DATE AND SIGNATURE (to be given at the end of last page of specification) I
6. ABSTRACT OF THE INVENTION (to be given along with complete specification on separate page)

Novel Amine Salts of a Drug
Field of the Invention:
The present invention relates to novel amine salts of a drug i.e. active pharmaceutical ingredient (API) and their intermediates. The novel amine salts of a drug having the following general formula-1.

Formula-1 Wherein each R1 and R2 are independently selected from hydrogen, straight or branched alkyl group having 1 to 4 carbon atoms and n denotes an integer from 0 to 5.
Background of the Invention:
The number of amine salts of active pharmaceutical ingredients (API) and their intermediates are known in the art. Even though amine salt of most of the drugs are not likely to be used for administration of a patient, it is evident from the available prior art processes, they provide a method for purifying the Active pharmaceutical ingredient through crystallization.
The purity of the active pharmaceutical ingredient is necessary condition in the commercial manufacturing process. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. The ICH guidelines for Active Pharmaceutical Ingredient manufacturers requires that process impurities to be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction in the manufacturing process. Hence it is important to have a purification method in the manufacturing process of any API to remove the impurities which are formed in the chemical reactions as well as by unused reagents and raw materials etc. The purification can be done in any steps of the manufacturing process for example at an intermediate stage or at the final stage.

The prior art teaches number of ways for the purification of active pharmaceutical ingredients, in which purification through formation of amine salt of an intermediate compound or final stage compound proves to be beneficial in providing high pure form of drug. In the prior art, number of drugs and their intermediates are purified through the salt formation with amine. For example, in the synthesis of important drug like rosuvastatin the final compound purity attained by the formation of crystalline ammonium salts like methyl ammonium, ethyl ammonium, diethanol ammonium, tris(hydroxymethyl)methyl ammonium, benzyl ammonium, 4-methoxy benzyl ammonium, cyclohexyl ammonium, diisopropyl ammonium, isopropyl ammonium, dicyclohexyl ammonium and (S)-(+)- methyl benzyl ammonium and then converting the same in to rosuvastatin or its pharmaceutically acceptable salts (i.e., US 6841554). And also in the synthesis of pure Montelukast, the purity was attained by the formation of salts with amine like tertiary butyl amine, dicyclohexylamine, methylbenzyl amine, dicyclohexyl amine and cyclohexylethyl ammonium salts of montelukast and converting the same into montelukast or its pharmaceutically acceptable salts (i.e., in EP 0737186 & WO 2006/043846), The purification of hydroxy intermediate compound of ezetimibe through amine salt to prepare a high pure ezetimibe is disclosed in our application number PCT/IN07/00400.
It is evident from the available prior art processes, the purification through crystalline amine salt is mandatory for the most of the Active Pharmaceutical Ingredients or intermediates to get the required purity. Even though numbers of amine salts are known in the art for the purification of active pharmaceutical ingredients, it will be appreciable to have a new amine salt in a crystalline form to perform the purification and thereby increasing the purity of pharmaceutically useful compounds provides a new opportunity to improve the performance characteristics of a pharmaceutical product. Those skilled in the pharmaceutical arts understand that purification of an intermediate or final compound through crystallization offers the best method for attaining important qualities like chemical quality, particle size, and polymorphic content. Thus there is need in the art for a process for preparing other possible amine salts of Active pharmaceutical Ingredient in higher yields in a commercial scale.

Brief description of the Invention:
Accordingly, the first aspect of the present invention provides a salt of a Drug with an amine, characterized in that said amine is selected from the group consisting of amines of the following formula-1,

