FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
THE PROVISIONAL SPECIFICATION
(See section 10)
1. "Preparation of Alkyl 4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methyIsuIfonyl)amino]-pyrimidine-5-carboxylate and its subsequent conversion to N-[4-(4-fluorophenyl)-5-formyl-6-isopropyl pyrimidin-2-yl]-N-methylmethanesulfonamide-a Key intermediate in the synthesis or Rosuvastatin".
2. CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD - 382210, GUJARAT, INDIA, AN INDIAN COMPANY.
3. THE FOLLOWING SPECIFICATION DESCRIBES AND ASCERTAINS THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

Title:Preparation of Alkyl 4-(4-fluorophenyl)-6-isopiopyl-2-
[methyl(methylsulfonyl)amino]-pyirimidine-5-carboxylate and its subsequent conversion
to N-[4-(4-[fluorophenyl)-5-formyl-6-isopropyl pyrimidin-2-yl]-N-
methylmetbanesulfonamide-a Key intermediate in the synthesis of Rosuvastalin.

FIELD OF INVENTION :
The present invention discloses a novel and improved synthesis of Alkyl 4-(4-fluorophenyl)-6-isopropyl-2-[metliyl(methylsulfonyl)amino]-pyrirnidine-5-carboxylate [herein referred to as "Ester intermediate" - a compound of formula 11A J and its subsequent conversion to N-[4-(4-fluorophenyl)-5-formyl-6-isopropyl pyrimidin-2-yl]-N-methylmethanesulfonamide ( herein referred to as aromatic aldehyde-a compound of formula- II) which is one of the key intermediates to prepare Rosuvastatin( herein referred to as compound of formula-I), the structures of which are as shown below.

BACKGROUND OF INVENTION :
Japan Patent Application no. JP-3-188015 dated I-7-1991, its corresponding US Patent no. 5260440 and EP052I47I disclose a process for synthesis of the ester intermediate [ more particularly ethyl ester] and aromatic aldehyde with a compound of formula -II, as per scheme-1 :
Scheme-1


The use of column chromatography for purification in various steps such as aromatisation, reduction of ester to alcohol and oxidation of alcohol to aldehyde makes this process unattractive for industrial exploitation.
PCT Publication WO03/097614A2 describes the synthesis of aromatic aldehyde of formula-II as per Scheme-2:

This process uses activated y-MnO2 for aromatizalion and a large excess of y-MnO2 is
used at the oxidation step of aryl alcohol to aldehyde conversion.
PCT Application WO 2004/103977 A2 describes the synthesis of ester intermediate of
fomula-IIA as per scheme-3 :
Scheme-3


This method of synthesis uses catalyst such as Lanthanum chloride heplahydrale in the first step DDQ in aromalizalion step mCPBA in the conversion of methyl thio to methanesul fonyl compound.
US6841554 B2 , US2003/00457I8 AI describes the preparation of ester intermediate by a process which is depicted in scheme-4.
Scheme-4

US2003/0199695A1 [ Equivalent to US2004018l065,US6579984,WO2001004l00 ] describes the synthesis of ester intermediate by a process which is described in Scheme-5A and Scheme-5B:

The process uses cyanogens chloride gas which is a toxic and hazardous reagent, difficult to handle on plant and results in impure products with low yields; requires long hour reaction time, and involve column chromatographic isolation procedure at different steps hence unsuitable for commercial manufacture.
It is therefore a longstanding need of the industry to develop a process which does not
have
disadvantages as mentioned in the prior art processes so as to improve upon the overall
economics and feasibility of Rosuvastalin manufacture on a commercial scale.

