A

Process for the preparation of rosuvastatin by new intermediates

The present invention relates to a new process for the preparation of a HMG-CoA reductase inhibitor rosuvastatin of formula I

which comprises one of the following processes a.) reacting a compound of formula II

-wherein R represents C _1-4 alkyl except tert-butyl group- by alkalic hydrolysis to give a compound of formula III

thereafter reacting with an organic or inorganic base to form a salt, eliminating the acetonide group and reacting with calcium-chloride in a base; or b.) reacting a compound of formula III

with an organic or inorganic base to form a salt, eliminating the acetonide group and reacting with calcium-chloride in a base; or c.) reacting a salt of a compound of formula III

-formed with an organic or inorganic base- by eliminating the acetonide group and reacting with calcium-chloride in a base.

The further subject of the present invention is a compound of formula III and its salts formed by organic and inorganic base.

Rosuvastatin (chemical name: (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy -hept-6-anoic acid calcium salt) and its preparation process is described in European Patent EP 521471. The active ingredient is prepared by the reduction of 7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]ρyrimidin-5-yl](3R)-3-hydroxy- 5-oxo-(E)-heptenoic acid and further steps of preparation. It is not a cost-effective preparation process because the 5S- hydroxy group of the side chain forming heptanoic acid is synthesized at the and of the preparation process, in one of the last steps.

Another preparation process of rosuvastatin is described in International Patent Application WO 00/49014. According to this process tert-butyl-E-(6-{2-[4-(4-fluorophenyl)- 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-v inyl}-((4R,6S)-2,2- dimethyl[l,3]dioxan-4-yl) acetic acid which is a key intermediate and abbreviated as BEM, is prepared by the reaction of diphenyl-[4-(4-fluorphenyl)-6-isopropyl-2-

[methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl]phosphi ne oxide and tert-butyl-2- [(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl] acetic acid.

According to the WO 00/49014 PCT-application the sodium salt of the end product is prepared from BEM by the cleavage of the acetonide protecting group by acid hydrolysis using 0,02 M hydrochloric acid at 40 °C and by the cleavage of the tert-butyl protecting group using 1 M sodium hydroxide at 25 ⁰ C. The carboxylic acid is liberated from the sodium salt of

rosuvastatin with hydrochloric acid (1 M) at -5 °C at a pH between 3. 4 and 4. 0. The methylamine salt is isolated from carboxylic acid with 40 % methylamine solution in water with a yield of 82 %. The methylamine salt is converted again to sodium salt with 8 % w/w aqueous sodium hydroxide solution and the methyl amine is eliminated with a complicated distillation process. The end product is prepared from the sodium salt by calcium chloride dihydrate. The application does not contain any data about the yield of the end product.

International Patent Application WO 00/49014 describes a long, complicated preparation process containing six-operational steps for the preparation of the pharmaceutical drug. The disadvantage of the above mentioned process is the use of methylamine, which is unhealthy. The basic character and the volatility of methylamine induce its toxic, mucosa- destroying, mutagen and teratogen effects. (MSDS Data Sheet: http://physchem.ox.ac.uk/MSDS/; NCI Chem Carcinogenesis Res Info System: http://toxnet.nlm.nih.gov/ ; Schardein JL Chemically Induced Birth Defects 1993;2:842-69 ). The last part of the preparation -before the separation of the calcium salt- does not contain any possibility for the ideal purification. The first obtained sodium salt can not be purified and the methylamine salt prepared from the carboxylic acid can contaminate the product, because its elimination by distillation is difficult.

The above mentioned disadvantages result the low yields, altogether 60-70 % of the preparation process described in WO 00/49014.

International Patent Application WO 2004/108691 relate to an alternative solution for the preparation of rosuvastatin using the BEM intermediate. The end product is obtained from the ester without the preparation of a salt of the intermediate. The difference compared to the preparation process described in WO 00/49014 PCT-application is that the purification

step with methylamine salt is missing and E-7-[4-(4-fluorphenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dili ydroxyhept-6-enoate salt is prepared directly from the sodium salt, obtained by ester hydrolysis. The sodium salt obtained by this process can not be purified.

Considering to the above mentioned disadvantages our aim was to work out a new, simple process for preparing crystalline intermediates of high purity which enables to prepare rosuvastatin with a high purity and with significantly improved yields.

During our experiments a new compound of formula III

and its salts formed by organic or inorganic base was prepared.

