FIELD OF THE INVENTION
The invention relates to rosuvastatin amine and indanamine salts and a process for preparing the same. More particularly  invention relates to rosuvastatin amine salts of disclosed formula- 1  wherein when n=1  said salt is indanamine salt. The invention also relates to a process for preparing such rosuvastatin amine and indanamine salts. The obtained rosuvastatin amine or indanamine salts are used as intermediates in preparation of purified rosuvastatin and rosuvastatin calcium salt.

BACKGROUND OF THE INVENTION
Statins are a class of drugs useful to reduce blood levels of low-density lipoprotein (LDL) cholesterol (“bad cholesterol”). Rosuvastatin is statin  used to treat high cholesterol levels and related conditions like triglycerides in the blood  while increasing levels of "good" cholesterol (high-density lipoprotein  or HDL)  thereby preventing cardiovascular diseases.

Although similar in structure with most other synthetic statins  like atorvastatin  cerivastatin  pitavastatin  yet rosuvastatin unusually is also known to contain sulfur. The most active salt of rosuvastatin is Rosuvastatin Calcium salt  a competitive inhibitor of the enzyme HMG-CoA reductase and converts HMG-CoA to mevalonate  an early rate limiting step in biosynthesis of cholesterol.

Rosuvastatin is (3R  5S  6E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl (methylsulfonyl)amino] -5-pyrimidinyl]-3 5-dihydroxy-6-heptanoic acid. Rosuvastatin calcium is a bis-compound in which calcium replaces hydrogen in the carboxylic acid group.
Structurally  rosuvastatin calcium salt can be represented by Figure-1 below:

Fig. 1: Rosuvastatin Calcium salt structure.
Many intermediates which are amine salts of rosuvastatin have been reported till date  which are used to produce Rosuvastatin calcium.

WO2005/077916 by Ranbaxy Laboratories Limited discloses an intermediate compound of rosuvastatin amine salt of the given formula:

in which the amine residue has a Formula NR1R2 R3 wherein independently R1; R2 and R3 are H  straight or branched chain C1-5 alkyl or hydroxyalkyl  C3-10 single or fused ring optionally substituted cycloalkyl  optionally substituted aryl  optionally substituted aralkyl  alkylcycloalkyl  or independently R1 R2 and R3 can combine with each other to form a C3-7 membered cycloalkyl ring or heterocyclic residue containing one or more heteroatoms (selected from S  N or O)  with the proviso that the amine is not selected from ammonia  methylamine  ethylamine  diethanolamine  tri(hydroxymethyl)-methylamine  benzylamine  or 4-methoxybenzylamine.
WO2008/130678 by Teva Pharmaceutical discloses chirally pure rosuvastatin intermediates comprising a chiral base amine as shown below:

wherein amine is 1-phenylethylamine  1-phenylpropylamine  1-phenylisobutylamine  1-phenyl butyl amine and 1-phenylpentylamine.

WO/2010/081861 discloses a rosuvastatin salt of formula

Wherein Z is an amine selected from the group consisting of optionally substituted piperazine  sec-butylamine  tert- butylamine  cyclopentylamine  cycloheptylamine such piperazine are selected from 1- (diphenylmethyl) piperazine; 1- [ (4-chlorophenyl) -phenyl-methyl] piperazine; 1- [ (4-methoxyphenyl) -phenyl-methyl] piperazine; 1- [ (3  5-dichlorophenyl) -phenyl-methyl] piperazine; 1- [ (3  4-dichlorophenyl) -phenyl-methyl] piperazine; 1- [ (4-fluorophenyl) -phenyl-methyl] piperazine; 1- [ (4-methylphenyl) -phenyl-methyl] piperazine; 1- [ (4-trifluoromethylphenyl) -phenyl-methyl] piperazine; (-) -1- [ (4-chlorophenyl) -phenyl-methyl] piperazine; (-) -1- [ (4-methoxy?henyl) -phenyl-methyl] piperazine; (-) -1- [ (3  5-dichlorophenyl) -phenyl-methyl] piperazine; (-) -1- [ (3  4-dichlorophenyl) -phenyl-methyl] piperazine; (-) -1- [ (4-fluorophenyl) -phenyl-methyl] piperazine; (-) -1- [ (4-methylphenyl) -phenyl-methyl] piperazine; and (-) -1- [ (4-trifluoromethylphenyl) -phenyl- methyl] piperazine .

