WO2008072078A1

WO2008072078A1 - An improved process for preparing rosuvastatin caclium

Info

Publication number: WO2008072078A1
Application number: PCT/IB2007/003936
Authority: WO
Inventors: Ramesh Dandala; Sambhu Prasad Sarma Mallela; Sukumar Nandi; Gangadhar Bhima Shankar Nangi; Sunil Kumar Buridipadu; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Ltd
Current assignee: Aurobindo Pharma Ltd
Priority date: 2006-12-13
Filing date: 2007-12-11
Publication date: 2008-06-19
Anticipated expiration: 2009-06-13
Also published as: US8212034B2; US20100029940A1

Abstract

The present invention relates to an improved process for preparing (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-propenal of Formula I which is an intermediate useful in the preparation of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt of Formula II

Description

AN IMPROVED PROCESS FOR PREPARING ROSUVASTATIN CALCIUM

FIELD OF THE INVENTION

The present invention relates to an improved process for preparing (2E)-3-[4-(4- fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]- propenal of Formula I

Formula I

which is an intermediate useful in the preparation of bis[(E)-7-[4-(4-fluorophenyl)-6- isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5- dihydroxyhept-6-enoicacid] calcium salt of Formula II

Ca²⁺ Formula II

BACKGROUND OF THE INVENTION

Rosuvastatin, which is an antihyperchlolesterolemic drug, is chemically known as (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3R,5S)-3,5- dihydroxyhept-6-enoic acid calcium (2: 1) salt of Formula I. Rosuvastatin was for the first time disclosed in US 5,260,440. Rosuvastatin is being marketed under the proprietary name CRESTOR, as an oral tablet, for the treatment of hypercholesterolemia. In view of the importance of Rosuvastatin as a lipid- lowering agent, several synthetic methods have been reported in the literature to prepare Rosuvastatin, some of which are summarized below:

US 5,260,440 discloses a process for preparing Rosuvastatin in examples. The process is as shown below:

IO piethvlmethoxyborane

Il 12 The difficulties in the above process are that the intermediate (A) is not obtained in pure form readily and its purification is tedious and overall yield is extremely low. Even when intermediate (A) is obtained in pure form, further condensation with intermediate (X) to form Rosuvastatin, does not result in Rosuvastatin of right quality as the product contains unacceptable quantity of impurity levels.

WO 03/097614 describes a modified procedure for the preparation of the starting material 4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin- 5-carbaxldehyde and further conversion to Rosuvastatin by condensing with methyl (3R)-3-[(tert-butyldimethylsilyl)oxy]-5-oxo-6-triphenylphosphoranylidene hexanoate. The condensed product was deprotected using methanesulfonic acid and subsequently converted to Rosuvastatin calcium (2:1) salt.

WO 2004/052867 describes a process to prepare Rosuvastatin by condensing 1-cyano (2S)-2-[(tert-butyldimelhylsilyl)oxy]-4-oxo-5-triphenylphosphoran-ylidene pentane with 4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyI)amino]pyrimidin-5- carbaldehyde and subsequent deprotection of silyl group, followed by reduction and hydrolysis.

WO 2000/049014 discloses a novel chemical process for the manufacture of tert- butyl (E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2- methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl}-(4R,6S)-2,2- dimethyl[l,3]dioxan-4-yl)acetate which comprises reaction of diphenyl {4-(4- flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl- methyl}phosphineoxide with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan- 4-yl]acetate and its further conversion to Rosuvastatin.

WO 2004/014872 describes a process for the manufacture of Rosuvastatin calcium (2: 1) salt which comprises mixing a solution of calcium chloride with a solution of water soluble salt of (E)7-[4-(4-fluorophenyl)-6-isopropyl-2-

[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid. This process for the preparation of Rosuvastatin employs the use of phosphorane side chain, the preparation of side chain requires eight synthetic steps and involves expensive reagents. The process is both uneconomical and time consuming, hence not appropriate for commercial scale operation.