Formula-1 Wherein each R1 and R2 are independently selected from a hydrogen atom, straight or branched alkyl group having 1 to 4 carbon atoms and n denotes an integer from 0 to 5.
The salts of a drug with an amine can be prepared by treating the crude form of a drug with suitable amine salts in a suitable solvent and maintaining the reaction mixture for a sufficient period of time to form the amine salt of drug and finally recovered the compound from the reaction mixture by filtration.
The second aspect of the present invention is to provide thiophene-2-ethyl amine salt of montelukast compound of formula-la in a crystalline form. The thiophene-2-ethylamine salt of montelukast compound of formula-la of the present invention is characterized by PXRD pattern, IR spectrum and DSC thermo gram.
The novel amine salts of montelukast of the present invention is readily isolable in a crystalline form and can be used for the purpose of purification in the preparation of montelukast and/or its pharmaceutically acceptable salts like sodium.
The third aspect of the present invention is to provide a process for the preparation of thiophene-2-ethyl amine salt of montelukast compound of formula-la, which comprises of the following steps,
a) Treating the crude montelukast free acid with thiophene-2-ethylamine in a suitable solvent,
b) stirring the reaction mixture for sufficient period of time for the formation of thiophene-2-ethylamine salt of montelukast,
c) separating the solid by filtration and washing with suitable solven

d) optionally purifying the montelukast thiophene-2-ethylamine salt compound of formula-1 using suitable solvent,
e) drying the solid to get the thiophene-2- ethyl amine salt of montelukast.
The fourth aspect of the present invention is to provide the use of novel thiophene-2-ethylamine salt of montelukast in the preparation of pure montelukast and/or its pharmaceutically acceptable salts.
The process for the preparation of pure montelukast and/or its pharmaceutically acceptable salts such as sodium from the thiophene-2-ethyl amine salt compound of formula-la comprises of the following steps;
a) Adding thiophene-2-ethylamine salt of montelukast to a agitated mixture of suitable solvent and water,
b) adding suitable organic acid to the above suspension,
c) distilling the organic layer containing montelukast free acid,
d) adding a suitable solvent to above crude followed by treating it with sodium ion source in a suitable solvent to get montelukast sodium compound of formula-2.
The fifth aspect of the present invention is to provide thiophene-2-ethyl amine sah of rosuvastatin compound of formula-lb in crystalline form. The thiophene-2-ethylamine salt of rosuvastatin compound of the present invention is characterized by PXRD pattern, IR spectrum and DSC thermo gram.
The sixth aspect of the present invention is to provide a process for the preparation of thiophene-2-ethyl amine salt of rosuvastatin compound of formula-lb in crystalline form, which comprises of the following steps,
a) Hydrolysing the rosuvastatin amide with suitable base in a suitable alcoholic solvent followed by treating with thiophene-2-ethylamine,
b) stirring the reaction mixture for a sufficient period of time to produce the thiophene-2-ethylamine salt of rosuvastatin,
c) separating the solid by filtration and washed with suitable solvent.

d) optionally purifying the rosuvastatin theiophene-2-ethyl amine salt compound of formula-1 using suitable solvent,
e) drying the solid to get the thiophene-2- ethyl amine salt of rosuvastatin.
The seventh aspect of the present invention is to provide the use of novel organic amine salts of rosuvastatin in the preparation of pure rosuvastatin and/or its pharmaceutically acceptable salts especially calcium salt of rosuvastatin, which comprises of reacting the thiophene-2-ethylamine salt of rosuvastatin with suitable alkali base in a suitable solvents followed by treating with suitable calcium ion source.
Advantages of the present invention:
• Provide a novel thiophene alkyl amine salt of a drug such as montelukast and rosuvastatin.
• Provides improved quality of a drug through novel amine salts
• The thiophene-2-ethylamine salt of montelukast & rosuvastatin is free flow solid which is easy to handle in further reaction.
• Thiophene-2-ethylamine is easily recoverable and reusable/recyclable, which leads to more economic product.
• Environment friendly and cost-effective process.
Brief Description of the Drawings
Figure-1: Illustrates the powder X-ray diffraction pattern of thiophene-2-ethylamine salt
of montelukast.
Figure-2: Illustrates the IR spectrum of thiophene-2-ethylamine salt of montelukast.
Figure-3: Illustrates the DSC of thiophene-2-ethyl amine salt of montelukast.
Figure-4: Illustrates the powder X-ray diffraction pattern of thiophene-2-ethylamine salt
of rosuvastatin.
Figure-5: Illustrates the IR spectrum of thiophene-2-ethylamine salt of rosuvastatin.
Figure-6: Illustrates the DSC of thiophene-2-ethyl amine salt of rosuvastatin.