WO2008067440 by Dr. Reddy""s Laboratories discloses a compound which is dehydroabietylamine salt of rosuvastatin having the below structure and processes for making rosuvastatin calcium that include formation of dehydroabietylamine salt of rosuvastatin.

WO/2010/035284 by Matrix Laboratories discloses amine salt of rosuvastatin  wherein the amine is (S)-2 -Amino-3  3 -dimethyl butane or (S)-(-)-a-methyl benzyl amine.

Further  WO/2008/038132 by Aurobindo Pharma Limited discloses a rosuvastatin amine salt of below formula-

wherein R1  R2  R3  R4 independently represents hydrogen  straight or branched chain CM5 alkyl  cycloalkyl  optionally substituted aryl  aralkyl  heterocyclylalkyl  a heterocyclic residue containing one or more hetero atoms.

Therefore  it is observed that a number of amine salts are available in the prior art  which are used for preparation of rosuvastatin calcium salt. However  rosuvastatin amine salts and processes of preparing the same known in the art are costly  require more vigorous conditions and more time for completion. Therefore  there exists a continuous need for developing new intermediates to prepare and purify rosuvastatin calcium in appropriate economic and cost effective manners. Such rosuvastatin intermediate salt should be pharmaceutically acceptable for pharmaceutical preparations  should be able to be produced in more purified form and should be cost effective for large scale industrial production of rosuvastatin calcium.

Though many amine salts of rosuvastatin are known in the art as briefly discussed hereinabove paragraphs but none of the prior art discloses about indanamine salt of rosuvastatin which could be used as an intermediate to prepare rosuvastatin calcium. The present invention describes new amine salts that are hitherto unreported without having any larger organic group as prescribed by the prior art  yet a better compound to generate the end product rosuvastatin calcium.

OBJECTS OF THE INVENTION

Primary object of the invention is to provide novel amine salts of rosuvastatin.

Another object of the invention is to provide novel indanamine salts of rosuvastatin.

Another object of the invention is to provide a process for preparation of rosuvastatin amine salts.

Another object of the invention is to provide a process for preparation of rosuvastatin indanamine salt.

A further object of the invention is to provide rosuvastatin amine and indanamine salts for the preparation of pharmaceutically acceptable purified rosuvastatin calcium salt.

SUMMARY OF THE INVENTION

Accordingly  there are provided novel rosuvastatin amine and indanamine salts which can be used for preparation of pharmaceutically acceptable salts of rosuvastatin like rosuvastatin calcium or rosuvastatin magnesium. Also there are provided processes for preparation of rosuvastatin amine and indanamine salts. Whereas  indanamine and other amine salts of rosuvastatin are prepared by the same process. The obtained rosuvastatin amine and/or indanamine salts have purity of more than 99% and diastereomeric impurity of less than 0.25%. The rosuvastatin amine or indanamine salts of the invention may be represented by the general structural formula-I:

Formula-I
Wherein the amine can be selected from the compounds represented in Figure-1

Figure-1

wherein  n = 1  2  3  4  5 or any multiple of 1.
When n =1  it is indanamine and the obtained salt is rosuvastatin indanamine salt.

The process of preparing the rosuvastatin indanamine salt and other amine salts of the invention illustrated as Formula-1 above comprises:

a). dissolving rosuvastatin with free carboxylic group in a first organic solvent at a temperature between 0 to 100 C to obtain a first organic solution;

b). dissolving amine base selected from the compounds represented in Figure-1 in a second organic solvent at temperature between 0 to 100 C to obtain a second organic solution;

c). adding second organic solution obtained in step (b) to the first organic solution of step (a) drop wise with continuous stirring of the reaction mixture at temperature between 0 to 100 C;

d). raising temperature of the reaction mixture obtained in step (c) to room temperature and stirring the mixture for 12 to 17 hours  preferably for 12 to15 hours.

e). cooling the temperature of the reaction mixture of step (d) to -2 to 20 C and stirring at this temperature for 0.5 to 2 hours  preferably for 1 hour;

f). filtering the reaction mixture of step (e) and obtaining the solid precipitate;

g). washing the precipitates obtained from step (f) with a chilled third organic solvent to obtain rosuvastatin indanamine salt  when amine compound in Figure-1 has a value of n = 1.

