FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
THE PROVISIONAL SPECIFICATION
(See section 10)
1. "A NOVEL AND IMPROVED METHOD OF PREPARATION OF 4-[2-(METHYL-2-PYRIDINYLAMINO)ETHOXY]-BENZALDEHYDE - A KEY INTERMEDIATE OF ROSIGLITAZONE"
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 :
A Novel and improved method of preparation of 4-[2-(methyl-2-
pyridinylamino)ethoxy]-benzaldehyde - a key intermediate of rosiglitazone.
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FIELD OF INVENTION :
The present invention relates to a disclosure of a novel and improved method of preparation of 4-[2-(methyl-2-pyridinylamino)ethoxy]-benzaldehyde [ herein refered to as compound of formula-I] -a key intermediate of rosiglitazone via 4-[2-(methyl-2-pyridinylamino)ethoxy]-benzonitrile [ herein referred to as compound of formula- II]-which is a novel compound. Compound of formula - II is easily and efficiently converted into compound of formula -I for the first time by method disclosed herein.


BACKGROUND OF INVENTION
Organic & Biomolecular Chemistry (2003), 1(24), 4392-4395 describes polymer assisted solution phase synthesis of Rosiglitazone in high purity without the need of conventional chromatographic purification of any intermediates
The process uses hazardous reagents like BH3-THF, polymer assisted solution phase synthesis which require special reagent and infrastructure making it unsuitable for industrial application. As disclosed in WO 2002/051823
European patent application 0306228, describes the coupling reaction of 2-(N-methyl-N-(2-pyridyl)amino)ethanol with 4-fluorobenzaldehyde in the presence of dimethyl formamide as solvent and sodium hydride as a base but no yield has been reported. Cantello et. Al. (J. Med. Chem. 1994,37,3977-85 prepared rosiglitazone and reported a yield of 48 % for the coupling reaction of 2-(N-methyl-N-(2-pyridyl) amino)ethanol with 4-fluorobenzaldehyde at room temperature in the presence of dimethyl formamide as solvent and sodium hydride as base for the synthesis of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde . Further Cantello et. al . ( Bioorg & Med. Chem.. Letters vol 45,p. 1181-84 (1994) have reported a yield of 72 % when the same reaction was carried out at 80 C.
WO 2002/051823 discloses the reaction of 2-(N-methyl-N-(2-pyridyl)amino)ethanol with 4-fluorobenzaldehyde and potassium tert. butoxide in N,N-dimethyl formamide as solvent .The reaction mass was quenched in water and extracted in ethyl acetate with further work up to give 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde with 88 % yield.
Li, Jiaming; Li, Feng; Cha, Dajun describe in Zhongguo Yaowu Huaxue Zazhi (2001), 11(5), 291-292, 294 , describe the synthesis of rosiglitazone wherein 2-chloropyridine is reacted with 2-methylaminoethanol at 120°C for 18 h under bubbling N2, and reacted with 4-fluorobenzaldehyde in DMF in the presence of KOH and TEBA at 120°C for 10 h under bubbling N2 to obtain 4-[2-(N-methyl-2-pyridylamino)ethoxy]benzaldehyde, condensing with 2,4-thiazolidinedione, and hydrogenating in dioxane in the presence of 10%Pd/C. The overall yield was 36.2%.
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WO 200100044240 describes the preparation of 4-[2-(N-methyl-2-
pyridylamino)ethoxy]benzaldehyde as follows:
Pot. tert. butoxide in DMF was added to 2-(N-methyl-N-(2-pyridyl)amino)ethanol in
DMF, followed by addition of 4-fluorobenzaldehyde in DMF and further stirred under
nitrogen for 4 hours at 80°C ; solvent was evaporated and the residue was dissolved in
toluene and extracted with water and brine and solution containing 77% of 4-[2-(N-
methyl-2-pyridylamino)ethoxy]benzaldehyde was used directly in the next step.
A Chinese publication Huaxue Shiji (2000), 22(6), 372 describes Improved method
for the synthesis of 4-[2-(methyl-2-pyridinylamino)ethoxy]benzaldehyde
Reaction of 2-chloropyridine with 2-methylaminoethanol at 120°C for 18 h gave 73.3%
2(N-methyl-N-(2-pyridyl)amino)ethanol , condensation of which with p-
fluorobenzaldehyde in DMF in the presence of KOH and triethylbenzylammonium
chloride at 120°C for 10 h gave 76.1% 4-[2-(methyl-2-
pyridinylamino)ethoxy]benzaldehyde
US 5002953 [Equivalent to EP306228 ] describes preparation of 4-[2-(methyl-2-pyridinylamino)ethoxy]benzaldehyde [in preparation-33 , by an analogous process described in preparation 22] as follows:
Sodium hydride ( 60 % dispersion in oil) was added to a stirred solution of 2(N-methyl-N-(2-pyridyl)amino)ethanol in DMF under an atmosphere of nitrogen. After the vigorous reaction was subsided, 4-fluorobenzaldehyde was added and the reaction mixture was stirred at 80°C for 16 hours , after cooling, the reaction mixture was added to water and extracted with diethyl ether, organic extracts were washed with brine, dried over anhydrous Magnesium sulfate ,filtered and evaporated to dryness. The product was column chromatographed over silica-gel using 1 % methanol in dichloromethane. The prior art processes described above have some of the following drawbacks such as
Low yield processes, involves multi-step extractive work up procedures ,give impure products and degradation products at the step of etherification step, involve chromatographic purification technique, and involve long reaction times. It is therefore a long-felt need of the industry to provide a process which does not have these disadvantages.