Salts of the new compound of formula III can be prepared with high purity and a yield of 90 %. Salts formed from the compound of formula III with an organic or inorganic base can be prepared by a good yield an it can be easily purified. The crystalline nature of these salts ensures a pure end product, which is acknowledged as an important active ingredient in the pharmaceutical industry. The following bases can be used advantageously for the salt formation: methylamine, diethanolamine, ethanolamine, magnesium sulfate, L-lysine,

benzylamine, L(-)-α-methyl-benzylamine or N-methyl-D-glucosamine. Especially preferred

salts are diethanolamine, L-lysine and magnesium salts. These bases are known salt-forming

agents at the salt formation of other active ingredients, as well. (P.H.Stahl, C.G.Wermuth (Eds.) Handbook of Pharmaceutical Salts; Properties, Selection and Use, Wiley-VCH, 2002). The subject of the present invention is a process for the preparation of rosuvastatin of formula I

which comprises one of the following processes b.) reacting a compound of formula II,

-wherein R represents C _1-4 alkyl except tert-butyl group- by alkalic hydrolysis to give a compound of formula III

thereafter reacting with an organic or inorganic base to form a salt, eliminating the acetonide group and reacting with calcium-chloride in a base; or b.) reacting a compound of formula III

with an organic or inorganic base to form a salt, eliminating the acetonide group and reacting with calcium-chloride in a base; or c.) reacting a salt of a compound of formula III

-formed with an organic or inorganic base- by eliminating the acetonide group and reacting with calcium-chloride in a base.

In the preparation of compound of formula I the salt formation is carried out in a hydrous or anhydrous, neutral organic solvent.

In the preparation of compound of formula I the neutral organic solvent is preferably acetonitrile, ethyl-acetate or ethanol.

In the preparation of compound of formula I the salt formation from compound of formula III is carried out with methylamine, diethanolamine, ethanolamine, magnesium

sulfate, L-lysine, benzylamine, L(-)-α-methyl-benzylamine or N-methyl-D-glucosamine.

In the preparation of compound of formula I the salt formation is carried out preferably with diethanolamine, L-lysine or magnesium sulfate.

In the preparation of compound of formula I the elimination of the acetonide group is carried out in neutral solvent in the presence of an acid.

In the preparation of compound of formula I the neutral solvent is tetrahydrofuran.

A further subject of the present invention is a compound of formula III

and its salts formed by organic or inorganic base.

A further subject of our invention is a salt of a compound of formula III formed by methylarnine, diethanolamine, ethanolamine, magnesium sulfate, L-lysine, benzylamine, L(-)-

α-methyl-benzylamine or N-methyl-D-glucosamine.

Other subjects of our invention are (6-{(E)-2-[4-(4-fluorophenyl)-6~isopropyl-2- (methanesulfonyl-methyl-amino)-6-methyl-pyrimidin-5-yl]-viny l}-(4R,6S)-2,2-dimethyl- [l,3]dioxan-4-yl)-acetic acid-diethanolamine salt, (6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl- 2-(methanesulfonyl-methylamme)-6-methyl-pyrimidin-5-yl]-viny l}-(4R,6S)-2,2-dimethyl- [l,3]dioxan-4-yl)-acetic acid-L-lysine salt and (6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methylamine)-6-methyl-pyrimidin-5-yl]-vinyl }-(4R,6S)-2,2-dimethyl- [l,3]dioxan-4-yl)-acetic acid-magnesium salt.

Alkylesters of general formula II was prepared according to the process described in

International Patent Application WO 00/49014 by the reaction of N-[5-[(

diphenylphosphinoil)-methyl]-4-(4-fluorophenyl)-6-isoprop yl-pyrimidin-2-yl]-N-methyl-

methansulfonamide and 6-formyl-2,2-dimethyl-l,3-dioxan-4-yl-acetic acid in the presence of a strong base.

The preparation of an acid of formula III can be carried out by the alkalic hydrolysis of alkylesters of formula II advantageously in tetrahydrofuran with IM sodium hydroxide.

Thereafter a new salt is formed from the compound of formula III with organic or inorganic base in hydrous or anhydrous, neutral solvent. The salt formation is carried out preferably with methylamine, diethanolamine, ethanolamine, magnesium sulfate, L-lysine,

benzylamine, L(-)-α-methyl-benzylamine or N-methyl-D-glucosamine.

Salts formed from the a compound of formula III can be used for the preparation of calcium-E-7-[4-(4-fluorphenyl)-6-isopropyl-2-[methyl(methyls ulfonyl)amino]pyrimidin-5-

yl](3R,5S)-3,5-dihidroxihept-6-enoic acid. Acetonide protecting group was cleaved by heating of the above mentioned salts with 1 M hydrochloric acid solution at 80 ⁰ C and the filterable amorphous solid product can be prepared from a salt -formed with a strong base, preferably with alkali hydroxide- with calcium-chloride solution. After filtering and drying 90 % yield of the active ingredient was obtained.