DETAILED DESCRIPTION OF THE INVENTION

Detailed embodiments of the present invention are disclosed herein following paragraphs. However  it is to be understood that the disclosed embodiments are merely exemplary of the invention  which can be embodied in various forms. Therefore  specific structural and functional details disclosed herein are not to be interpreted as limiting  but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed structure. Further  the terms and phrases used herein are not intended to be limiting but rather to provide an understandable description of the invention.

The novel amine or indanamine salts of the invention may be represented by the general structural formula-I given below:

Formula-I

wherein  n = 1  2  3  4  5 or any multiple of 1.
When n =1  the salt is rosuvastatin indanamine salt.

The rosuvastatin amine and/or indanamine salts have purity of more than 99% and diastereomeric impurity of less than 0.25%. The obtained rosuvastatin amine or indanamine salts may be crystalline  amorphous  hydrate  solvate or anhydrous solid. However  in any of the solid form  the purity of the obtained rosuvastatin amine or indanamine salts is always more than 99% and the diastereomeric impurity is always less than 0.25%.

The rosuvastatin amine or indanamine salts provide purified form of rosuvastatin which can be used for preparation of pharmaceutically acceptable salts of rosuvastatin like rosuvastatin calcium or rosuvastatin magnesium.

The amine in the rosuvastatin amine salt may be selected from amines having different stereoisomeric configuration represented below-

wherein  n = 1  2  3  4  5  or any multiple of 1.
When n =1  it is indanamine.

In exemplary embodiment  the process of preparing rosuvastatin amine or indanamine salt of general formula-I comprises following steps:

a). dissolving rosuvastatin with free carboxylic group in a first organic solvent at a temperature between 0 to 100 C to obtain a first organic solution;

b). dissolving amine base in a second organic solvent at temperature between 0 to 100 C to obtain a second organic solution;

c). adding second organic solution obtained in step (b) to the first organic solution of step (a) drop wise with continuous stirring of the reaction mixture at temperature between 0 to 100 C;

d). raising temperature of the reaction mixture obtained in step (c) to room temperature and stirring the mixture for 12 to 17 hours;

e). cooling the temperature of the reaction mixture of step (d) to -2 to 20 C and stirring at this temperature for 0.5 to 2 hours;

f). filtering the reaction mixture of step (e) and obtaining the solid precipitate;

g). washing the precipitates obtained from step (f) with a chilled third organic solvent to obtain rosuvastatin indanamine salt  when amine compound in Figure-1 has a value of n = 1.

The first organic solvent used for dissolving rosuvastatin with free carboxylic group in step (a) is characterized in that the rosuvastatin is highly soluble or soluble in such solvent. Some examples of such solvents which may be used in step (a) for dissolving rosuvastatin  without being limited to  are ketones such as acetone  ethyl methyl ketone  methyl isobutyl ketone and diisobutyl ketone; esters such as methyl acetate  ethyl acetate  n-propyl acetate  isopropyl acetate  n-butyl acetate and isobutyl acetate; chlorinated hydrocarbons such as methylene chloride  chloroform  carbon tetrachloride and ethylene dichloride; nitriles such as acetonitrile and propionitrile; alcohols such as methanol  ethanol  isopropyl alcohol and n-propanol; ethers such as diethyl ether  dimethyl ether  diisopropyl ether and 1 4-dioxane  hydrocarbons such as toluene  xylene  n-heptane  cyclohexane  n-hexane or mixtures thereof or their combination with water.

In one embodiment  the first organic solvent is acetonitrile. In another embodiment  the first organic solvent is an alkyl acetate  preferably ethyl acetate. In another embodiment  the first organic solvent is acetone. In another embodiment  the first organic solvent is isopropyl alcohol. In another embodiment  the first organic solvent is chloroform. An appropriate quantity of first organic solvent is used to completely dissolve the rosuvastatin at a temperature between 0 to 100 C and to obtain a first organic solution. The first organic solution may be optionally filtered to remove any un-dissolved particle or impurity.