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SUMMARY OF THE INVENTION
We disclose herein a novel and improved process , which overcomes the
disadvantages mentioned above.
It is an object of this invention to provide a novel and improved process Other object of the present invention is to develop a process which gives high yield of product at the etherification stage
Yet another object of the present invention is to develop a process with shorter reaction times
Yet another object of the present invention is to develop a process which does not give impure products and degradation products at the step of etherification step. Yet another object of the present invention is to develop a process which does not involve chromatographic purification technique.
Yet another object of the present invention is to develop a process which does not involve multi-step extractive work up procedures.
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DETAILED DESCRIPTION
The present invention is described in scheme-A:
Step-1 2-[methyl(pyridin2-yl)amino]ethanol is reacted with 4-halobenzonitrile (say for example 4-chlorobenzonitrile) using a base in a solvent to give 4-{2-[methyl(pyridin-2-yl)amino]ethoxy]benzonitrile In 4-halobenzonitrile the halogen can be CI, Br, F ; The solvent used for this step is selected from :
Substituted amide solvents like DMF , N,N-dimethyl acetamide, N-methyl pyrrolidone, 1,1,3,3, tetramethyl urea, 1,3-dimethyl imidazolidin2-one and their like, optionally mixtures thereof;
Aromatic solvents like Benzene, toluene, Xylene, ethylbenzene; optionally mixtures thereof;
Ethers like THF ,2-Methyl THF, di-n-propyl ether, di-n-butyl ether, monoglyme, diglyme 1,4- dioxane; DMSO, sulfolane,and their like, optionally mixtures thereof; The preferred solvents are DMF and N,N-dimethyl acetamide , optionally mixtures thereof; The base used for this condensation reaction is selected from:
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Hydrides such as NaH, LiH, CaH2 ; alkoxides of CI to C5 alcohols such as tert.
butoxides of Na and K, Li ; isopropoxides of Na, K; The preferred bases among this
group are sodium hydride; potassium tert. butoxide and sodium tert. butoxide ; the more
preferred base is sodium hydride.
Alkali metal carbonates such as Na2C03, K2C03 Li2C03, Cs2C03 or mixtures thereof;
The preferred base of this group is K2C03 in polar aprotic solvent such as DMF or
DMSO optionally using Phase transfer catalyst.
Alkali metal hydroxides such as NaOH, KOH, LiOH, Ca(OH)2, Ba(OH)2 ; the more
preferred among these are NaOH or KOH with DMSO or sulfolane
Strong tertiary amine bases such as DBU,DBN , TMEDA, and their like;
Phase transfer catalysts used for the coupling reaction is selected from quat. ammonium
salts and phosphonium salts
Quat. ammonium salts have general formula (N+ R1R2R3R4)4 X- and X is monovalent
anion
Where Rl to R4 is CI to C7 alkyl; heteroaryl , aryl such as :
TBAB, TEBA-C1, TBA hydroxide; cetrimide, aliquat-336;
PEG ethers such as PEG -400 PEG-600 ; crown ethers such as 18 crown-6
The temperature of this reaction is from 10 to 150°C ; preferably at 30-35°C for sodium
hydride / DMF ;
The temperature of the reaction is dependent on the type of base selected, and the solvent
selected.
The mode of addition is such that either
A base is added to a mixture of both the reactants taken to gather ; or a mixture of both
the reactants are added to a base in solvent or the 4-halobenzonitrile in solvent is added to
an alkali metal (or alkali earth metal) salt of 2-(N-methyl-N-(2-pyridyl)amino)ethanol) in
solvent.
The progress of this reaction is determined by TLC. The reaction product separated by
aqueous quenching of reaction mass and product is isolated.
Alternatively Reaction of 2-[methyl(pyridin2-yl)amino]ethanol with 4-
hydroxybenzonitrile under Mitsunobu conditions (* pi. refer for analogous example
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ES2154551 page 4 of 26 using PPh3 / DEAD ) can also be used to give 4-{2-[methyl(pyridin-2-yl)amino]ethoxy]benzonitrile .