The main aspect of the present invention is the preparation of rosuvastatin preparing a new carboxylic acid of formula III from the alkyl ester of formula II and purifying by its salts, which were formed with organic or inorganic base. HMG-CoA reductase inhibitor rosuvastatin can be prepared from these salts with a yield of 90%. The advantage of the preparation process of the present invention contrary to the preparation process described in the International Patent Application WO 00/49014 is that methylamine salt is not used. Consequently the difficult elimination of methylamine by distillation has not to bee carried out. A further advantage is that the salt prepared from the base used for the salt formation does not contaminate the end product, because the acetonide protecting group is eliminated at the last step by hydrochloric acid (1 M) and the base is located in the aqueous phase as a hydrochloride salt. This preparation does not increases the number of steps of the process, in the contrary, it makes the process simpler because the base is eliminated by simple salt formation instead of distillation.

The new salts prepared according to the invention can be purified easily. Contrary to the process described in International Patent Application WO 2004/108691, wherein the purification of the amorphous end product can not be carried out, our process ensures the preparation of pure calcium-E-7-[4-(4-fiuorphenyl)-6-isopropyl-2-

[memyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-di hidroxihept-6-enoic acid.

Examples

Example 1

C6-/CE)—2-F4-C4-fluorophenyl)-6-isopropyl-2-methanesulf onyl-methyl-amino) — 6-methyl-

pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethvUl,31dioxan-4-yl) -acetic acid- ethylester

N-[5-[(diphenylphosphinoyl)-methyl]-4-(4-fluorophenyl)-6- isopropyl-pyriinidin-2-

yl]-N-methyl-methanesulfonamide (6.4 g, 14.3 mmol) was dissolved in anhydrous

tetrahydroforan (105 ml) in a flask dried in vacuum at 120 ⁰ C in argon atmosphere and 3 g molecular sieve (Merck, 3 A) was added to the solution and it was cooled to -75-78 ⁰ C in the mixture of acetone and solid carbone dioxide. Sodium-bis-trimethylsilyl-amide (21.2 ml, 21.1 mmol, 1.0 M/THF) was added dropwise to the reaction mixture over 20 minutes. It was stirred and kept at the same temperature for 10 minutes then 6-formil-2,2-dimethyl-l,3- dioxan-4-yl-acetic acid-ethylester (4.1 g, 18 mmol) in toluol (83 ml) was added to the mixture over 20 minutes.

The reaction mixture was stirred at -75 °C for 1 hour and the resulted suspension was warmed up to -20 °C over 1 hour. The reaction mixture was added to water (50 ml) in extraction runnel and the flask was washed with toluol-THF mixture (50 ml, ratio= 1:1) and water then it was extracted twice with brine (2 x 50 ml). The residue was solved in ethanol (30 ml) and the product was crystallized at +4 °C. The crystals were filtered and washed in cold ethanol (20 ml) and dried. Yield: 4.7 g (60%). Melting point: 191-3 ⁰ C.

(6-{(E)-2-[4-(4-fluowphenyl)-6-isopropyl-2-(methanesulfon yl-methyl-amino)-6-methyl- pyrimidin-5-yl] -vinyl}-(4R, 6S)-2,2-dimethyl-[l, 3] dioxan-4-yl)-acetic acid-methylester was prepared according to the method described above in example 1 with the difference that after adding dropwise sodium-bis-trimethylsilil-amide to the parent material 6~formil-2,2-dimethyl- l,3-dioxan-4-yl-acetic acid-methylester was added to the solution. Yield: 4.8 g (63 %) Melting point: 130-132 °C

Example 2 (6-{(E)-2-f4-(4-fluorophenyl)-64sopropyl-2-(methanesulfonyl- methyl-amino)-6-methyl- pyrimidin-5-yl] -yinyl}-(4R, 6S)-2, 2-dimethyl-fl, 3] 'dioxan-4-yϊ) -acetic acid

(6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfo nyl-methyl-amino)-6- methyl-pyrimidin-5-yl]-vinyl}-(4R,6S)-2,2-dimethyl-[l ,3]dioxane-4-yl)-acetic acid ethylester

(5.52g, 10 mmol) was dissolved in tetrahydrofuran (10 ml) and IM sodium hydroxide 30 ml, 30 mmol) was added to the solution by stirring and it was heated to 90-100 ⁰ C. The reaction mixture was kept at this temperature until the parent material is transformed (ca. 4-6 hours).