SUMMARY OF INVENTION :
[1] Methyl 4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-
5-carboxylate [ Methyl Ester intermediate] and subsequent conversion to N-|'4-(4-
fluorophenyl)-5-formyl -6-isopropylpyrmidin-2-y I |-N-methyl methanesulfonamide-
[Aromatic aldehyde] are synthesized by a process which does not involve
(a)use of strong bases like Butyl Lithium, Nail etc for N-methancsulfonylalion of
arylmethanamine,
(b) use of heavy metal oxidizing agents like MnO2 for a normalization step or in oxidation of alcohol to aldehyde step,
(c) use of chromatographic isolation technique at any stage for commercial manufacture of aromatic aldehyde.
(d) use of toxic hazardous gas such as cyanogens chloride
[2] Also it is the object of the present invention to use sodium N-methyl methanesulfonamide as nucleophile for introduction of N-methyl methanesulfonainide group in the pyrimidine ring which involves simultaneous replacement of alkylsulfonyl or aryl sulfonyl group. The present invention is also meant to interpret N-methylmethanesulfonamide as nucleophiie when used with other anion generating bases like carbonates, alkoxides or tertiary amine group of bases or any other class of resins or other super bases.
[3] It is also the object of the present invention to disclose the use of hypochlorite based reagent such as Calcium hypochlorite / TEMPO as an oxidant for effecting the conversion of N-[4-(4-nuorophenyl)-5-hydroxymelhyl-6-isopropyl pyrimidin-2-yl]-N-methylmelhanesulfonamide to N-[4-(4-fluorophenyl)-5-formyl-6-isopropyl pyrimidin-2-yl]-N-methylmethanesulfonamide.

DETAILED DESCRIPTION OF THE INVENTION :
The present invention discloses a novel process to prepare a compound of formula IIA
r-

Formula- HA
And its subsequent conversion to a compound for formula - [B]

Formula-[B] By a known process and finally its conversion to a compound of formula-II by a novel orocesl


Formula-II
The aromatic aldehyde intermediate used to prepare Rosuvastatin can be cost effectively synthesized by our improved method [ by taking Rl as methyl group as representative example] as described below:
The present invention is described by a flow chart given in Scheme-A: Scheme-A

[a] Knoevenagel condensation can be successfully carried out in solvents such as
C|-6 alcohols like isopropanol, ethanol, propanol, butanol; alkanes and cycloalkanes
like hexane, heptane
Cyclohexane , cyclopentane , cycloheptane or mixtures thereof; more preferably
isopropanol,
Arenes like benzene, toluene, xylene etc. and mixtures thereof ; ethers such as
THF,dioxane, n-butyl ether
The base catalyst used to effect the condensation is selected from weak acid salt of strong
secondary nitrogeneous bases like piperidine acetate, pyrrolidine acetate, morphemic
acetate, diethyl amine acetate,
Diisopropylamine acetate; tertiary amines like triethyl amine, N-methyl morpholine, N-
methylpyrrolidine,N-ethyl morpholine , N-ethyl pyrrolidine, diisopropyl cthylamine,
DBU, DBN,TMEDA,
Inorganic catalysis like bicarbonates,carbonates etc.The preferred catalyst is piperidine
acetate.
Use can be made of molecular sieve to enhance reaction efficiency and Dean and stark
method of separating water can be used for solvents which are lighter and immiscible
with water.
The temperature may range from 25º C to reflux temperature of the solvent up to max.
150°C.
As the ketoses to be used is to be converted to aromatic aldehyde, the alkyl part in the
keto ester can be generic alkyl group which may be C1-6 alkyl group, preferably methyl.
By using methyl isobutyroylacetate and p-Fluorobenzaldchyde in I PA as solvent and
using piperidine acetate as catalyst, 86 % yield of condensed ester is obtained with a
GC purity of 98%.
[b] The reaction of Knoevenagel product with S-alkyl [ optionally benzyl ] substituted
thiourea gives cyclized dihydro pyrimidine with correspondingly substituted alkylthio
[optionally benzyl thio] group.
The preferred compound is S-Methyl isothiouronium sulfate.
The solvents used for the cyclization is selected from polar aprotic solvents like dimethyl
sulfoxide, N,N-dimethyl formamide, N,N-dime(hyl acetamidc or mixtures thereof ;
nitrites like acetonitrile, prorjionitrile or mixtures thereof, often involving use of catalysts
which favors the progress of reaction like molecular sieve or other optional water
scavengers.
[c] The aromatization of substituted dihydropyrimidine can be carried out using any
known reagents like
HN03, Mn02, C1O3, Se02 Pt, Pd, RaNi, S, Se, DDQ , Chloranil etc. The preferable is chloranil. Chloranil is recyclable thus not involving ant heavy metal contamination in the finished product.
The solvent selected for aromatization are such as dichloromethane, chloroform, benzene, toluene ,ethyl acetate or mixtures thereof preferably toluene.

