FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"NOVEL PROCESS FOR THE PREPARATION OF KEY INTERMEDIATES OF
ROSUVASTATIN"
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company's Act 1957
and having its registered office at
Glenmark House, HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE
INVENTION
1

BACKGROUND OF THE INVENTION
1. Technical Field
The present invention generally relates to a novel process for the preparation of key intermediates of rosuvastatin. More specifically, the present invention relates to an improved process for the preparation of key intermediates of rosuvastatin.
2. Description of the Related Art
The present invention is directed to an improved process for the preparation of compounds having formula I

which are useful for the preparation of rosuvastatin and its pharmaceutically acceptable salts.
2

The rosuvastatin (also known as bis [(E)-7-[4-(4-fiuorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S)-3, 5-dihydroxy hept-6-enoic acid]). Rosuvastatin has the following structural Formula III:

Generally, rosuvastatin is a synthetic lipid-lowering agent that acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMG-CoA Reductase inhibitor). This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. HMG-CoA reductase inhibitors are commonly referred to as "statins." Statins are therapeutically effective drugs used for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. Rosuvastatin is used in the treatment of hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Type Ha and lib). Rosuvastatin calcium is sold under the brand name CRESTOR®.
U.S. Patent No. 5,260,440 ("the '440 patent") discloses pyrimidine derivatives
such as rosuvastatin, its calcium salt (2:1) and its lactone form. The '440 patent discloses
a process for the preparation of rosuvastatin comprises condensing the compound of
formula I with methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-
triphenylphosphoranylidene hexanate followed by desilylation of the resultant product and further reduction of the obtained compound with 1M diethylmethoxy borane in THF/sodium borohydride gives rosuvastatin,which further converted its pharmaceutically acceptable salts.
3

United State patent No. '440 patent', herein incorporated by reference, discloses a process for preparing the compound of formula I. In general, the process includes reacting ethyl isobutyryl acetate with 4-fluorobenzaldehyde to produce Ethyl-3-(4-fluorophenyl)-2-(2-methyl- l-oxopropyl)-prop-2-enoate, which is then reacted with S-methyl isothiourea sulfate to provide ethyl-4-(4-fluoro-phenyl)-6-isopropyl-2-methylthio-3H-pyrimidine-5-carboxylate,which is then reacted with DDQ to give ethyl-4- (4-fluorophenyl)-6-isopropyl-2-methylthio- pyrimidine-5-carboxylate.This intermediate is reacted with m-chloroperbenzoic acid to yield ethyl-4- (4-fluorophenyl)-6-isopropyl)-6-isopropyl-2-methylsulphonyl pyrimidine-5-carboxylate ,which is then further reacted with methyl amine to produce ethyl-4- (4-fluorophenyl)-6-isopropyl-2- (N-methylamino) pyrimidine-5-carboxylate,which is then reacted with sodium hydride and methane sulfonyl chloride to give ethyl-4- (4-fluorophenyl)-6-isopropyl-2- (N-methyl-N-methylsulphonylamino) pyrimidine-5-carboxylate.This intermediate is further reduced using DIBALH followed by oxidation of corresponding hydroxy compound using oxidizing agent like tetrapropylammonium perruthenate (TPAP)/4-methylmorpholin-N-oxide.Oxidation with TPAP is described in Lenz et al. J.Chem.Soc. PT1, 1997, 3291-3292 and in Ley et al., Synthesis 1994, 639-666.The disadvantages associated with this process includes lengthy process, use of hazardous materials like m-chloroperbenzoic acid, sodium hydride, methane sulfonyl chloride, use of expensive oxidizing agent like tetrapropylammonium perruthenate, reagents that are difficult to use on a commercial scale. Also column chromatographic purifications are used for isolation of intermediates. This makes process tedious on plant scale. A process of '440' is schematically represented as below:
4


Patent application no. WO 03/097614A2 describes a process for preparation of rosuvastatin and its pharmaceutically acceptable salts thereof. According to this patent, the compound of formula I is prepared by oxidation of corresponding hydroxy compound using hazardous and expensive chemicals like y-manganese dioxide. The process is not industrially feasible and also is economically expensive.
5