The second organic solvent used to dissolve an amine  more particularly  indanamine in step (b) is characterized in that such amine and indanamime is highly soluble or soluble in such solvent. Some examples of such second organic solvents which may be used in step (b) for dissolving indanamine  without being limited to  are ketones such as acetone  ethyl methyl ketone  methyl isobutyl ketone and diisobutyl ketone; esters such as niethyl acetate  ethyl acetate  n-propyl acetate  isopropyl acetate  n-butyl acetate and isobutyl acetate; chlorinated hydrocarbons such as methylene chloride  chloroform  carbon tetrachloride and ethylene dichloride; nitriles such as acetonitrile and propionitrile; alcohols such as methanol  ethanol  isopropyl alcohol and n-propanol; ethers such as diethyl ether  dimethyl ether  diisopropyl ether and 1 4-dioxane  hydrocarbons such as toluene  xylene  n-heptane  cyclohexane  n-hexane or mixtures thereof or their combination with water.

In one embodiment  the second organic solvent is acetonitrile. In another embodiment  the second organic solvent is an alkyl acetate  preferably ethyl acetate. In another embodiment  the second organic solvent is acetone. In another embodiment  the second organic solvent is isopropyl alcohol. In another embodiment  the second organic solvent is chloroform. An appropriate quantity of second organic solvent is used to completely dissolve the amine and/or indanamine at a temperature between 0 to 100 C and to obtain a second organic solution. The amount of amine or indanamine should be sufficient to convert the rosuvastatin free carboxylic acid into corresponding amine or indanamine salt. Any undissolved amine and/or indanamine may be filtered from the second organic solution and re-dissolved in second organic solvent and this step may be repeated  if required.

The addition of second organic solution into first organic solution is done with continuous stirring at the same solution temperature which is maintained between 0 to 100 C.

After mixing the second organic solution with first organic solution  the temperature of the obtained reaction mixture is increased to room temperature  preferably 20 to 300 C  more preferably 25 to 270 C. The obtained reaction mixture is then stirred at this temperature for about 12-17 hours  preferably for 12-15 hours.

After stirring the reaction mixture at this temperature for 12-17 hours  preferably 12-15 hours  the reaction mixture is then cooled to a temperature between -2 to 20 C  preferably to 00 C and stirred for ½ to 2 hours preferably for 1 hour. The rosuvastatin amine or indanamime salts are isolated and precipitated as solid precipitates from the reaction mixture. The precipitated rosuvastatin amine or indanamine salts are filtered from the reaction mixture and washed with a chilled third organic solvent to obtain the purified rosuvastatin amine or indanamine salts.

The third organic solvent used for washing of rosuvastatin indanamine salt are ketones such as acetone  ethyl methyl ketone  methyl isobutyl ketone and diisobutyl ketone; esters such as methyl acetate  ethyl acetate  n-propyl acetate  isopropyl acetate  n-butyl acetate and isobutyl acetate; chlorinated hydrocarbons such as methylene chloride  chloroform  carbon tetrachloride and ethylene dichloride; nitriles such as acetonitrile and propionitrile; alcohols such as methanol  ethanol  isopropyl alcohol and n-propanol; ethers such as diethyl ether  dimethyl ether  diisopropyl ether and 1 4-dioxane  hydrocarbons such as toluene  xylene  n-heptane  cyclohexane  n-hexane or a combination thereof.

In one embodiment the third organic solvent is a nitrile  preferably acetonitrile or propionitrile   more preferably acetonitrile. In another embodiment  the third solvent is ethyl acetate. In another embodiment  the third organic solvent is acetone. In another embodiment  the third organic solvent is isopropyl alcohol. In another embodiment  the third organic solvent is chloroform.

In another embodiment  the rosuvastatine indanamine salts may be washed with a 1:1 combination of nitrile solvent and alcohol solvent.

In another aspect of the invention  the obtained rosuvastatin indanamine salts are converted into rosuvastatin calcium or magnesium salts  preferably into calcium salts. The process of converting indanamime salt into calcium salt comprises treating rosuvastatin indanamine salt with an alkali metal base. In one embodiment  the alkali metal base is an alkali metal hydroxide. Such alkali metal hydroxide may be selected from lithium hydroxide  sodium hydroxide  potassium hydroxide. In other embodiments  other alkali metal base like sodium carbonate  sodium bicarbonate  potassium carbonate and potassium bicarbonate may also be used. The alkali metal base is used as aqueous solution with concentration between 5 to 50%.