The temperature of the reaction is between 25º C to 150º C , preferably 65º C to 70º C. The progress of the reaction is monitored by TLC. After the reaction is over the reaction mass is cooled to room temperature and filtered .The organic phase is treated with water and tetrachloride hydroquinone is removed by washing the organic phase with aq. sodium hydroxide solution ,washed with water , dried over anhydrous sodium sellable and solvent is removed under vacuum to isolate crude product. The crude material is crystallized in 1PA to precipitate aromatized product i.e. methyl 4-(4-lluorophenyl)-6-isopropyl-2-(methylthio)-pyrimidine-5-carboxylate.
[d] Methyl 4-(4-fluorophenyl)-6-isopropyl-2-(methylthio)-pyrimidine-5-carboxylate is
then converted to
Methyl 4-(4-fiuorophenyl)-6-isopropyl-2-(melhanesullbnyl)-pyrimidine-5-carboxylale by using various oxidizing agents such as organic peroxy compounds such as H2O2, perbenzoic acid, m-CPBA, aliphatic percarboxylic acids like peracclic acid, sodium and potassium periodates , sodium percarbonale, sodium perborate, magnesium monoperphlhalale , urea-C1-4 optionally simultaneously using catalyst like sodium tungstate, ammonium amolybdate etc. The preferred reagent is hydrogen peroxide (50 % w/w) and using ammonium molybdate catalyst with it.
The solvent for the reaction is selected from protic solvents such as water,C1-4 alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol ; acids like acetic acid, propionic acid etc. or mixtures thereof . The reaction is exothermic and the temperature of the reaction being maintained at 50 to 52 C and stirred at this temperature till all the starting material is consumed. The progress of the reaction is monitored by performing thin layer chromatography. After the reaction is over the reaction mass is cooled to 0 to 5 C and the product is isolated by filtration. The wet cake is washed with solvent and the product is dried at 55 to 60°C. The yield at this stage is about 88 %.
[e] Methyl 4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl)-pyrimidine-5-carboxylate
is then converted to Methyl 4-(4-fluorophenyl)-6-isopropyl-2-
[methyl((methylsulonyl)amino]-pyrimidine-5-carboxylate by using sodium salt of N-
methyl methanesulfonamide acting as a nucleophile for displacing melhylsulfonyl group
at 2- position.This step offers a general methodology for replacement of pyrimidine 2-
substiluted alkylsulfonyl or arylsulfonyl group by a N-methyl N-methylsullbnyl group,
where the alkyl part of alkylsulfonyl constitute C 1 to C8 aliphatic or branched chain alkyl
orcycloaklyl group and aryl group may be phenyl or substituted phenyl group, preferably
alkyl group is methyl or ethyl , more preferably methyl ; the preferred aromatic part ol'
the arylsulfonyl group is phenyl or benzyl group.
The reagent required for this puipose can be procured from commercial sources or can be conveniently prepared as follows.
A 40 % solution is taken in the multi-necked flask and is cooled to 0 to 2°C and to it is added dropwise methanesullbnyl chloride from dropping funnel.After stirring for about 1 hour, the reaction mass is raised to 25°C and stirred the reaction mass at 25-30°C for 1 hour. The reaction mass is again cooled to 0°C and a concentrated solution of sodium hydroxide is added dropwise at 0 to 2°C and stirred further for about one hour at 0 to