Further, patent application no. WO 2006/017357 Al describes a process for preparation of rosuvastatin and its pharmaceutically acceptable salts thereof. This patent discloses the preparation of compound of formula I by oxidation of corresponding hydroxy compound using 2, 2, 6, 6-tetramethyl piperidinyl oxy free radical (TEMPO) in the presence of sodium hypochlorite (0.7M ,pH-8.8-9.2).The process is not industrially feasible because of hazardous oxidizing agent and also is economically expensive.
U.S. Pat. No. 4,970,313 describes a process for preparation of key intermediates of rosuvastatin and its related compounds. A process for the preparation of the compound of Formula II involves oxidation of its corresponding hydroxy compound by using oxalyl chloride. The process involves the hazardous and expensive chemicals like oxalyl chloride. This process is carried out at cryogenic temperatures like -78°C which is not suitable for scale-up on industrial scale and also economically not viable on commercial scale.
Further, patent application no. US2006/0004200 Al describes a process for preparation of key intermediates (compound formula I and II) of rosuvastatin. This patent discloses the preparation of compound of formula I and II by oxidation of corresponding hydroxy compound using 2, 2, 6, 6-tetramethyl piperidinyl oxy free radical (TEMPO) in the presence of sodium hypochlorite (10%).This process is not industrially feasible because of hazardous oxidizing agent and also is economically expensive.
Accordingly, there remains a need for an improved process for the preparation of a key intermediates of rosuvastatin that eliminates and reduces the problems of the prior art on a commercial scale in a convenient and cost efficient manner.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, a process for the preparation of 4-(4-fluorophenyl)-6-isopropyl-2- (N-methyl-N-methylsulfonylamino)-5-pyrimidine carboxaldehyde,compound of formula I is provided. The process comprising:
A) Condensation of methyl isobutyryl acetate of compound formula XIII and 4-fluorobenzaldehyde of compound formula V in presence of suitable catalyst in organic solvent followed by reacting condensed product with S-Methylisothiourea sulfate and
6

suitable oxidative dehydrogenating agents to yield Methyl-4-(4-fluorophenyl)-6-isopropyl-2-methylthio- pyrimidine-5-carboxylate of compound formula XIV,
B) Oxidation of 2-methylthiopyrimidine of compound formula XIV to give
Methyl-4- (4-fluorophenyl)-6-isopropyl-2-methylsulfonyl pyrimidine-5-carboxylate of
compound formula XV,
C) Reacting the 2-methylsulfonylpyrimidine of compound formula XV with N-methyl methane sulfonamide to give Methyl-4- (4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonylamino) pyrimidine-5-carboxylat of compound formula XVI,
D) Reducing the compound of formula XVI with suitable reducing agent to yield [4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonylamino)pyridin-5-yl] methanol of compound Formula XII,
E) Oxidation of [4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl
amino) pyridin-5-yl] methanol of compound Formula XII with pyridine-sulfur trioxide
complex in the presence of dimethyl sulfoxide/diisopropylethyl amine to give 4-(4-
fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-pyrimidine
carboxaldehyde ,compound of formula I.

In accordance with a second embodiment of the present invention, a process for the preparation of tertiary butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl] acetate comprising oxidation of corresponding hydroxy compound (4R-cis)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxane-4-acetic acid, 1,1-dimethlethyl ester of Formula V using pyridine-sulfur trioxide complex in the presence of dimethyl sulfoxide/diisopropylethyl amine.
7


The advantages of the present invention include at least:
1. Economical process at commercial scale because of the use of inexpensive raw materials.
2. Less reaction steps.
3. Simple reaction conditions provide easier and more economical production.