WO 2006/100689 Al discloses a process for preparation of Rosuvastatin as shown below :

In the above scheme R|, R₂, R₃ represent substituted or unsubstituted phenyl and R₄ represents an aliphatic residue selected from Ci-C₄ alkyl, R₅ represents C₁-C₄ alkyl which is optionally substituted by hydroxyl, R₆ represents hydrogen, halogen, Ci-C₄ alkyl or Cj-C₄ alkoxy, R₇ represents aliphatic residue, R₈ represents Ci-C₄ alkyl

WO 2006/106526 A l describes the preparation of Rosuvastatin as shown below :

Resolution

In the above mentioned scheme Ri, R₂, R₃ are substituted or unsubstituted phenyl and R₄ is an aliphatic residue selected from C₁-C₄ alkyl, R₅ represents C₁-C₄ alkyl, M is an alkali metal salt, X represents a halogen, R₆ represents Ci-C₄ alkyl which is optionally substituted by hydroxy I, R₇ represents hydrogen, halogen, Ci-C₄ alkyl or Ci-C₄ alkoxy, R₈ is an aliphatic residue selected from Ci -C₄ alkyl.

We have now found an improved process to prepare (2E)-3-[4-(4-fIuorophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-propenal of Formula I and subsequently converting the compound of Formula I to Rosuvastatin.

OBJECTIVE

The main objective of the present invention is to provide an improved process for preparing (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylarnino)pyrimidin-5-yl]-propenal which is useful intermediate in the preparation of Rosuvastatin.

Yet another objective of the present invention is to provide an improved process for preparing (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-propenal, which is simple, industrially applicable and economically viable.

Another objective of the present invention is to provide a process for a novel intermediate that is used in the preparation of Rosuvastatin calcium.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for preparing (2E)-3-[4-(4- fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]- propenal of Formula I, Formula I

which comprises: a) reacting 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-carboxaldehyde of Formula III,

Formula III

with a compound of Formula IV a or Formula IV b in an inert organic solvent

Formula IV b

Formula IV a

wherein Ri, R₂, R_3, represents phenyl, substituted phenyl, R₄ represents an aliphatic residue selected from C₁-₄ alkyl, R₅ and R₆ represent CM alkyl, aralkyl, phenyl and substituted phenyl to obtain a compound of Formula V,

U Formula V

wherein R₄ is as defined above, b) converting the compound of Formula V with an aqueous base in a water miscible solvent to give a compound of Formula VI,

F^{θrmula VI}

wherein M represents hydrogen or alkali metal, c) treating the compound of Formula VI with a compound of Formula VII,

o Il X-C-O- R Formula VII

X represents halogen and R represents Ci_-4 alkyl in the presence of an organic base in an inert solvent to give a compound of Formula VIII,

Formula VIII

wherein R is as defined above, d) reducing the compound of Formula VIII to give a (2E)-3-[4-(4-fluorophenyl)- 6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]propen-l-ol of Formula IX,

Formula IX

e) oxidizing the compound of Foπnula IX to give 3-[4-(4-fluorophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-propenal of Formula I.

In another embodiment of the present invention, the (2E)-3-[4-(4-fluorophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-propenal of Formula I is converted to Rosuvastatin and its pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The main objective of the present invention is to provide a new improved process for the preparation of Rosuvastatin in high yield and high purity.

Another objective of the present invention is to develop a new process for the preparation of compound of Formula I so as to facilitate the preparation of Rosuvastatin in high yield and high purity.

The compound of Formula III is reacted with phosphorane of Formula IV a or phosphonate of Formula IV b in an inert organic solvent like acetonitrile, tetrahydrofuran or alcholic solvents like isopropyl alcohol, methanol, ethanol or methyl tert-butyl ether, toluene, halogenated hydrocarbons like methylene chloride or ethylene dichloride, optionally in the presence of a base at temperature in the range of 0-100 ⁰C, preferably between 20-80 ⁰C. The preferred solvent is isopropanol. The condensation reaction of compound of Formula III with compound of Formula IV a or IV b results in the formation of compound of Formula V.

The compound of Formula V is converted to compound of Formula VI in the presence of aqueous base in water miscible solvent. The aqueous base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide etc more preferably sodium hydroxide. The water miscible solvent is selected from ethanol, methanol, tetrahydrofuran, isopropyl alcohol etc. The reaction is conducted at a temperature ranging from 0-80⁰C, preferably at 0-30⁰C. The hydrolysis reaction yields the compound of Formula VI that is isolated as an r.lkali metal salt.

The compound of Formula VI is further converted to its mixed anhydride by treating the compound of Formula VI with a compound of Formula VII in the presence of an organic base like trialkylamines in an inert solvent. The compound of Formula VII is selected from methyl chloroformate, ethyl chloroformate, 2,2,2- trichloroethylchloro formate etc. more preferably methyl chloroformate.