2 ºC. Raise the temperature of the reaction mass to 25 C and stirred at this temperature for
one hour. The reaction mass is then cooled to 0 to 2 C and stirred at 0 to 2 C and filtered
washed with chilled acetone and dried.
The use of sodium salt of N-methyl methanesulfonamide as a nucleophile has several
special advantages due to its structural feature. The advantage lies in (he acidity of N-H
proton adjacent to -SO2- group in the sulfonamide reagent and is far more acidic than N-
H proton of aryl methanamine . In the attachment of melhanesulfonyl group al the N-H
proton of aryl methanamine in the prior art process a strong base like Butyl lithium is
required , but in our case due to acidity of N-H proton in N-methyl methanesulfonamide
even a base like NaOH is sufficient to knock off acidic proton. Moreover negative charge
on sulfonamide N is stabilized due to electron withdrawing adjacent -S02- group and is
thus a stable nucleophile.
Alternatively N-methyl methanesulfonamide and other bases like DBU. diisopropylethyl
amine, DBN, TMEDA etc which effect the abstraction a N-H proton in N-methyl
methanesulfonamide ,can also be used. The solvent selected for nucleophilic substitution
is selected from solvents like DMF, DMSO,NMP,
N,N,N',N'-telramelhyl urea, l,3-Dimethyl-2-imidazolidinone, acetoniliile, sullolane
dimethylacetamide ,THF, dioxane , IPA, butanol, ,dichloromethane , chloroform, toluene
etc. or mixtures thereof.
The temperature of the reaction is between 10 to 120 C and is dependent on the choice of
the solvent.
The preferred solvent is DMF and the preferred temperature of the reaction is from 20 to
35 °C.
The progress of the reaction is monitored by performing thin layer chromatography.
After the reaction is over, the reaction is quenched in chilled water and precipitated
product Methyl 4-(4-nuorophenyl)-6-isopropyl-2-[methyl((methylsulonyl)amino]-
pyrimidine-5-carboxylate is isolated by filtration. The yield of this step is 92 to 95 % .
[f] Methyl 4-(4-fluorophenyl)-6-isopropyl-2-[methyl((methylsulony l)amino]-
pyrimidine-5-carboxylate is converted to N-[4-(4-lluorophenyl)-5-(hydroxvrnethyl)-6-
isopropylpyrimidin-2-yl]-N-methyl methanesulfonamide by carrying out reduction of an
ester to alcohol. Reagents known in the literature for converting an ester to an alcohol
can be used which comprises hydride base reagents like DIBAL,Vilride, NaBH4 based
reagents like tetrabutyl ammoniuin borohydride. DIBAL in hcxane is a reagent of choice
which cleanly converts an ester to an alcohol.
Solvent for the reaction is selected from hcxane, toluene, cyclohexane, THF etc. The
preferred solvent is hexane. The solvent selection is partly fixed by the reagent itself in
that hydride based reducing agents are commercially offered in Hcxane, toluene etc. so
as far as possible use of single solvent is preferable although mixtures thereof can also be
used depending on the solubility requirements of readmits and products formed.
The temperature for the reduction is between 10 to 80° C the preferable temperature is 25
to 30°C.
The progress of the reaction is monitored by thin layer chromatography. After the
reaction is over
Acetic acid is added dropwisc followed by ethyl acetate. The reaction mass is quenched
in water and the layers are separated. Aqueous phase is extracted with ethyl acetate and