4. Cryogenic temperatures are eliminated.
5. Hazardous chemicals avoided.
6. Higher yields and purity of key intermediates achieved.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides an efficient, cost effective and ecofriendly process for the preparation of compounds of formula I and II.
One aspect of the present invention provides an improved process for the preparation of key intermediates of Rosuvastatin i.e. compounds of formula I and II on commercial scale.
In another aspect of present invention provides a process for the preparation of 4-
(4-fluorophenyl)-6-isopropyl-2- (N-methyl-N-methylsulfonylamino)-5-pyrimidine
carboxaldehyde, compound of formula I. The reaction sequence can also be represented by following synthetic scheme:
8


This process generally includes the steps of at least:
A) Condensation of methyl isobutyryl acetate of compound formula XIII and 4-
fluorobenzaldehyde of compound formula V in presence of suitable catalyst in organic
solvent followed by reacting condensed product with S-Methylisothiourea sulfate and
suitable oxidative dehydrogenating agent to yield Methyl-4-(4-fluorophenyl)-6-isopropyl-
2-methylthio- pyrimidine-5-carboxylate of compound formula XIV,
B) Oxidation of 2-methylthiopyrimidine of compound formula XIV to give
Methyl-4- (4-fluorophenyl)-6-isopropyl-2-methylsulfonyl pyrimidine-5-carboxylate of
compound formula XV,
C) Reacting the 2-methylsulfonylpyrimidine of compound formula XV with N-
methyl methane sulfonamide to give Methyl-4- (4-fluorophenyl)-6-isopropyl-2-(N-
methyl-N-methylsulphonylamino) pyrimidine-5-carboxylate of compound formula XVI,
9

D) Reducing the compound of formula XVI with reducing agent to yield [4-(4-
flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonylamino)pyridin-5-yl] methanol
of compound Formula XII,
E) Oxidation of [4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl
amino) pyridin-5-yl] methanol of compound Formula XII with pyridine-sulfur trioxide
complex in the presence of dimethyl sulfoxide/diisopropylethyl amine to give 4-(4-
fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-pyrimidine
carboxaldehyde ,compound of formula I.
Step A) of the foregoing process may be carried out in a suitable solvent, for example toluene, cyclohexane, benzene, dichloroethane and mixture (s) thereof at a reflux temperature in the presence of basic catalysts like cyclic secondary amines, beta-alanine, DL-alanine, glycine esters and acidic catalysts like pyridyl carboxylic acids, acetic acid or mixture (s) thereof. The time of reaction may vary from about 15 to about 25 hours. The product can be isolated by conventional method followed by drying or used as is in the next step without purification.The cyclization process may be carried out in a suitable solvent such as hexamethylphosphoric acid triamide,dimethyl formamide, dimethyl sulfoxide,dimethyl acetatmide and mixture thereof using S-methylisothiourea sulfate. The reaction temperature may vary from about 20°C to about 130°C. The time for the reaction may vary from about 18 hour to about 25 hours. The product can be isolated by conventional process. This process can be carried out as per disclosed in prior art. The oxidation process can be carried out in suitable solvent such as toluene, cyclohexane, ethanol, methanol, aliphatic and aromatic halogenated hydrocarbons and mixture thereof. The oxidative dehydrogenating agents can be selected from DDQ, Copper chloride / K2CO3 / TBHP, Ceric Ammonium Nitrate, Nitric acid and Pd/C. The reaction temperature may vary from about 20°C to about 50°C. The time may vary from about 1 hours to about 10 hours. The product can be isolated by conventional techniques followed by drying.
Step (B) of the foregoing process may be carried out in the presence of a suitable solvent such as aromatic hydrocarbons, e.g., toluene, xylene and the like; halogenated solvents, e.g., dichloromethane, 1, 2-dichloroethane, chloroform and the like; and mixtures thereof. A suitable oxidizing agent includes ammonium heptamolybdate
10