The inert solvent is selected from methylene chloride, ethylene dichloride, toluene, hexane etc more preferably methylene chloride. This reaction is conducted at a temperature ranging from -5O⁰C to 50⁰C, more preferably at 0-10⁰C to obtain compound of Formula VIII. The compound of Formula VIII can be optionally crystallized using suitable organic solvent like hexane, heptane, ethyl acetate, toluene or a mixture thereof. The compound of Formula VIII is reduced to compound of Formula IX with reducing agents like lithium aluminium hydride, diisobutyl aluminium hydride, sodium borohydride, vitride etc. The reduction is performed in suitable inert organic solvent like tetrahydrofuran, toluene, methyl tert-butyl ether, isopropyl ether etc more preferably tetrahydrofuran. The reduction step is performed in the temperature ranging from -80 °C to 80 ⁰C, more preferably -80 ° to -15°C. to give compound of

Formula IX.

The compound of Formula IX is further oxidized to compound of Formula I using Pyridinium dichromate, pyridinium chloro formate, 1,2,2,6,6-tetramethyl-l- piperidinyloxy catalyzed sodium hypochlorite, tetrapropyl ammoniumperruthenate with N-methylmorpholine N-oxide, swern oxidation, manganese dioxide etc, more preferably manganese dioxide in an inert organic solvent like methylene chloride, ethylene dichloride, toluene, hexane, heptane etc, more preferably toluene.

Finally the compound of Formula I is converted to Rosuvastatin by the known methods reported in literature.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

Example 1

Preparation of 3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl](2E)-propenoic acid A suspension of methyl 3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl](2E)-propenoate (10 g) in ethanol (200 ml) was treated with aqueous sodium hydroxide solution (0. IN, 246 ml) at 0-5⁰C. The reaction mixture was stirred at 25-3O⁰C for 12 h for completion of hydrolysis and ethanol was evaporated under reduced pressure. The resulting mass was acidified and extracted with methylene chloride (2 X 100 ml). The organic layer was washed with water, dried and concentrated to give the title product (Yield 9.4 g).

¹H NMR (300 MHz) in DMSO-d₆ δ(ppm) : 1.32 [d, J = 9Hz, 6 H), 3.35-3.46 [m, 1 H), 3.60 (s, 3H,), 3.62 (s, 3H), 5.8 (d, 1 H, J = 15Hz, H), 7.17 (m, 2H), 7.59 (m, 2H), 7.84 (d, 2H, J = 15 Hz}

Example 2

Preparation of 3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl](2E)-propenoyl methyl carbamate

3-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin- 5-yl](2E)-propenoic acid (5 g, 0.012 m) was dissolved in methylene chloride (25 ml) and triethylamine (1.54 g, 0.015 m) was added at 25⁰C. The mixture was cooled to O⁰C and methyl chloro formate (1.31 g, 0.013 m) was added to the reaction mass slowly over a period of 10 min keeping the temperature below 5⁰C. The reaction mixture was stirred at 0-5⁰C for 30 min and water (25 ml) was added to it. The organic layer was separated and washed with aqueous sodium bicarbonate solution (5% w/v, 20 ml) followed by water (20 ml). Methylene chloride was distilled out under reduced pressure at 40-45⁰C to obtain the product as an oily mass, which was crystallized from n-hexane to obtain while crystalline solid (Yield: 5.4 g, 98%).

¹H NMR (300 MHz in CDCI₃;δ(ppm) : 1.32 [d, 6H, J = 9Hz), 3.35-3.42 [m, IH), 3.52 (s, 3H ), 3.6 (s, 3H), 3.94 (s, 3H),5.87 (d, IH, J = 15Hz, H), 7.15 (m, 2H), 7.59 (m, 2H),7.91 (d, 2H, J = 15 Hz).

Example 3

Preparation of 3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl](2E)-propenol

LiAIH₄ (0.5 g, 0.01 m) in tetrahydrofuran (50 ml) was cooled to -5O⁰C and a solution of 3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl](2E)-propenoyl methyl carbamate (5 g, 0.01 m)

!6 in tetrahydroftiran (15 ml) was added dropwise, over a period of 15 min, keeping the temperature below -45⁰C. The reaction mixture was stirred for 30 min at -45 to - 5O⁰C and brought to room temperature. The reaction mixture was quenched by adding IN hydrochloric acid (20 ml) and filtered through hyflo. The product was extracted using ethyl acetate (2 x 25 ml) and washed with water (25 ml). The organic layer was dried over sodium sulfate and evaporated to obtain the pure pyrimidine alcohol (Yield: 4.3 g, 98%).