combined with main organic phase. The organic phase is washed with aqueous sodium bicarbonate, water and dried over anhydrous sodium sulfate. Removal of solvents under vacuum hexane is added and the product is stirred with hexane at room temperature and filtered to give N-[4-(4-fiuorophenyl)-5-(hydroxymelhyl)-6-isopropylpynmidin-2-yl]-N-methyl methanesulfonamide in 91 to 95 % yield with HPLC purity of 99.6 %
[g] N-[4-(4-nuorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl]-N-melhyl
methanesulfonamide is converted to N-[4-(4-fluorophenyl)-5-lbrmyl -6-
isopropylpyrimidin-2-yl]-N-methyl methanesulfonamide- Aromatic aldehyde. There are many reagents in the literature to carry out this transformation., like Mn02. chromium based reagents , Ni-peroxide, hypochlorite based reagents like NaOCI -TEMPO, Calcium hypochlorite etc. The preferred reagent according to present invention is Calcium hypochlorite- TEMPO [2,2,6,6-Tetramelhyl-l-piperidinyloxy, free radical].
Solvent used for this reaction is from a class of halogenated solvent such as dichloromelhane, chloroform etc. N-[4-(4-lluorophenyI)-5-(hydroxymelhyl)-6-isopropylpyrimidin-2-yl]-N-methyl methanesulfonamide is dissolved in dichloromelhane and the solution is cooled to 0-to5 Ccatalytic quantity of TEMPO is added to it followedby aq. KBr solution. To it is added a slurry of Ca hypochlorite in water at 0 to 5 C.After that a solution of sodium bicarbonate is added in a reaction mixture at 0 to 5 C within 90 minutes.The reaction mass is maintained at 0 to 5 C for 1 hour.The progress ol" the reaction is monitored by TLC. Repeat fresh addition of oxidant if required. Increase the temperature of the reaction mass. Added to it hyllo super eel, reaction mass is filtered and compound is isolated from dichloromethane phase. The residue left after removal of dichloromelhane,. is stirred with hexane and solid product N-[4-(4-fluorophenyl)-5-formyl -6-isopropylpyriinidin-2-yl]-N-methyl methanesulfonamide- Aromatic aldehyde is isolated from reaction mass by nitration and dried. Yield= 85 to 90 % Assay by HPLC=99.6%
The foregoing process is exemplified by the procedures given below. These procedures are understood to be illustrative only and are not intended to limit the scope of the invention in any way.
Stage: -1 Preparation of 2-|(4-fluorophenyl) methylene-4 methyl-3-oxo Pentatonic acid methyl ester
In a round bottom flask , equipped with stirrer, hot plate, water bath, condenser, thermometer and N2 gas purging facility , charge 600 ml Isopropyl alcohol, piperidine (30.08g, 0.3532 mol), Acetic Acid (21.2 g, 0.3530 mol), 4-metliyl-3-oxopcnU.inoie acid methyl ester (200g, 1.3888 mol) and p-fluorobenzaldehyde (189.6g,l .528 mol) under nitrogen atmosphere at 25 °C to 35 "C . Stir reaction mass for 20 lirs and check the progress of the reaction on thin layer chromatography. Distill isopropyl alcohol under vacuum at 55 "C to 65 "C. Cool the reaction mass to 25 "C to 35 °C. Add 400 ml of