tetrahydrate, sodium tungstate, hydrogen peroxide, oxone, sodium metaperiodate, vanadium pentoxide or mixture thereof. The transformation can be carried out in presence of phase transfer catalyst or absence of catalyst. The temperature of the reaction may vary from about 20°C to about 50°C. The time of reaction varies from about 15 to about 20 hours. The product can be isolated by conventional method followed by drying or used as is in the next step without purification.
Step (C) of the foregoing process can be carried out by reacting the compound of formula XV with N-methyl methane sulfonamide using a suitable base such as sodium tert-pentoxide, potassium tert-butoxide, sodium hydride, sodium amide, lithium hexamethyl disilazide (LiHMDS), lithium diisopropyl amide (LDA), potassium carbonate, cesium carbonate and the like in a suitable solvent such as methanol, 2-propanol, dimethylsulfoxide, tetrahydrofuran, toluene,tert-butyl acetate ,n-butyl acetate and the like and mixture thereof. The reaction temperature can vary from room temperature to about 110°C and the time for the reaction can range from about 2 to about 8 hours. The product can be isolated by conventional method followed by drying or used as is in the next step without purification.
Step (D) of the foregoing process can be carried out in the presence of a suitable solvent such as toluene, xylene, mesitylene, dichloromethane, tetrahydrofuran, cyclohexane and the like and mixtures thereof. Suitable reducing agents include, but are not limited to, lithium aluminum hydride,diisobutylaluminum hydride, sodium borohydride/Nickel chloride,lithium triethylborohydride and the like and mixtures thereof. The reaction temperature may vary from about -70°C to about -5 C. The time may vary from about 1 hour to about 5 hours. The product can be isolated by conventional techniques followed by drying or used in the next step without further purification.
Step (E) of the foregoing process can be carried out in the presence of a suitable solvent such as toluene, xylene, mesitylene, dichloromethane, tetrahydrofuran, cyclohexane and the like and mixtures thereof. Suitable oxidizing agent is pyridine sulfur trioxide complex. Suitable bases include, but are not limited to, diisopropyl ethyl amine, triethyl amine, triisopropyl amine and the like. The reaction temperature may vary from about 0°C to about -5°°C. The time may vary from about 1 hour to about 5 hours, product can be isolated by conventional method followed by drying under reduced pressure at

40°C to about 45°C to afford desired product,4-(4-fluorophenyl)-6-isopropyl-2- (N-methyl-N-methylsulfonylamino)-5-pyrimidine carboxaldehyde,compound of formula I.
Thus, obtained compound of formula I can be further used as a key intermediate in the preparation of rosuvastatin or pharmaceutically acceptable salt.
In another aspect of present invention also provides a process for the preparation of tertiary butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl] acetate e,compound of formula II comprising oxidation of corresponding hydroxy compound, (4R-cis)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxane-4-acetic acid, 1,1-dimethlethyl ester of Formula V using pyridine-sulfur trioxide complex in the presence of dimethyl sulfoxide/diisopropylethyl amine in suitable reaction media at temperature less than about 0°C. Above reaction sequence can also be represented by following synthetic scheme:
SCHEME-II
x y
O ^O 0 i Py.S03/DIPEA/ O^^O O .
xvn ° n
This process generally includes the steps of at least (a) oxidation (4R-cis)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxane-4-acetic acid, 1,1-dimethlethyl ester of Formula V using pyridine-sulfur trioxide complex in the presence of suitable base and dimethyl sulfoxide in suitable reaction media; (b) Quenching of reaction mass by addition of water; (c) Organic layer separation and washing with water; (d) drying organic layer over sodium sulfate and evaporation of organic layer.
Step (a) of the foregoing process can be carried out in the presence of a suitable solvent such as toluene, xylene, mesitylene, dichloromethane, tetrahydrofuran, cyclohexane and the like and mixtures thereof. Suitable oxidizing agent is pyridine sulfur trioxide complex. Suitable bases include, but are not limited to, diisopropyl ethyl amine, triethyl amine, triisopropyl amine and the like. The reaction temperature may vary from about 0°C to about -5°°C. The time may vary from about 1 hour to about 5 hours. Step (b) of the foregoing process can be carried out by adding water at about 0°C to about 20°C.
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Step (c) can be carried out by separating organic layer followed by extraction of aqueous layer with reaction solvent and water washing to organic layer to make pH neutral. The temperature may vary from about 20°C to about 25°C.
Step (d) of the foregoing process can be carried out by adding sodium sulfate at about 20°C to about 25°C and solvent may be distilled at about 40°C to about 45°C under reduced pressure to afford the desired compound, tertiary butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl] acetate,compound of formula II.
Thus, obtained compound of formula II can be further used as a key intermediate in the preparation of rosuvastatin or pharmaceutically acceptable salt.
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It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention.