(It was analyzed by thin layer chromatography on silica gel in toluol-ethyl acetate (6:1)).

The reaction mixture was diluted with ethyl-acetate (50 ml), the aqueous phase was separated and the organic phase was extracted with water (20 ml) then the organic phase was concentrated in vacuum. Water (100 ml) was added to the residue and the solution was treated with 1 M hydrogen chloride solution by cooling with ice-cold water. The precipitated product was filtered off, washed with cold water (2x 50 ml) and dried at 50 ⁰ C.

Yield: 4.9 g (95%)

Melting point: 172-174 °C

Example 3

(6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfo nyl-methyl-amino)-6-methyl- pyrimidin-5-yll -vinyl}-(4R, 6S)-2,2-dimethyl-[l ,3] dioxan-4-yl)-acetic acid -methylamine salt (6-{(E)-2-[4-(4-fluorphenyl)-6-isopropyl-2-(methanesulfonyl- methyl-amino)-6- metliyl-pyriniidm-5-yl]-vinyl}-(4R,6S)-2,2-dimethyl-[l,3]dio xan-4-yl)-acetic acid (4.9 g, 9.4 mmol) prepared according to the method described in example 2 was dissolved in acetonitrile and methylamine (1.7 ml, 25 mmol) in 1 M ethanol was added to the solution and it was heated to 80-90 °C and kept at this temperature for 30 minutes. Then the reaction mixture was stirred at room temperature for 10-16 hours and the product was filtered and washed with cold acetonitrile (30 ml) and dried. Yield: 4.7 g (85%). Melting point: 190-192 °C.

Example 4

(6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfo nyl-methyl-amino)-6-methyl- pyrimidin-5-yl] '-vinyl}-(4R,6S)-2,2-dimethyl-[l ,3) ' dioxan-4-yl) -acetic acid-diethanolamine salt

(6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfo nyl-methyl-amino)-6- memyl-pyrimidin-5-yl]-vinyl}-(4R,6S)-2,2-dimethyl-[l,3]dioxa n-4-yl)-acetic acid- was prepared according to the method described in example 2.

To the solution of (6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl - methyl-ammo)-6-memyl-pvrimidin-5-yl]-vinyl}-(4R,6S)-2,2-dime thyl-[l,3]dioxan-4-yl)- acetic acid (4.9 g, 9.4 mmol) with ethyl-acetate diethanolamine (1.6 ml, 17 mmol) was

added dropwise at 80 ⁰ C. The reaction mixture was stirred for 10-16 hours at room temperature, and the precipitate was filtered, washed with cold ethyl acetate (30 ml) and dried at room temperature. Yield: 4.7 g (75%). Melting point: 151-3 °C.

Example 5

(6-{(E)-2-[4-(4-fluorophenyl}-64sopropyl-2-(methanesulfon yl-methyl-amino)-6-tnethyl- pyrimidin-5-yl] ' -vinyl}-(4R, 6S)-2,2-dimethyl-[l ,3] ' dioxan-4-yl)-acetic acid -ethanolamin salt A (6- {(E)-2-[4-(4-fluorophenyl)-6-isoρropyl-2-(methanesulfonyl-m ethyl-amino)-6- methyl-pyrimidin-5-yl]-vinyl}-(4R,6S)-2,2-dimethyl-[l,3]diox an-4-yl)-acetic acid- was prepared according to the method described in example 2.

A solution of (6- {(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-me thyl- amino)-6-methyl-pyrimidin-5-yl]-vinyl}-(4R,6S)-2,2-dimethyl- [l,3]dioxan-4-yl)-acetic acid (4.9 g, 9.4 mmol) and acetonitrile (110 ml) was heated to 70 °C and 1,1 equivalent ethanolamine was added dropwise to the solution then it was cooled to 50 ⁰ C and kept at this temperature for 120 minutes. The reaction mixture was cooled to room temperature over 2 hours and the mixture was cooled in ice-cool water for another 2 hours, filtered and washed with cold acetonitrile (30 ml). The product was dried in vacuum at 40 ^° C. Yield: 4.9 g (85%).

Melting point: 151 - 153 °C.

Example 6

C6-{fE)-2-f4-C4-fluorophenyl)-6-isopropyl-2-fmethanesulfonyl -methyl-amino)-6~methyl- yyrimidin-5-yl] '-vinyl}-( ^' 4R,6S)-2,2-dimethyl-fl ,3] 'dioxon-4-yl) -acetic acid)-masnesium salt

A (6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl -methyl-amino)-6- methyl-pyrimidin-5-yl]-vinyl}-(4R,6S)-2,2-dimethyl-[l,3]diox an-4-yl)-acetic acid was prepared according to the method described in example 2.