DCM at 25 °C to 30 °C into the flask and wash with 20% w/v aqueous sodium metabisulphite (2x 200 ml); 10% w/v sodium bicarbonate 400 ml, followed by 133 ml of DM water to get the neutral pH. Dry the organic layer over anhydrous sodium sulfate. Distill out DCM under vacuum at the temperature below 50 "C. Weight of oily mass 298.5-303 gm % yield = 86.11% GC purity >97.7 %.
Stage: - 2 Preparation of S-methyl isothiourea sulfate
In a round bottom flask equipped with stirrer, hot plate, water bath, condenser , thermometer add at 25 "C to 30 "C , 77 ml of demineralized water, thiourea (lOOg, 1.3137 mol), stir and add dimethyl sulfate (90.64g, 0.7186 mol) slowly over a period of 1.5 hours. Raise temperature to 80 °C and maintain for 30 minutes. Further raise temperature to reflux temperature and maintain for 5 hours. Cool (he reaction mass to 25 to 35 ('C and add 133 nil of isopropyl alcohol and slir for 60 minutes. Filler (he mass and wash the cake twice with 73.5 ml of mixture (100 ml isopropyl alcohol : 47 ml deminaralized water). Dry the product at 70 -75 "C. Weight of dry product =148-152 gin. % Yield = 80-82%; Assay > 98.00%
Stage: -3 Preparation of Methyl 6-(4-fluorophenyl)-4-isopropyl-2-(Methylthio)-1,4-dihydropyrimidine-5-carboxylate
In a round bottom flask equipped with stirrer, hot plate, water bath, condenser , thermometer, charge
1800 ml of dimethyl sulfoxide at 25 to 35 "C. Add 2-[(4-lluorophenyl) methyl one-4 methyl-3-oxo pentanoic acid methyl ester (600g, 2.40 mol), S-Methyl isothiourea sulphate (373.2g, 1.3424 mol), and Triethylamine (147.6g, 1.4588 mol). Stir the mass. Raise the temperature between 70"C to75 "C & maintain for I 7 hrs. Check TLC for product formation. Cool the reaction mass to 10 to 15"C. Add MCI solution (3036 ml of demineralised water & 480 ml of cone. HCI). Extract this aq. Layer with twice with 1020 ml toluene. Separate layers and discard toluene layer. To aqueous layer, add 780 ml of toluene into the flask at 25 to 35 °C. Add 882 ml of 20%) aqueous ammonia slowly. Slir and settle for 30 minutes. Separate the aqueous layer and preserve toluene layer. Extract aqueous layer with 510 ml toluene separate layers and combine organic layer with main organic layer. Wash organic layer with 630 ml DM water. Dry this organic layer over sodium sulfate. Unload & weigh the organic layer. Volume of organic layer containing product = I 710 ml (1.5630 kg) Yield: 49%; purity by HPLC- NLT 80%
Stage: -4 Preparation of Methyl 4-(4-fluorophenyl)-6-isopropyl-2-(methylthio) pyrimidine-5-carboxylic.
In a round bottom flask equipped with stirrer, hot plate, water bath, condenser , thermometer,