To a four neck clean RB flask, charged cyclohexane (1600.0 ml), acetic acid (50.0 gm, 0.832 moles) and p-alanine (25.0 gm, 0.404 moles) were stirred for 15 min at room temperature. This was followed by addition of 4-fluorobenzaldehyde (174.0 gm, 1.40 moles) and methylisobutyryl acetate (200.0 g, 1.386 moles) at room temperature. The reaction mixture was heated to reflux with azeotropic water removal for 20 to 24 hours. After the completion of reaction, the mixture was cooled and washed with water (400.0 ml), 5% sodium carbonate solution (400.0 ml) and water (2 x 500.0 ml).The evaporation of the solvent furnished olefin as a oil. The obtained residue was taken for next step without purification.
Hexamethylphosphoric acid triamide (1640.0 ml) and S-Methylisothiourea sulfate (218.0 gm, 0.782 moles) added to the above resulted oil at room temperature. This was followed by heating at 100 to 110°C under stirring for 24 hrs. The reaction mass was cooled after the completion of reaction at room temperature. This was followed by addition of toluene (1400.0 ml) and purified water (1400.0 ml) under stirring. The reaction mixture was further stirred for 20 min. This was followed by layer separation. The aqueous layer was extracted with toluene (2 x 350.0 ml toluene) followed by washing, combined toluene layers with 2.5% sodium carbonate solution (700.0 ml) and 25% sodium chloride solution (2 x 700.0 ml).Toluene layer was dried over sodium sulfate (100.0 gm).
To the above dried toluene layer charged slowly 2, 3-dichloro-5, 6-dicyano-l, 4-benzoquinone (184.0 gm, 0.81 moles) over period of 1 hr at 25 to 45 °C under stirring. The reaction mass was stirred for 2 hrs at 25 to 30 °C followed by filtration of reaction mass and washing with 400.0 ml toluene followed by washing with water (3 x 500.0 ml)
14

at 25 to 30 °C. Toluene was distilled under reduced pressure at 50 to 55 °C and Degassed mass for 1 hr under reduced pressure at 50 to 55 °C. This was followed by addition of 400 ml isopropyl alcohol and distilled out completely under reduced pressure at 50 to 55 °C. This was further followed by addition of 400.0 ml isopropyl alcohol and reaction mass was heated to 60 to 65 C get clear solution. The reaction mass was cooled to 25 to 30 °C and stirred for 8 hrs at 25 to 30 °C, cooled to 0 to 5 °C and stirred for 2 to 3 hrs at 0 to 5 °C.Filtered and washed with chilled (0 °C) isopropyl alcohol (2 x 100.0 ml). The wet product was dried at 40 to 45°C under reduced pressure to obtain Methyl-4- (4-fluorophenyl)-6-isopropyl-2-methylthio- pyrimidine-5-carboxylate, compound of formula XIV (174.0 g, 39.15%).

To a four neck clean RB flask, charged dichloromethane (1500.0 ml), Methyl-4-
(4-fluorophenyl)-6-isopropyl-2-methylthio-pyrimidine-5-carboxylate (150.0gm,0.468
moles),ammonium heptamolybdate tetrahydrate (8.62 gm,0.00697 moles) and tricaprylyl
methyl ammonium chloride (Aliquat®336) (21.0 gm,0.047 moles) were stirred at 25 to
30°C. This was followed by the slow addition of 50 % hydrogen peroxide solution (96.5
gm, 1.42 moles) at 20 to 35°C over period of 1 to 1.5 hrs. Reaction mass were further
stirred at 25 to 30°C for 18 to 20 hours. After the completion of reaction charged water
(450.0 ml) and continued stirring for 10 min. This was followed by layer separation. The
aqueous layer was extracted with 130.0 ml dichloromethane. Combined all organic layers
and Washed with water (2 x 500.0 ml). Dichloromethane was distilled under reduced
pressure at 40 to 45°C and followed by degassing for 30 min at 50 to 55°C under reduced
pressure. Isopropyl alcohol (175.0 ml) was added and distilled out under vacuum at 50 to
15