Detailed description of the present Invention:
As used herein the term "drug" refers to Active Pharmaceutical Ingredient
The term "polar protic solvents" refers to water and the like
The term "hydrocarbon solvents" refers to toluene, xylene, cyclohexane, hexane, heptane and the like.
The term "ketone solvents" refers to acetone, methyl isobutyl ketone and the like
The term "esters solvents" refers to ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like.
The term "alcoholic solvents" refers to the methanol, ethanol, isopropanol, 2-butanol, ethylene glycol and the like.
The term "chloro solvents" refers to methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like.
Accordingly the first aspect of the present invention provides a new salt of a drug with an amine salt, characterized in that said amine is selected from the group consisting of amine of the following formula-1,

Formula-1 Wherein each R1 and R2 are independently selected from a hydrogen atom, a straight or a branched alkyl group having 1 to 4 carbon atoms and n denotes an integer from 0 to 5.
The preferable amines according to the present invention which form the salts with drugs are 2-amino-thiophene, thiophene-2-methylamine, thiophene-2-ethyl amine, thiophene-2-propyl amine.

Any type of drug can be used according to the present invention. For example the drugs are selected from montelukast and HMG-CoA reductase inhibitors such as rosuvastatin shown good results and are particularly preferred.
The present invention also provides a process for the preparation of novel amine salts which are specified above. For isolating and purifying the desired drug, the amine salt is most effectively formed directly from the crude medium of respective drug. The crude medium of a respective drug are usually derived from the reaction mixture as a result of semi or total synthesis and usually contains the respective drug together with unwanted side products and impurities. The crude medium may preferably contain the respective drug in its acid form. The formation of amine salt can be effected by adding the suitable amine to crude medium contain montelukast free acid. The crude medium may be an organic phase or a mixture of an organic phase or aqueous phase where the impure drug is present in a suitable organic solvent. The suitable hydrocarbon solvent selected from toluene, xylene, cyclohexane, heptane and the like.
The process for the preparation of salt of a drug with an amine may comprise of the following steps;
a) Treating the crude medium containing the respective drug, which is preferably in acid form in a suitable solvent, with at least one amine which specified above,
b) stirring the reaction mixture for a sufficient period of time to produce the corresponding amine salts,
c) optionally recrystallising/purifying using suitable solvent,
d) filtering the solid and washing with a suitable solvent,
e) drying the solid to get the corresponding amine salt of a drug.
The novel amine salts of a drug according to the present invention are suitable used as a processing aid, a starting substance or as an intermediate in a process for preparing a corresponding drug product in a purified form, in a modified form, in a pharmaceutically active sah form. For example, the modified form is obtained by chemical modification, which modifications are known to those one skilled in the art. The purified form is obtained by any known method, for example, crystallization. The


The novel thiophene-2-ethyl amine salt of the present invention can be easily isolated from the reaction mixture in crystalline form, and then, if necessary, purified by recrystallisation from typical organic solvents to reduce the impurities down to pharmaceutically acceptable level. The novel thiophene-2-ethyI amine salt of montelukast is easily converted into pure montelukast and/or its pharmaceutically acceptable salts, for example sodium salt.
The thiophene-2-ethyl amine salt of montelukast of the present invention is characterized by X-ray powder diffraction pattern having peaks at about 8.2, 13.2, 15.5, 16.5, 18.4, 18.6, 20.6, 21.7, 24.3, 24.3, 25.0, 32.0 degrees two-theta ± 0.2 degrees two-theta. The X-ray powder diffraction pattern of thiophene-2-ethyleamine is substantially as shown in figure-1.
The thiophene-2-ethylamine salt of montelukast of the present invention is further characterized by IR spectrum as shown in figure-2.
The thiophene-2-ethylamine salt of montelukast of the present invention is further characterized by DSC thermo gram shown in figure-3.
The third aspect of the present invention is to provide a process for the preparation of thiophene-2-ethylamine amine salt of montelukast compound of formula-la