Charge toluene (249 ml) at 25 to 35 °C. Add p-Chloranil (42g, 0.1708 mol). Raise the temperature to 65 °C to 70 "C. Add Methyl 6-(4-fluorophenyl)-4-isopropyl-2-(methylthio)-l,4-dihydropyrimidine-5-carboxylale (205.25 g toluene solution) & 70 ml toluene at 65 to 70 "C over a period of 1 hour. Stir the mass at 65 to 70 "C for 4 hours. Check TLC for the completion of the reaction. Filter the contents at room temperature. Wash the wet cake with 42 ml of toluene. Add the filtrate (560 ml) into the flask at room temperature. Wash this organic layer twice with 2% aqueous NaOH solution (394 ml. demineralized water + 7.88 gm NaOH) at 25 to 35"C. Add organic layer into 11.13. Flask. Wash this organic layer twice with (280 ml) of demineralized water at 25 lo 35"C. Dry organic layer using anhydrous sodium sulfate. Distill toluene under vacuum at 50- 55°C. Add (30 ml) of isopropyl alcohol into the flask. Raise the temperature & Stir the contents at 75 to 80('C for 15 minutes. Then cool to 25 to 35 "C. Again stir and cool lo 0 to 2"C & stir for 1 hour. Filter the contents. Wash the cake twice with (10 ml) chilled Isopropyl alcohol. Dry the material at 55 lo 60 "C.
Yield = 25.88- 27.0 gm.;
% yield = 52.12-54.38%
% Purity by IIPLC- 97.46 %
%; Assay- 97.44 %
Stage: -5 Preparation of Methyl 4-(4-tluorophenyl)-6-isopropyl-2- methyl sulfonylpyrimidine-5-carboxylate
In a round bottom flask equipped with stirrer, hot plate, water bath, condenser , thermometer,
charge 1000 ml methanol, start stirring and add methyl 4-(4-fluorophenyl)-6-isopropyl-2-(methylthio)pyrimidine-5-carboxylate (100g,0.3 125 mol) at 25°-300C. Add Ammonium Molybdate tetra hydrate (4.95g, 0.004005 mol) & sulfuric acid (0.32g, 0.00326 mol) at 250-30°C into the flask. Add 106.2 ml H2O2(50%) drop wise in 30 minutes into the flask. Stir for 2 hrs at 40°C - 45°C.Raise the temperature lo 50°C. Slir for 5 hr at 50 C. Check TLC for completion of reaction. Cool the reaction mass to 0 "C. Stir 1 hr at 0 C. Filter it & give 6 times (200 ml) water wash. Dry the material in dryer for 7-8 hr at 55º-60ºC. Weight - 97.5-98.33 gm;
Yield = 0 .98w/w;
Yield = 88.63-89.39 % Purity = 99- 100% by HPLC
Stage: -6 Preparation of Methyl sulphonamidc-N-mcthyl sodium salt:
In a round bottom flask equipped with stirrer, hot plate, water bath, condenser , thermometer,
Charge 272 ml of monomethylamine .Stir and cool to 0°C. Add Methanesulphonyl chloride (lOOg, 0.8723 mol) drop wise into the (flask at 0°C. Stir for 1 hr at 0°C. Raise the temperature of the contents of the flask to 25"-30°C. Slir for I hr at 250-30°C. Cool the contents of the flask to 0°C. Add solution of sodium hydroxide (72gm NaOH in 72 ml water) drop wise at 0°C into the flask. Stir for 1 hr at 0°C. Raise the temperature of reaction mass to 25-30°C and stir for 1 hr. Cool the contents of the flask to 0°C. Stir for 1 hr at 0 C. Filter it; & give washing twice lo the cake with (25 ml) chilled mixture of

methanol: water 40:10 (at 0 C.) Wash the cake with 133 ml chilled acetone (at 0 C). Dry
the wet cake at 55 -60 C for 5-6 hr.
Weight of dry product- 72.5-104 gm.
Actual Yield= 1.476-1.55 w/w, 80-82%;
Assay = NLT- 73.71 % (as such basis) Assay =NLT - 92.33 % (on anhydrous Basis);
Moisture = 22-25% W/W
Stage: -7 Preparation of Methyl 4-(4-Fluorophenyl)-6-isopropyl-2-(N-Methyl-N-Methyl Sulphonyl Amino) Pyrimidine-5-Carboxylate
In a round bottom flask equipped with stirrer, hot plate, water bath, condenser , thermometer, charge 1000 ml DMF at 25-30'C. Add Sodium salt of N-mcthyl methane sulphonamide (106g, 0.63 10 mol), and Methyl 4-(4-fluorophenyl)-6-isopropyl-2-methyl sulfonylpyrimidine-5-carboxylate (lOOg, 0.28406 mol) Stir for I hr at 3()V. Check TLC for completion of reaction. Add 1000 ml of demincralizcd water of 2-5 C. Stir I brat 30°C.Filter it; give 5 X 200 ml water wash .Dry the material at 60°C-65"C lor 8-10 hr. Yield:- 100-102 gm. % Yield-92.42-95.19%, moisture NMT- 0.3 %w/w, Purity by HPLC= 99.85 - 99.9 %
Stage: -8 Preparation of |4-(4-fluorophenyl)-6-isopropyl-2-(N-mefhyl-N-methylsulfonylamino) pyrimidinc-5-yll methanol
In a round bottom flask equipped with stirrer, hot plate, water bath, condenser , thermometer, charge 7.50 lit hexane and (1.00 kg, 2.625 mol) of Methyl 4-(4-Fluorophenyl)-6-isopropyl-2-(N-Methyl-N-Melhyl Sulphonyl Amino) Pyrimidine-5-Carboxylate under stirring under N2 atmosphere at 25- 30 C . Add (6.81 lit, 6.708 mol) DIBAL-H (20 % in hexane) drop wise at 25-30°C into the flask. Stir at 25-30°C lor I hr; check TLC for absence of starting material. Add 1.7 lit. Acetic acid drop wise below 20°C. Add 10.0 lit of ethyl acetate. Stir well for 30 min. Add 7.0 lit water and 2.0 lit HCI into the flask & stir well for 15 min. Separate ethyl acetate layer. Extract the aqueous layer with 5.0-liter ethyl acetate. Add 5.0 liter 6% sodium bicarbonate solution into the flask & stir well for 15 min. (pH 8-9) Separate layer; Give 5.0 lit water wash (twice) lo ethyl acetate layer, (pll neutral) Dry ethyl acetate layer over 0.5 kg Aphid sodium sulphate. Distill ethyl acetate under vacuum at 45°C. Remove traces of ethyl acetate with hexane stripping 5.0 lit (twice). Cool to 25-30"C and add 5.0 lit hexane stir well for 30 min. and filter the solid. Give 1.0 lit hexane wash to the solid. Dry the material in oven at 55°C.
Approx weight of solid = 0.8 kg, Actual yield:-0.85-0.88 kg;
Yield-91.79-95.28%.;
Purity by HPLC= 99.66 - 99.8 %
Stage: -9 Preparation of-(4-fluorophenyl)-6-isopropyl-2(N-methyl-N-Mcthylsulfonylamino) pyrimidine-5-carboxaldehyde