Alternatively 2-[methyl(pyridin2-yl)amino]ethanol can be converted to 2-[methyl(pyridin2-yl)amino]ethyl chloride by using conventional reagents used for the transformation of primary alcohol group to corresponding chloride which can be O-alkylated in 4-hydroxybenzonitrile with or without Phase transfer catalyst using a base to give a 4-{2-[methyl(pyridin-2-yl)amino]ethoxy]benzonitrile i.e. a compound of formula-II.
Step-2
4-{2-[methyl(pyridin-2-yl)amino]ethoxy]benzonitrile -i.e. compound of formula-II is
converted to 4-[2-(methyl~2-pyridinylammQ)ethoxy]-benzaldehyde i.e. a compound of
formula-I by reaction of a compound of formula-II with Raney Nickel and aqueous
formic acid.
The reference method to effect this conversion is as given in organic Syntheses collective
volume volume-6 page 631.
Raney nickel is taken up in water and to it is added a solution of nitrile dissolved in
formic acid at 30-35 C; The initial quantity of water is taken in such a way that the
concentration of formic acid becomes -75 % v/v.
The reaction mass is stirred at 95-100°C and maintained at this temperature for 4 hours.
The reaction mass is cooled to 30-35°C and filtered thru hyflo bed. The filtrate is cooled
to5-10°C and pH was adjusted to 4.7 to 5 using aqueous ammonia *[ * Other bases such as NaOH, KOH , Na2C03 , K2C03, CsC03 can also be used]. Solid material is separated , filtered and characterized as 4-[2-(methyl-2-pyridinylamino)ethoxy]-benzaldehyde.
In an alternative procedure 4-{2-[methyl(pyridin-2-yl)amino]ethoxy]benzonitrile can be saponified to give 4-{2-[methyl(pyridin-2-yl)amino]ethoxy]benzoic acid which can be converted to 4-{2-[methyl(pyridin-2-yl)amino]ethoxy]benzoyl chloride which can be converted to 4-[2-(methyl-2-pyridinylamino)ethoxy]-benzaldehyde under Rosenmund reaction conditions.
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The present invention is illustrated with following examples which do not limit the scope of this invention.

Example-1
Preparation of 4-[2-(methyl-2-pyridinylamino)ethoxy]-benzonitrile N,N-dimethylformamide (75 ml) was charged, under nitrogen atmosphere, in round bottom flask equipped with mechanical stirrer, addition funnel , condenser and guard tube. To it sodium hydride ( -55-60 % in paraffin oil- 8.2 gm) was added at 30 to 35 C. The reaction mass was stirred for 15 minutes and to it a solution of 2-(N-methyl-N-(2-pyridyl)amino)ethanol) (25 gm) in 50 ml of N,N-dimethyl formamide was added at 30 to 35°C over about 30 minutes. The reaction mass was stirred for one hour at 30 to 35 C .To it a solution of 4-chlorobenzonitrile (22.13 gm) in 50 ml of N,N-dimethyl formamide was added at 30 to 35 C over one hour. The reaction mass was stirred for about four hours at 30 to 35 C.The progress of the reaction was monitored by TLC. The reaction mass was then dumped into 350 ml of ice chilled water. The reaction mass was stirred for 30 minutes. The reaction mass is extracted with toluene (150ml x 2) and collected toluene layer was filtered through hyflo bed and washed with water (350 ml x 2 ) and dried over anhydrous sodium sulfate. The solvent was stripped off with cyclohexane under vacuum to give oily mass .To this was added cyclohexane (75 ml) and stirred for 3-4 hours. The solid was filtered and dried. Weight = 35 gms Yield = 84.4 % Example-2
Preparation of 4-[2-(methyl-2-pyridinylamino)ethoxy]-benzaldehyde from 4-[2-(methyl-2-pyridinylamino)ethoxy]-benzonitrile.
Raney Nickel (6 gm) in 21 ml water were charged in 250 ml capacity round bottom flask equipped with stirrer, condenser, dropping funnel, thermometer . The reaction mass was stirred for 10 minutes . To it, a solution of 4-[2-(methyl-2-pyridinylamino)ethoxy]-benzonitrile ( 12 gm) dissolved in 63 ml of (98% ) formic acid were added at 30-35°C. After the addition was over, the reaction mass was stirred up to 95-100°C and maintained at 95-100°C for four hours. The reaction mass was cooled to 30-35°C and filtered through hyhlo bed. The filtrate was cooled to 5-10°C, pH of the filtrate was adjusted to 4.7 to 5 using 25 % aqueous ammonia. The solid separated, was filtered and washed with water.
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The product was characterized as 4-[2-(methyl-2-pyridinylamino)ethoxy]-benzaldehyde which can be carried forward to rosiglitazone by Knoevenagel condensation followed by reduction of exocyclic double bond. Weight = 9 gm Yield= 73.30 %
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