The rosuvastatin amine or indanamine salt is converted into an intermediate alkali metal salt of rosuvastatin by treatment with aqueous solution of alkali metal base. This intermediate alkali metal salt is then converted into calcium salt in presence of a calcium ion source like calcium chloride  calcium carbonate  calcium hydroxide  calcium sulfate  calcium acetate  calcium borate  calcium tartarate  calcium bromide or any other compound which is capable of generating calcium ions. In one preferred embodiment  calcium chloride is used as source of calcium ions.

The reaction process of converting rosuvastatin indanamine salt into rosuvastatin calcium salt is carried out at temperature between 10 to 500 C  preferably at 10 to 450 C  even more preferably at 15 to 450 C for an appropriate period of time to complete the salt formation.

The precipitated calcium salts may be separated from the reaction mixture by filtration or centrifugation. The obtained calcium salts may be dried by any conventional method know in the art in air or in vacuum and at a temperature suitable for complete drying of the calcium salts.

The calcium salts of the rosuvastatin are used in pharmaceutically effective amounts for preparation for pharmaceutical compositions comprising rosuvastatin calcium salts for treatment of cardiovascular diseases.

The rosuvastatin with free carboxylic acid which is used for preparation of rosuvastatin amine or indanamine salts may be prepared by the process known in the art or by any of the following processes described in Scheme-I or Scheme-II.

Scheme-I

In one embodiment  the rosuvastatin is prepared by a process represented herein below as Scheme-I. The process of Scheme-I comprises:

a). dissolving tert-butyl (4R-cis)-6-formaldehydel-2  2-dimethyl-1 3-dioxane-4-acetate in dimethyl sulfoxide (DMSO) with continuous stirring at room temperature;

b). adding [4-(4-floorophenyl)-6-(1-methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidyl]methyl] triphenylphosphonium bromide and potassium carbonate (K2CO3) in the solution of step (a) at room temperature;

c). increasing temperature of the reaction mixture obtained in step (b) to about 70-750 C and maintaining this temperature for about 4 hours;

d). cooling the temperature to 400 C and adding toluene followed by stirring for about 30 minutes;

e). filtering the reaction mixture of step (d)  washing organic layer with water and concentrating organic layer under vacuum at 600 C to obtain a residue;

f). adding methanol to the residue of step (e) and stirring for 30 minutes at about 55 to 600 C;

g). cooling the reaction temperature to 100 C and filtering the precipitate;

h). Washing the precipitate of step (g) with chilled methanol and drying at 50-550 C to obtain 6-[(1E)-2-[4-(4-Fluorophenyl)-6-(1-methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl] ethenyl]-2 2-dimethyl-1 3-dioxane-4-acetic acid 1 1-dimethylethyl ester;

i). hydrolyzing the rosuvastatin tert-methyl ester compound obtained in step (h) with NaOH to obtain rosuvastatin compound with free carboxylic acid.

The rosuvastatin obtained in step (i) of the above process is then converted into rosuvastatin indanamine salt according to the process described herein above paragraphs.

Scheme-I

Scheme-II

In another embodiment  the rosuvastatin is prepared by a process represented herein below as Scheme-II. The process of Scheme-II comprises:

a). reacting 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5pyrimidine carboxaldehyde with methyl (3R)-3-(tert-butyl dimethyl silyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanate in tolune under reflux to obtain methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidine-5-yl]-(3R)-3-(tert-butyldimethyl silyloxy)-5-oxo-(E)-6-heptenate;

b) cleaving silyl group in compound obtained in step (a) with methane sulfonic acid in methanol-water mixture;

c). reducing keto group of compound obtained in step (b) with NaBH4 and diethyl methoxy borane in THF to obtain a methyl ester of rosuvastatin;

d). hydrolyzing methyl ester of rosuvastatin obtained in step (c) with NaOH in methanol to obtain rosuvastatin compound with free carboxylic acid.

The rosuvastatin compound obtained in step (d) of the above process is then converted into rosuvastatin indanamine salt according to the process described herein above paragraphs.

Scheme-II

The invention is further described in following examples  which are mere exemplary  and not limiting to the scope of the claims.