which comprises of the following steps;
a) Treating the crude montelukast free acid with thiophene-2-ethyiamine in a
suitable solvent selected from hydrocarbon solvents and/or ketone solvents and/or
ester solvents, preferably hydrocarbon solvents more preferably toluene,
b) stirring the reaction mixture for sufficient period of time for the formation of
thiophene-2-ethylamine salt of montelukast preferably 3-16 hours at 25-35°C,
c) separating the solid by filtration and washing with suitable hydrocarbon solvent,
d) optionally purifying the montelukast thiophene-2-ethylamine salt compound of
formula-la using hydrocarbon solvents or ketone solvents or mixtures thereof,
e) drying the solid to get the thiophene-2- ethyl amine salt of montelukast.
The fourth aspect of the present invention is to provide a process for the preparation of pure montelukast and/or its pharmaceutically acceptable salt for example sodium salt compound of formula-2 in amorphous form, from thiophene-2-ethylamine salt of montelukast compound of formula-la,

Which comprises of the following steps;
a) Adding thiophene-2-ethylamine salt of montelukast to an agitated mixture of suitable solvent and water, the suitable solvent selected from chloro solvent or hydrocarbon solvent like toluene or ester solvent like ethyl acetate or ether solvent like tertrahydrofuran or mixture thereof, at 0-20°C,

b) adding suitable organic acid selected from acetic acid, oxalic acid and the like;
preferably acetic acid to the above suspension at 0-20°C,
c) separating the organic layer,
d) distilling the organic layer containing montelukast free acid,
e) adding a suitable alcohol solvent like methanol to the above obtained crude in step d) followed by treating with sodium ion source like sodium hydroxide, sodium methoxide in methanol at a temperature of 0-40°C for 15 to 90 minutes under inert atmosphere, followed by distillation of methanol to get the sodium salt of montelukast, which is then dissolved in a suitable solvent like toluene and saturated the toluene layer with a solvent selected from cyclohexane, hexane and heptane gives montelukast sodium compound of formula-1 in amorphous form.

The novel thiophene-2-ethyl amine salt of the present invention can be easily isolated from the reaction mixture in crystalline form, and then, if necessary, purified by recrystallisation from typical organic solvents to reduce the impurities down to pharmaceutically acceptable level. The novel thiophene-2-ethyl amine salt of rosuvastatin is easily converted into pure rosuvastatin and/or its pharmaceutically acceptable salts, for example calcium salt.
The thiophene-2-ethyl amine salt of rosuvastatin of the present invention is characterized by X-ray powder diffraction pattern having peaks at about 6.3, 9.7, 11.9, 12.7, 15.8, 16.4, 18.0, 18.7, 19.3, 23.0, 23.7, 24.4, 28.0, 31.6 degrees two-theta ± 0.2

degrees two-theta. The X-ray powder diffraction pattern of thiophene-2-ethyleamine is substantially as shown in figure-4.
The thiophene-2-ethylamine sah of rosuvastatin of the present invention is further characterized by IR spectrum as shown in figure-5.
The thiophene-2-ethylamine sah of rosuvastatin of the present invention is further characterized by DSC diagram shown in figure-6.