Example 4 Preparation of 3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(2E)-propenol

To a cold mixture of 3-[4-(4-fluorophenyl)-6-isopropyl-2-

[methyl(methylsulfonyl)amino]-pyrimidin-5-yl]-(2E)-acrylic acid (5 ml) in THF (50 ml) methylchloroformate (1.5 ml) was added dropwise at 0-5⁰C. Reaction mixture was stirred at this temperature for 30 min and sodium borohydride (0.5 g) was added at 0-5⁰C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 h. After completion of the reaction, mixture was poured on a cold HCl (100ml) and extracted with ethyl acetate (50ml). Organic phase was washed with aqueous sodium bicarbonate (2x50 ml), dried and evaporated to give crude product which was purified by column chromatography using ethyl acetate and hexanes (1 :9) to give pure 3-[4-(4-fIuorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(2E)-propenol.

Example 5 Preparation of 3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(2E)-propenol

To a solution of 3-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amine]- pyrimidin-5-yl]-(2E)-l-oxo-propenyl-methylcarbonate (0.5 g) in THF (50 ml) sodium borohydride (0.05 g) was added at 0-5⁰C and the reaction mixture was allowed to warm to room temperature and stirred for 30 h. After the usual work-up, the reaction product was purified by column chromatography using hexanes and ethylacetate (9: 1) to yield 0.4 g of 3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonyiamino)pyrimidin-5-yl]-(2E)-propenol.

Example 6

Preparation of 3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(2E)-propenal 3-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin- 5-yl](2E)-propen-l-ol (5 g ) was dissolved in toluene (50 ml) at 25⁰C and manganese dioxide (20 g) was added to it. The reaction mixture was stirred for 5 h at 25⁰C. After completion of the reaction, reaction mixture was filtered through hyflo and toluene was evaporated under reduced pressure at 4O⁰C to obtain the product as a semi solid. The product was further crystallized from hexane-ethyl acetate (20 ml, 9: 1 v/v) (Yield: 4.8 g).

Claims

We Claim:

1. An improved process for preparing (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N- methyl-N-methylsulfonylamino)pyrimidin-5-yl]-propenal of Formula I,

Formula I

which comprises: a) reacting 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amino)pyrimidin-5-yl]-carboxaldehyde of Formula III,

Formula III

with a compound of Formula IV a or Formula IV b, in an inert organic solvent

Formula IV b

Formula IV a

wherein Ri, R₂, R₃, represents phenyl, substituted phenyl, R₄ represents an aliphatic residue selected from Ci_-4 alkyl, R₅ and R₆ represent C M alkyl, aralkyl, phenyl and substituted phenyl to obtain a compound of Formula V, Formula V

Formula VI

O Il X-C-O- R Formula VII

X represents halogen and R represents Ci^ alkyl in the presence of an organic base in an inert solvent to give a compound of Formula VIII,-

Formula VIII

Formula IX

e) oxidizing the compound of Formula IX to give 3-[4-(4-fluorophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-propenal of Formula I.

2. The process according to claim 1 converting the 3-[4-(4-fiuorophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-propenal of

Formula I to Rosuvastatin and its pharmaceutically acceptable salts.

3. The process according to claim 1, wherein the inert organic solvent used in step (a) is selected from acetonitrile, tetrahydrofuran or alcholic solvents like isopropyl alcohol, methanol, ethanol or methyl tert-butyl ether, toluene, halogenated hydrocarbons like methylene chloride or ethylene dichloride.

4. The process according to claim 1, wherein aqueous base used in step (b) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide etc more preferably sodium hydroxide.

5. The process according to claim 1, wherein the water miscible solvent is selected from ethanol, methanol, tetrahydrofuran, isopropyl alcohol.

6. The process according to claim 1, wherein the organic base is a trialkylamine.

7. The process according to claim 1 , wherein the inert solvent is selected from methylene chloride, ethylene dichloride, toluene, hexane etc more preferably methylene chloride.

8. The process according to claim 1, wherein the reducing agent used in step (d) is selected from lithium aluminium hydride, diisobutyl aluminium hydride, sodium borohydride, vitride.

9. The process according to claim 1, wherein the oxidixing agent used in step (e) is selected from pyridinium dichromate, pyridinium chloroformate, 1,2,2,6,6- tetramethyl-1-piperidinyloxy catalyzed sodium hypochlorite, tetrapropyl ammoniumperruthenate with N-methylmorpholine N-oxide, swern oxidation, manganese dioxide etc, more preferably manganese dioxide.