Examples:

Example-1A

140g  (0.54 mol) of tert-butyl (4R-cis)-6-formaldehydel-2 2-dimethyl-1 3-dioxane-4-acetate was dissolved in 1275 mL of DMSO and stirred. To this solution  334.5g (0.49 mol) of [4-(4-floorophenyl)-6-(1-methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidyl]methyl] triphenyl phosphonium bromide and 102g (0.73 mol) of K2CO3 were added at room temperature. The reaction mixture was heated to 70-750 C for 4 hours. After completion of the reaction monitored by HPLC  reaction mixture was cooled to 400 C. 1900 mL of toluene was added and stirred for 30 min. at same temperature. Reaction mixture was filtered to remove the unwanted solid. Organic layer washed trice with water (3x1900 mL). Organic layer was concentrated under vacuum at 600 C.

To the residue methanol was added at 55-600 C and stirred for 30 min at same temperature. The reaction mixture temperature was slowly cooled to room temperature and then further cooled to 100 C and stirred for 30 min. Precipitated product was filtered and washed with chilled methanol. The product was dried at 50-550 C until to get the constant weight.
Weight of the compound: 144 g.

Example-1B

To stirred solution of 6-[(1E)-2-[4-(4-Fluorophenyl)-6-(1-methylethyl)-2-[methyl (methylsulfonyl)amino]-5-pyrimidinyl]ethenyl]-2 2-dimethyl-1 3-dioxane-4-acetic acid 1 1-dimethylethyl ester (240g  0.41 mol) in acetonitrile (4180mL)  dilute HCl (36 mL of conc HCl in 3000 mL water) was added slowly at 20-250 C. Reaction mixture was stirred for 4-8 hours at room temperature. After completion of the reaction monitored by HPLC  NaOH in water (41.5 g of NaOH in 64 mL water) was added slowly at room temperature. Total reaction mass was stirred for 3 hours at 30-350 C. Completion of the reaction was monitored by HPLC. After completion of the reaction  acetonitrile was completely distilled under reduced pressure below 550 C. Water (1000 mL) was added to the reaction mixture and aqueous layer pH was adjusted at pH 3-4 using dilute hydrochloric acid solution (48.4 mL of HCl in 360 mL water) at 15-200 C. Aqueous layer extracted with ethyl acetate (4x350 mL). Combined organic layer was washed with water (300 mL). Separated organic layer was dried with sodium sulphate. This organic layer either concentrated under reduced pressure to get Resuvastatin as residue or as such proceeded for the next step without concentration.

Example-1C- (Resuvastatin indanamine salt)

Above dried organic layer was cooled to 0-100 C and 58 g of 1-Indanamine in 65 mL of ethyl acetate solution was added drop wise to the above rosuvastatin solution at the same temperature. Reaction mixture was stirred for 15 hours at room temperature. Reaction mixture was cooled to 00 C and stirred for 1 hr. Solid precipitate was filtered and washed with chilled ethylacetate.
Dry weight of the compound: 230 g

Example-2A

250 g of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-pyrimidine carboxaldehyde was dissolved in toluene to obtain a solution. To this solution  methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene hexanate was added at room temperature. Reacton mixture was refluxed for 30 hours under nitrogen atmosphere. After completion of the reaction monitored by HPLC  reaction mixture was cooled to room temperature and washed with water (2X1500 mL). Organic layer was dried with sodium sulphate and concentrated under reduced pressure to get the residue. The residue was dissolved in isopropyl ether (740 mL) at room temperature and stirred for 1 hr at same temperature. Un-dissolved material was filtered (triphenyl phosphine oxide bi-product).Then bi-product was again slurred in isopropyl ether (370 mL) and filtered solid was washed with 180 mL isopropyl ether. Organic layer was distilled initially under normal pressure and finally under vacuum.

Example-2B

Methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidine-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate (194 g) obtained from Example-2A was dissolved in MeOH (970 mL) then cooled to 100 C. Methane sulphonic acid (20 g) in MeOH water mixture (682 mL) was added drop wise at same temperature. Total solution temperature was raised to room temperature and stirred for 10 hours. Again reaction mass was cooled to 100 C and remaining methane sulphonic acid (9g) in MeOH water mixture (288 mL) was added drop wise at same temperature. Total reaction mixture temperature was raised to room temperature and stirred for 1 hr. After completion of the reaction monitored by HPLC  MeOH was completely distilled under reduced pressure at 50-550 C. To the obtained residue  water was added (620 mL) and stirred for 30 minutes. Aqueous layer was extracted with toluene (2x1 Lit). Organic layer was washed with saturated NaHCO3 solution (120 g in 1lit water) then washed with water (1 lit). Organic layer was dried with sodium sulphate and concentrated under reduced pressure (below 500 C)
Crude weight: 202 g