which comprises of the following steps;
a) Reacting the rosuvastatin amide with a suitable base like sodium hydroxide or
potassium hydroxide in a suitable alcohol solvent like isopropyl alcohol,
ethyleneglycol at a temperature range from 40-60°C, preferably 50-55°C,
b) stirring the reaction mixture for a sufficient period of time preferably 10-45 hours,
c) distilling off the solvent and dissolving the residue in suitable aqueous solvent
like acetonitrile followed by cooling the reaction mixture to 0-20°C,
d) adjusting the pH of the reaction mixture to 3-4 with suitable acid selected from
hydrochloric acid, acetic acid,
e) adding thiophene-2-ethylamine to the above organic phase at 0-20°C,
f) stirring the reaction mixture for 45-60 minutes at 0-20°C,
g) separating the solid by filtration and washing with suitable solvent,
h) optionally purifying the rosuvastatin thiophene-2-ethylamine salt compound of formula-1 using suitable alcoholic solvents like methanol, ethanol, isopropyl

alcohol, organic solvent like toluene, hexanes, heptane, keto solvents like acetone, nitrile solvents like acetonitrile or mixtures thereof preferably mixture of actonitrile and isopropyl alcohol, i) drying the solid to get the thiophene-2- ethyl amine salt of rosuvastatin.

Which comprises of the following steps
a) Treating thiophene-2-ethylamine salt of rosuvastatin with a suitable alkali base
like sodium hydroxide or potassium hydroxide in a suitable polar solvent like
water,
b) stirring the reaction mixture for 1-1.5 hours,
c) washing the reaction mixture with suitable acetate solvent like tertiary butyl acetate,
d) adding suitable calcium source like aqueous calcium acetate or aqueous calcium
chloride to the above aqueous reaction mixture,
e) heating the reaction mixture to 20-3 5 °C,
f) cooling the reaction mixture,
g) separating the solid by filtration,
h) drying the solid to get the rosuvastatin calcium.

XRD analysis of thiophene-2-ethylamine salt of montelukast is carried out using SIEMENS/D-5000 X-Ray Diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045/min.
FI-IR spectrum of thiophene-2-ethylamine salt of montelukast was recorded on Thermo model Nicolet-380 as KBr pellet.
The thermal analysis of thiophene-2-ethylamine salt of montelukast was carried out on Waters DSC Q-10 model differential scanning calorimeter.

The processes described in the present invention were demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples: Reference Example-l:
Process for the preparation of Montelukast free acid:
A mixture of 8 grams of [(E)]-2-[3(S)-[3-[2-(7-chloro-2-quinolinyl)ethenyl)phenyl]-3-hydroxypropyl]phenyl]-2-propanol, 16 ml toluene and 71.5 ml acetonitrile is heated to 40-50°C. Stirred the reaction mixture for 30 minutes at 40-50°C. Cooled the reaction mixture to -20 to -15°C. Added 2.74 grams of diisopropylethylamine slowly to the above reaction mixture at -20 to -15°C. Stirred the reaction mixture for 45 minutes at -20 to -15°C. Added 2.2 grams of methanesulfonylchloride to the above reaction mixture at -20 to -15°C. Stirred the reaction mixture for 10 hours at -20 to -15°C. Filtered the precipitated solid and washed with chilled acetonitrile followed by hexanes to get the wet solid material. Added 3.12 grams of l-(mercapto methyl) cyclopropane methyl ester to the pre cooled mixture of 32 ml of dimethyl sulfoxide and 14.2 ml of sodium methoxide solution at -5 to 0°C. Stirred the reaction mixture for one hour at -5 to 0°C. The above obtained wet solid material added lot wise to the reaction mixture at -5 to 0°C. Stirred the reaction mixture for 10 hours at -5 to 0°C. Added the above reaction mixture to the pre cooled 238 ml of water at belowlO°C. Stirred the reaction mixture for 30 minutes. Added 32 ml of toluene to the above reaction mixture at 25-30°C. Adjusted the pH of the reaction mixture to 13.4 with aqueous sodium hydroxide (6.3 grams in 238 ml of water) solution. Stirred the reaction mixture for 30 minutes at 25-30°C. Separated the organic and aqueous phases. Washed the aqueous phase thrice with toluene. Then cooled the aqueous phase to 10-20°C. Adjusted the pH of the reaction mixture to 6.6 with aqueous acetic acid solution. Extracted the reaction mixture thrice with ethyl acetate. Washed the organic phase with aqueous sodium bicarbonate solution. Separated the organic and aqueous phases. Dried the organic phase with sodium sulphate. Distilled the solvent completely under reduced pressure at below 60°C. Cooled the reaction mixture to 25-30'^C. Added 32 ml of toluene