55 °C, followed by the addition of isopropyl alcohol (350.0 ml) and heat to 60 to 65°C to get clear solution. Cooled solution to 25 to 30°C and stirred for 2.0 hrs at 25 to 30°C .Further cooled to 0 to 5 °C and stirred for 2.0 hrs at 0 to 5 °C. Filtered and washed with chilled (0 °C) isopropyl alcohol (100.0 ml). The wet product was dried at 40 to 45°C under reduced pressure to obtain Methyl-4- (4-fluorophenyl)-6-isopropyl-2-methylsulfonyl pyrimidine-5-carboxylate (150.0 g, 90.92%).

Acetonitrile (1000ml), Methyl-4-(4-fiuorophenyi)-6-isopropyl-2-
methylsulfonylpyrimidine-5-carboxylate (145.0 g, 0.411 moles), freshly dried powdered potassium carbonate (85.45 gm,0.618 moles) and N-methyl methane sulfonamide (58.40 gm,0.535 moles) at 25 to 30°C added in four neck round bottom flask. The reaction mass was reflux under stirring under at 80 to 85°C for 2.5 to 3 hours. The reaction mass was cooled at 25 to 30°C after the completion of reaction, which is then followed by filtration and washing with acetonitrile (245.0 ml). Acetonitrile was distilled under reduced pressure at 50 to 55°C followed by degassing for 30 min at 55 to 60°C under reduced pressure. This was followed by addition of isopropyl alcohol (165.0 ml) and distillation under reduced pressure at 50 to 55 °C. Isopropyl alcohol (575.0 ml) was again added and reaction mass was heated to 65 to 70°C to get clear solution. The reaction mixture was cooled to 25 to 30°C followed by stirring for about 4.0 hrs at 25 to 30°C. The reaction mixture was cooled to 0 to 5 °C and stirred for 2.0 hrs at 0 to 5 °C. The reaction mass was filtered and washed with chilled (0 °C) isopropyl alcohol (100.0 ml). The wet product was dried at 40 to 45°C under reduced pressure to obtain Methyl-4- (4-fluorophenyl)-6-
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isopropyl-2-(N-methyl-N-methylsulphonylamino) pyrimidine-5-carboxylate, (138.0 gm, 87.93%)

Dissolved Methyl-4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl
sulphonylamino) pyrimidine-5-carboxylate (130.0 g, 0.340 moles) in toluene (1300.0 ml)
under nitrogen at 25 to 30 °C. The reaction mass was cooled to -10 to -15 °C followed by
the addition of diisobutyl aluminum hydride (730.0 ml, 20% wt in toluene, 1.0266
moles) over period of 1 to 1.5 hrs at -10 to -15.0 °C under stirring for 1 hrs at -5 to -10
°C. After the completion of reaction, diluted HC1 (137.0 ml in 1370.0 ml water) was
added over a period of 30 to 40 minutes, maintaining temperature below -10 °C and
followed by stirring at 35 to 40 °C for 30 to 40 min. This was followed by addition of
ethyl acetate (1000.0ml) and purified water (1000.0 ml) under stirring to the reaction
mass and continued stirring for 10 minutes. This was followed by layer separation.
Aqueous layer was extracted with ethyl acetate (2 x 500.0 ml). Ethyl acetate layer was
washed with 5% sodium bicarbonate solution (1000.0 ml) and 25% sodium chloride
solution (1000.0 ml) followed by the distillation of solvents under reduced pressure at 50
to 55 °C after drying over sodium sulfate followed by degassing mass for 30 min at 50 to
55 °C under vacuum. This was followed by addition of cyclohexane (650.0 ml), heating
the reaction mass at 60 to 65°C to get uniform slurry. The reaction mass was cooled at 25
to 30°C and stirred for 2 hrs at 25 to 30°C. The resulted mass was filtered and washed
with cyclohexane (200.0 ml). The wet product was dried at 40 to 45°C under reduced
pressure to afford [4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-
methylsulphonylamino) pyrimidin-5-yl] methanol (112.0 gm, 93.0%)
17