A solution of (6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl -methyl- amino)-6-methyl-pyrimidin-5-yl]-vinyl}-(4R,6S)-2,2-dimethyl- [l,3]dioxan-4-yl)-acetic acid (4.9 g, 9.4 mmol) and acetonitrile was concentrated and the residue was dissolved in water (80 ml). Sodium hydroxide (10 ml, 1 M) was added to the solution and a solution of magnesium sulfate dehydrate (1,4 g, 12 mmol) in water (5 ml) was added dropwise to the reaction mixture. It was stirred for 10-16 hours at room temperature, filtered, washed twice with icy water (2x30 ml) and dried. Yield: 4.8 g (90%). Melting point: 175-182 °C.

Example 7

(6-{(E)-2-[4-(4-βuorophenyl)-6-isopropyl-2-(methanesulfo nyl-methyl-amino)-6-methyl- pyrimidin-5-yll -vinyl}-(4R, 6S)-2, 2-dimethyl-Fl,31 dioxan-4-yl) -acetic acid-L-lysine salt (6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl -methyl-amino)-6- methyl-pyrimidin-5-yl]-vinyl}-(4R,6S)-2,2-dimethyl-[l ,3]dioxan-4-yl)-acetic acid was prepared according to the method described in example 2.

A solution of (6- {(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-me thyl- amino)-6-methyl-pyrimidin-5-yl]-λdnyl}-(4R,6S)-2,2-dimethyl -[l,3]dioxan-4-yl)-acetic acid

(4.9 g, 9.4 mmol) in 80 % ethanol- water 1,1 equivalent L-lysine was added dropwise and the product was filtered, washed with ethanol and dried.

Yield: 4.0 g (60%).

Melting point: 205-208 °C.

Examples 8-10

The following salt were prepared according to the method described in examples 3-7.

(6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfo nyl-methyl-amino)-6-methyl- pyrimidin-5-yl]-vinyl}-(4R, 6S)-2, 2-dimethyl-[l, 3] dioxan-4-yl)-acetic acid -benzylamine salt Yield: 89%;

Melting point: 171-173 °C

(6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfo nyl-methyl-amino)-6-methyl-

pyrimidin-5-yl] -vinyl}-(4R,6S)-2,2-dimethyl-[l,3] dioxan-4-yl)-acetic acid -L(-)-a-methyl-

benzylamine salt Yield: 84% ;

Melting point: 200-202 °C

(6-{(E)-2-[4-(4φuorophenyl)-64sopropyl-2-(methanesulfony l-methyl-amino)-6-methyl- pyrimidin-5-yl]-vinyl}-(4R, 6S)-2, 2-dimethyl-[l, 3]dioxan-4-yl)-acetic acid -N-methyl-D- glucosamine salt Yield: 75% ;

Melting point: 170-172 °C

Example 11

Amorphous (E)-7-f4-(4-fluorophenyl)-6-isopr-opyl-2-(methanesulfonyl-me thyl-amino)- pyrimidin-5-yl] -3 ,5-dihiώ'oxi-hept-6-anoic acid calcium salt (rosuvastatin-Ca)

(6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl -methyl-aniino)-6-methyl- pyrimidin-5-yl]-vinyl}-(4R,6S)-2,2-dimethyl-[l,3]dioxan-4-yl )-acetic acid -methylamine salt (5.52g, 10 mmol) prepared according to the method described in example 3 was suspended in tetrahydrofuran (150 ml) and by stirring hydrochloric acid (1 M, 20 ml, 20 mmol) was added to the suspension and the mixture was heated to 80 ⁰ C. Heating was carried out until the parent material was totally transformed (20-30 minutes). (It was analyzed by thin layer chromatography on silica gel in chloroform-methanol (10:1)).

The reaction mixture was cooled to room temperature and ethyl acetate was added to the solution, then by stirring sodium hydroxide solution (2 M, 15 ml, 30 mmol) was added to the reaction mixture. The organic and aqueous phase was separated and the organic phase was extracted with brine (2x20 ml), and concentrated. The residue was dissolved in water (40 ml) and by stirring and cooling with ice-cool water an aqueous solution of calcium-chloride (1.62 g,ll mmol) in 20 ml water was added dropwise to the solution. The reaction mixture was stirred for 1 hour by cooling then it was stirred for 10-15 hours at room temperature. The precipitated product was filtered off and washed with ice-cool water (3x20 ml). The title product was dried in vacuum at 40 ⁰ C. Yield: 4.5 g (90%). Melting point: 150-180 °C, protracted.