to the above reaction mixture. Again distilled the solvent completely under reduced pressure at below 60°C.
Example-1:
Preparation of thiophene -2-ethyl amine salt of montelukast compound of
formula-la:
Thiophene-2-ethylamine (26 grams) was added to the mixture of crude montelukast free acid (100 grams) obtained as per the reference example-1 in toluene (1000 ml) at 25-30°C. The reaction mixture was stirred for 16 hours at 25-35°C, The precipitated solid was filtered and washed the solid with toluene. The solid was dried initially for 2 hours at 25-30°C followed by drying for 8 hours at 50-60°C to get thiophene-2-ethyle amine salt of montelukast. Yield: 116 grams
Example-2:
Preparation of montelukast sodium compound of formula-1 from thiophene-2-ethyl
amine salt compound of formula-2:
A mixture of thiophene-2-ethylamine salt of montelukast (100 grams), methylene chloride (1200 ml) and water (600 ml) was cooled to 10-15°C. The pH of the reaction mixture was adjusted to 6.4 with aqueous acetic acid solution at 10-15°C. The layers were separated. The aqueous layer was extracted twice with methylene chloride. The combined organic layer was washed with aqueous acetic acid. The solvent from the organic layer was distilled off imder reduced pressure at below 40°C. Toluene (100 ml) was added to the above reaction mixture. The toluene from the above reaction mixture was distilled off under reduced pressure at below 55°C. The reaction mixture was cooled to 25-35°C. Methanol (300 ml) was added to the above residue and the reaction mixture was cooled to 0-5°C. Methanolic sodium hydroxide solution (5.8 grams in 150 ml of methanol) was added to the above reaction mixture at 5-10°C. The reaction mixture was stirred for 30 minutes at 5-10°C. The solvent from the reaction mixture was distilled off under reduced pressure at 55°C. The reaction mixture was cooled to 35-40°C. Toluene (100 ml) was added to the above mass and distilled the solvent completely under reduced

pressure at below 55°C. The reaction mixture was cooled to 25-30°C. Toluene (300 ml) was added to the above reaction mixture at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 30 minutes to get a clear solution. The reaction mixture was treated with activated carbon (30 grams). The reaction mixture was stirred to 30 minutes at 25-30°C. The reaction mixture was filtered through hyflow and washed with toluene. The solvent from the filtrate was distilled off partially under reduced pressure at below 60°C. The reaction mixture was cooled to 35-40°C. The above reaction mixture slowly added to heptane (900 ml) at 25-30°C. Te reaction mixture was stirred for 4 hours at 25-30°C. The obtained solid was filtered and washed with heptane. The solid dried initially for 2 hours at 25-35°C followed by at 40-45°C for Ihour, then at 50-55°C for 1 hour and finally at 75-80°C under reduced pressure to get the pure montelukast sodium compound of formula-2. Yield: 70 grams
Example-3:
Preparation of thiophene-2-ethyl amine salt of rosuvastatin compound of
formula-lb:
The (3R,5S,E)-N-butyl-7-(4-(4-fluorophenyI)-6-isopropyl-2-(N-methyl methyl sulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enamide (50 grams) was dissolved in 250 ml of isopropyl alcohol at 25-30°C. Aqueous sodium hydroxide solution (25 grams in 250 ml of water) was added to the above reaction mixture. The reaction mixture was heated to 50-55°C. The reaction mixture was stirred for 42 hours at 50-55°C. The solvent from the reaction mixture was completely distilled off under the reduced pressure. Cooled the reaction mixture to 25-30°C. Water (100 ml), acetonitrile (500 ml) and sodium chloride (25 grams) was added to the reaction mixture at 25-30°C. The pH of the reaction mixture was adjusted to 3.5 with acetic acid. The organic layer was cooled to 0-10°C. Thiophene-2-ethyl amine was added to the organic layer at 0-10°C. The reaction mixture was stirred for 60 minutes at 0-10°C. The solid obtained was filtered and washed with acetonitrile. The obtained solid was dried at 50-55°C to get the title compound. Yield: 32 grams

