the preparation of a compound of formula I

comprising the steps:

a) protection of the aldehyde group of the compound of formula II wherein X is halogen, to obtain a compound of formula HI'

wherein N-R4 is an aldehyde protecting group, b) reaction of a compound of formula HI' with a suitable isopropyl metallic compound to obtain a compound of formula IV'

c) reaction of a compound of formula IV' with a 4-fluorophenyl metal compound to obtain a compound of formula V

d) nucleophilic displacement at the 2-position with N-methyl methanesulfonamide to obtain a compound of formula VI '

and

e) deprotection the aldehyde group to obtain a compound of formula I.

3. The process according to claim 1 wherein Rl is OR5 or SR5 and R2 is OR5 or SR5 or NR5 and R5 is substituted or non substituted alkyl chain and they together form a linear or cyclic aldehyde protecting group.

4. The process according to claim 1 or 2 wherein the isppropyl metallic compound in step b) is isopropyl magnesium halide.

5. The process according to claim 1 wherein Rl and R2 together form a dioxolane group.

6. The process according to claim 2 wherein R4 is NMe₂, OMe or OBn.

7. The process according to claim 1 or 2 wherein the starting compound of formula II is 2,4,6-trichloropyrimidine-5-carbaldehyde.

8. The process according to claim 1 or 2 wherein the starting compound of formula II is made from barbituric acid by chlorination and formylation.

9. The process according to claim 1 further comprising reacting a compound of formula I to rosuvastatin or pharmaceutically acceptable salts thereof.

10. The process according to claim 2 further comprising reacting a compound of formula I to rosuvastatin or pharmaceutically acceptable salts thereof.

11. The process for the preparation of a compound of formula I comprising removing the aldehyde protecting group in compound of formula VI or formula VF.

12. The process of claim 11 wherein the resulting compound of formula I is further reacted to produce rosuvastatin or a pharmaceutically acceptable salt thereof.

13. Compound of formula VI wherein Rl is OR5 or SR5 and R2 is OR5, SR5 or NR5 and they together form a linear or cyclic aldehyde protecting group wherein R5 is a substituted or non-substituted alkyl.

14. Compound of formula VF wherein R4 is NMe₂, OMe or OBn.

15. N-[5-[ 1 ,3]Dioxolane-2-yl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2- yl]-N-methylmethanesulfonamide.

16. Compound of formula IV wherein X is a halogen and Rl is OR5 or SR5 and R2 is OR5, SR5 or NR5 and they together form a linear or cyclic aldehyde protecting group wherein R5 is a substituted or non-substituted alkyl.

17. Compound of formula V wherein X is a halogen and Rl is OR5 or SR5 and R2 is OR5, SR5 or NR5 and they together form a linear or cyclic aldehyde protecting group wherein R5 is a substituted or non-substituted alkyl.

18. Compound of formula IV', wherein X is a halogen and R4 is NMe₂, OMe or OBn.

19. Compound of formula V, wherein X is a halogen and R4 is NMe2, OMe or OBn.

20. Compound of formula HI₃ wherein X is a halogen and Rl is 0R5 or SR5 and R2 is 0R5 or SR5 or NR5 and R5 is substituted or non substituted alkyl chain and they together form a linear or cyclic aldehyde protecting group.

21. Compound of formula III' wherein X is a halogen and N-R4 is an aldehyde protecting group wherein R4 is NMe₂, OMe or OBn.