[4-(4-floiirophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonylamino) pyridine-5- yl] methanol (100.0 gm, 0.282 moles) was dissolved in dimethyl sulfoxide (110.0 gm, 1.41 moles) and dichloromethane (1000 ml). The reaction mass was cooled to 0 to -5 °C and stirred for 15 min at 0 to -5 °C. This was followed by addition of Diisopropylethyl amine (127.56 gm ,0.987 moles) at 0 to -5 °C and stirring continued for 15 min at 0 to -5 °C.
In another flask, pyridine-sulfur trioxide complex (90.0 g, 0.44 moles), pyridine (44.6 g, 0.44 moles) and dimethyl sulfoxide (110.0 g, 1.41 moles) were charged at room temperature and stirred for 10 min at room temperature. The resulting suspension was added to the above alcohol solution in dichloromethane at 0 to -5 °C and stirring was continued for 1 hr at 0 to -5 °C. After the completion of reaction, water (400.0 ml) was added and under stirring for 10 min. This was followed by layer separation. The aqueous layer was extracted with dichloromethane (2 x 200 ml). Dichloromethane layers washed with water (3 x 600.0 ml) followed by drying over sodium sulfate. Dichloromethane was distilled under vacuum at 40 to 45.0 °C and followed by degassed mass for 30 min at 40 to 45.0 °C. Isopropyl alcohol (100.0 ml) was added to the reaction mass and distilled out under reduced pressure at 50 to 55 °C. Isopropyl alcohol (250.0 ml) was again added to the reaction mass and heated the reaction mass at 60 to 65°C to get clear solution. The solution was cooled to 25 to 30°C and stirred for 4 hrs at 25 to 30°C. The reaction mixture was further cooled to 0 to 5 °C and stirred for 2 hrs at 0 to 5 °C. The solid mass and washed with chilled (0 °C) isopropyl alcohol (50.0 ml). The wet product was dried at 40 to 45°C under reduced pressure to obtain. The wet product was dried at 40 to 45°C
18

under reduced pressure to obtain 4-(4-fluorophenyl)-6-isopropyl-2- (N-methyl-N-methyl sulfonylamino)-5-pyrimidine carboxaldehyde, compound of formula I (90.0 gm, 90.5%).

(4R-cis)-6-(hydroxymethyl)-2,2-dimethyl-1,3 -dioxane-4-acetic acid, 1,1 -dimethyl ethyl ester (10.0 g ,0.0385 mol) mol) was dissolved in dimethyl sulfoxide (15.0 g , 0.192 mol) and dichloromethane (100 ml) followed by cooling at 0 to -5 °C. The reaction mass was cooled for 15 min at 0 to -5 °C followed by addition of Diisopropylethyl amine( 17.42 g ,0.1347 mol) at 0 to -5 °C and continued stirring for 15 min at 0 to -5 °C.
In another flask, charged pyridine-sulfur trioxide complex (12.25 g, 0.077 mol), pyridine (6.09 g, 0.077 mol) and dimethyl sulfoxide (15.0 g, 0.192 mol) at room temperature followed by stirring for 10 min. Resulting suspension was added to the above alcohol solution in dichloromethane at 0 to -5 °C and continued stirring for 1 hr at 0 to -5 °C. After the completion of reaction, water (50.0 ml) was added and stirred for 10 min. This was followed by layer separation. Aqueous layer was extracted with dichloromethane (2 x 20 ml).Dichloromethane layer was washed with water ( 3 x 100.0 ml) followed by drying over sodium sulfate and distilled dichloromethane under vacuum at 40 to 45.0 °C. Degased mass for 1 hr at 40 to 45.0 °C under reduced pressure to obtain tertiary butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl] acetate, compound of formula II (9.22 a. 93.0%).