Example-4:
Purification of Thiophene-2-ethylamine salt of rosuvastatin compound of
formula-lb:
A mixture of thiophene-2-ethylamine salt of rosuvastatin (100 grams), acetonitrile (1000 ml) and isopropyl alcohol (100 ml) was heated to reflux temperature of 75-80°C. The reaction mixture was stirred for 45 minutes at reflux temperature. The reaction mixture was cooled to 20-25°C. The reaction mixture was stirred for 45 minutes at 20-25°C. The reaction mixture was further cooled to 0-10°C and stirred for 1,5 hours. The precipitated solid was filtered and washed with acetonitrile. The solid was dried at 30-35°C for 4 hours followed by at 40-45°C for another 4 hours to get the pure title compound. Yield: 95 grams
Example-5:
Preparation of calcium salt of rosuvastatin from thiophene-2-ethylamine salt:
Aqueous sodium hydroxide solution ( 8.4 grams in 110 ml of water) was added to a mixture of rosuvastatin thiophene-2-ethyl amine (125 grams) and water (630 ml) at 20-30°C. The reaction mixture was stirred for 1.5 hours at 20-30°C. The reaction mixture was washed with tertiary butyl acetate (6x100ml). The solvent in the reaction mixture was evoporated with nitrogen under reduced pressure. The reaction mixture filtered through micron filter and washed with water. The mixture was heated to 35-40°C. Aqueous calcium acetate solution was added to the reaction mixture at 35-40°C. The reaction mixture was stirred for 45 minutes at 35-40°C. The reaction mixture was cooled to 25-30°C. The solid obtained is filtered and washed with water. The solid was dried at 6 hours at 25-35°C followed by at 40-45°C to get the title compound. Yield: 90 grams

We Claim:
1. The salt of a drug with amine, characterized in that the said amine is selected from the
group consisting of amine of the following structural formula,

Wherein each R1 and R2 are independently selected from hydrogen atom, a straight or a branched alkyl group having 1 to 4 carbon atoms and n denotes an integer from 0 to5.
2. The salt of a drug with an amine according to claim 1, where in the amine is selected from the group consisting of 2-amino-thiophene, thiophene-2-methylamine, thiophene-2-ethyl amine, thiophene-2-propyl amine.
3. A process for the preparation of the salt of a drug with amine, characterized in that the amine is added to the crude medium of a drug and the said amine is selected from the group consisting of amine of the following structural formula.

4. The drug according to any of the proceeding claim is selected from montelukast, rosuvastatin, perindopril, ezetimibe intermediate.
5. The use of novel amine salts of a drug according to any proceeding claim, as a processing aid, a starting substance or an intermediate substance in a process for preparing drug substance in a purified form, in a modified form and in a pharmaceutically acceptable salt form.
6. Thiophene-2-ethyl amine salt of montelukast having the following structure.


7. The thiophene-2-ethyl amine salt of montelukast according to claim 6, is
characterized by powder X-ray diffraction peaks at 8.2, 13.2, 15.5, 16.5, 18.4, 18.6,
20.6, 21.7, 24.3, 24.3, 25.0, 32.0 degrees two-theta ± 0.2 degrees two-theta as show
as shown in Figure-1, IR spectrum substantially as shown in Figure-2 and DSC
thermo gram substantially as shown in Figure-3.
8. A process for the preparation of crystalline thiophene-2-ethyl amine salt of
montelukast, comprises of the following steps;
a) Treating the crude montelukast free acid with thiophene-2-ethylamine in a
suitable solvent selected from hydrocarbon solvents like toluene, cyclohexane,
hexne, heptane and/or ketone solvents like acetone, butanone, methyl isobutyl
ketone and/or ester solvents like ethyl acetate, propyl acetate,
b) stirring the reaction mixture for sufficient period of time for the formation of
thiophene-2-ethylamine salt of montelukast preferably 3-16 hours at 25-35°C,
c) separating the solid by filtration and washing with suitable hydrocarbon solvent
like heptane,
d) optionally purifying the montelukast thiophene-2-ethylamine salt compound of
formula-1 using hydrocarbon solvents like toluene, hexanes, heptane or keto
solvents like acetone or mixtures thereof,
e) drying the solid to get the thiophene-2-ethyl amine salt of montelukast.