Example-2C

158 g of the compound of example 2 B was dissolved in mixture of methanol (790 mL) and THF (1580 mL) and cooled to -750 C under nitrogen atmosphere. Diethyl methoxy borane (319 mL  1M solution in THF) was added drop wise at the same temperature for 30-40 minutes. Reaction mixture was stirred for 30 minutes and then 15.7 g of sodium borohydride (NaBH4) was added portion wise for 1 hr at the same temperature. After completion of the addition reaction  mixture was stirred for 3 hours at same temperature. Progress of the reaction was monitored by HPLC. If reaction was completed  Hydrogen peroxide (H2O2) (350 mL  40% solution) was added at the same temperature. Reaction mixture temperature raised to room temperature and stirred for 1 hour. Organic solvent mixture was distilled completely under reduced pressure (at 50-550 C) and water was added (600 mL). Aqueous layer was extracted with ethyl acetate (3x1500 mL). Combined organic layer was washed with water (300 mL) and saturated sodium chloride solution (300 mL). Organic layer was dried with sodium sulphate and concentrated under reduced pressure (below 500 C)
Crude weight: 183 g.

Example-2D

160 g (0.32 mol) of the compound obtained from example 2-C was dissolved in methanol (320 mL) and cooled to 0-100 C. Sodium hydroxide solution (18 g NaOH in 160 mL water) was added drop wise at the same temperature. Temperature of the reaction mixture was raised to room temperature and stirred for 2 hours. Progress of the reaction was monitored by HPLC. If reaction was completed  the methanol (MeOH) was completely distilled under reduced pressure (50-550 C) and water was added (400 mL). Aqueous layer was washed with isopropyl ether (3x250 mL). Aqueous layer was cooled to 00 C and pH was adjusted to 3-3.3 using 1N hydrochloric acid (HCl). Aqueous layer was extracted with ethyl acetate (4x300 mL). Combined organic layer was washed with water (200 mL). This organic layer either concentrated under reduced pressure to get Resuvastatin as residue or as such proceeded for the next step without concentration.

Example-2E (Rosuvastatin indanamine salt)

Above dried organic layer was cooled to 0-100 C. Meanwhile In a separate vessel  45 g (0.33mol) of 1-indanamine was dissolved in 50 mL of ethyl acetate at 0-100 C to obtain indanamine solution. Indanamine solution was added drop wise to the solution of Resuvastatin acid in ethyl acetate at 0-100 C for 30 minutes. Temperature of reaction mixture was slowly raised to room temperature and stirred over night. After complete precipitation of the solid  again reaction was mixture cooled to 00 C and stirred for 1 hour. Solid precipitate was filtered and washed with chilled ethyl acetate (100 mL).
Dry weight: 170 g

Example -3 (preparation of indanamine salt in acetonitrile)

200g  (0.41mol) residue of rosuvastatin obtained from Example-1B or 2D was dissolved in 600 mL of acetonitrile and cooled to 0-100 C. 58 g of 1-Indanamine in 65 mL of acetonitrile solution was added drop wise to the above rosuvastatin solution at the same temperature. Reaction mixture was stirred for 15 hours at room temperature. Reaction mixture was cooled to 00 C and stirred for 1 hour. Solid precipitate was filtered and washed with chilled acetonitrile.
Dry weight of the compound: 221 g

Example- 4 (preparation of indanamine salt in acetone)

200g  (0.41mol) residue of rosuvastatin obtained from Example-1B or 2D was dissolved in 600 mL of acetone and cooled to 0-100 C. 58 g of 1-Indanamine in 65 mL of acetone solution was added drop wise to the above rosuvastatin solution at the same temperature. Reaction mixture was stirred for 15 hours at room temperature. Reaction mixture was cooled to 00 C and stirred for 1 hour. Solid precipitate was filtered and washed with chilled acetone.
Dry weight of the compound: 210 g

Example- 5 (preparation of indanamine salt in isopropyl alcohol)

200g  (0.41mol) residue of rosuvastatin obtained from Example-1B or 2D was dissolved in 600 mL of isopropyl alcohol and cooled to 0-100 C. 58 g of 1-Indanamine in 65 mL of isopropyl alcohol solution was added drop wise to the above rosuvastatin solution at the same temperature. Reaction mixture was stirred for 15 hours at room temperature. Reaction mixture was cooled to 00 C and stirred for 1 hr. Solid precipitate was filtered and washed with chilled isopropyl alcohol.
Dry weight of the compound: 225 g