In 2-lit 3-neck flask round bottom flask equipped with stirrer, hot plate, water bath, condenser , thermometer, charge 750 ml of dichloromethane. Add (lOOg, 0.283 mol) [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl- N-methylsulfonylamino)pyrimidine-5-yljmethanol
and stir it to dissolve at RT. Cool the reaction mixture to 0 C Add TEMPO solution (450 mg TEMPO +50 ml dichloromethane ) in reaction mixture at 0 C. Add KBr solution (3.4 gm KBr + 25 ml demineralized [DM] water) in to reaction mixture between 0 C. Add the slurry of Calcium Hypochlorite (60.05 gm Calcium Hypochlorite + 200 ml demineralized water) portion wise into reaction mixture at 0 C within 15 min. Add solution of sodium bicarbonate (sodium bicarbonate 46.8 gms + 468 ml DM water) drop wise in reaction mixture at 0 C within 90 min. Maintain temperature of the reaction mass at 0 C for 60 min. Check TLC for absence of starting material. Add Calcium Hypochlorite solution 2IK Jot drop wise at 0 C (2.9 gm Calcium Hypochlorite + 12 ml water) followed with Sodium bicarbonate (2.25 gm Sodium bicarbonate l 22.5 ml water) solution at the same temperature. Stir reaction mixture at 0 C for 15 min. Check TLC for absence of starting material. Increase the temperature of the reaction mixture to RT. Separate dichloromethane (" DCM] layer and aqueous layer. Extract aqueous layer with 2 X 100 ml DCM. Wash DCM layer with 2 X 100 ml DM water. Separate DCM layer. Dry DCM layer over 50 gm anhydrous sodium sulphates. Distill DCM layer under vacuum at 40 C.Strip reaction mixture with 100 ml hexanes. Stir the reaction mixture with 320 ml hexanes for 60 min at RT. Filter the slurry; give 2 X 100 ml hexanes wash; suck dry for 15 min. Dry the solid at 50 C in tray dryer. Weight of solid -85 gm;
Yield - 85-90%
Purity by HPLC= 96.79 - 98.9 %; Assay by HPLC= 99.05 - 99.63 %