Which comprises of the following steps
a) Adding thiophene-2-ethylamine salt of montelukast to a agitated mixture of
suitable solvent and water, the suitable solvent selected from chloro solvent or
hydrocarbon solvents like toluene or ester solvent like ethyl acetate or ether
solvent like tertrahydrofuran or mixture thereof, at 0-20°C,
b) adding suitable water soluble organic acid like acetic acid, oxalic acid, tartaric acid to the above suspension at 0-20°C,
c) distilling the organic layer containing montelukast free acid,
d) adding a suitable alcohol solvent like methanol to above crude followed by
treating with sodium ion source like sodium hydroxide, sodium methoxide in
methanol at a temperature of 0-40°C for 15 to 90 minutes under inert atmosphere,
followed by distillation of methanol and the by product of organic amine to get
the sodium salt of montelukast, which is then dissolved in a suitable solvent like
toluene and saturated the toluene layer with a solvent selected from cyclohexane,
hexane and heptane gives montelukast sodium compound of formula-2 in
amorphous form.

11. The thiophene-2-ethyl amine salt of rosuvastatin according to claim 10, is characterized by powder X-ray diffraction peaks at 8.2, 13.2, 15.5, 16.5, 18.4, 18.6, 20.6, 21.7, 24.3, 24.3, 25.0, 32.0 degrees two-theta ± 0.2 degrees two-theta as shown in Figure-4, IR spectrum substantially as shown in Figure-5 and DSC thermo gram substantially as shown in Figure-6.

12. A process for the preparation of crystalline thiophene-2-ethyl amine salt of rosuvastatin, comprises of the following steps;
a) Reacting the rosuvastatin amide with a suitable base like sodium hydroxide or potassium hydroxide in a suitable alcohol solvent like isopropyl alcohol, ethylene glycol at a temperature range from 40-60°C, preferably 50-55°C,
b) stirring the reaction mixture for a sufficient period of time preferably 10-45 hours,

c) distilling off the solvent and dissolving the residue in suitable aqueous solvent like acetonitrile followed by cooling the reaction mixture,
d) adjusting the pH of the reaction mixture to 3-4 with suitable acid selected from hydrochloric acid, acetic acid,
e) adding thiophene-2-ethylamine to the above organic phase at 0-10°C,
f) stirring the reaction mixture for 45-60 minutes at 0-10°C,
g) separating the solid by filtration and washed with suitable solvent,
h) optionally purifying the rosuvastatin thiophene-2-ethylamine salt compound of formula-1 using suitable alcoholic solvents like methanol, ethanol, isopropyl alcohol, organic solvent like toluene, hexanes, heptane, keto solvents like acetone, nitrile solvents like acetonitrile or mixtures thereof preferably mixture of actonitrile and isopropyl alcohol,
i) drying the solid to get the thiophene-2- ethyl amine salt of rosuvastatin.


a) Treating thiophene-2-ethylamine salt of rosuvastatin with a suitable alkali base
like sodium hydroxide or potassium hydroxide in a suitable polar solvent like
water,
b) stirring the reaction mixtixre for 1-1.5 hours,
c) washing the reaction mixture with suitable acetate solvent like tertiary butyl acetate,

d) adding suitable calcium source like aqueous calcium acetate or aqueous calcium chloride to the above aqueous reaction mixture,
e) the reaction mixture was heated to 20-35°C,
f) cooling the reaction mixture to 20-3 5 °C,
g) filtering the reaction mixture and washing the solid with water,
h) drying the solid to get the rosuvastatin calcium.