Example- 6 (preparation of indanamine salt in chloroform)

200g  (0.41mol) residue of rosuvastatin obtained from Example-1B or 2D was dissolved in 600 mL of chloroform and cooled to 0-100 C. 58 g of 1-Indanamine in 65 mL of chloroform solution was added drop wise to the above rosuvastatin solution at the same temperature. Reaction mixture was stirred for 15 hours at room temperature. Reaction mixture was concentrated under reduced pressure to obtain the rosuvastatin indanamine salt residue. To the residue 260 mL of fresh chloroform was added and cooled to 00 C. Total reaction mixture was stirred for 1 hour at same temperature. Solid precipitate was filtered and washed with chilled chloroform.
Dry weight of the compound: 205 g

Example -7 (Rosuvastatin calcium)

Suspension of rosuvastatin indanamine salt  obtained from any of the above examples  (50 g of rosuvastatin indanamine salt in 150 mL of water) was cooled to 15-200 C. NaOH (3.94g in 100 mL water) solution was added slowly to the reaction mass at 15-200 C. Total reaction mixture was stirred for 1.5 hours at same temperature. Aqueous layer was washed with tert-Butyl acetate (3x75 mL) at same temperature. Aqueous layer was carefully separated (product is in aqueous layer). Aqueous layer was distilled up to 90% below 400 C under vacuum. Now fresh water (800 mL) was added to the residue. Aqueous layer filter through Hyflow bed and wash the bed with 200 ml of water. Aqueous calcium chloride (10g in 50 ml of water) solution was slowly added to above reaction mass at 40-450 C. Reaction mixture was stirred for 45 minutes at same temperature. Separated solid compound was filtered and washed with 50 mL of water.

Dry weight of the compound: 45g

When tert-butyl acetate is used to wash the aqueous layer  the indanamine is separated from the salt and is available as free indanamine compound in the reaction mixture. This free indanamine may be removed  concentrated and re-used for preparation of rosuvastatin indanamine salt in the process.

We Claim:

1. A Rosuvastatin amine salt of the formula-I

wherein  n = 1  2  3  4  5  or any multiple of 1; and

wherein said salt is rosuvastatin indanamine salt when n=1.

2. A rosuvastatin amine or indanamine salt as claimed in claim 1  wherein said salt is a solid crystalline  amorphous  hydrate  solvate or anhydrous salt.

3. A rosuvastatine amine or indanamine salt as claimed in claim 1  wherein said salt is a crystalline salt having chemical purity of 99% or more.

4. A process of preparing rosuvastatin amine or indanamine salt of claim 1  wherein said process comprises:

a). dissolving rosuvastatin with free carboxylic group in a first organic solvent at a temperature between 0 to 100 C to obtain a first organic solution;

b). dissolving an amine base in a second organic solvent at temperature between 0 to 100 C to obtain a second organic solution;

c). adding second organic solution obtained in step (b) to the first organic solution of step (a) drop wise with continuous stirring of the reaction mixture at temperature between 0 to 100 C;
d). raising temperature of the reaction mixture obtained in step (c) to room temperature and stirring the mixture;

e). cooling the temperature of the reaction mixture of step (d) to -2 to 20 C and stirring the reaction mixture for 0.5 to 2 hours;

f). filtering the reaction mixture of step (e) and obtaining the solid precipitate;

g). washing the precipitates obtained from step (f) with a chilled third organic solvent to obtain rosuvastatin amine or indanamine salt.

5. A process as claimed in claim 4  wherein said first organic solvent used in step (a) is selected from ketones such as acetone  ethyl methyl ketone  methyl isobutyl ketone and diisobutyl ketone; esters such as niethyl acetate  ethyl acetate  n-propyl acetate  isopropyl acetate  n-butyl acetate and isobutyl acetate; chlorinated hydrocarbons such as methylene chloride  chloroform  carbon tetrachloride and ethylene dichloride; nitriles such as acetonitrile and propionitrile; alcohols such as methanol  ethanol  isopropyl alcohol and n-propanol; ethers such as diethyl ether  dimethyl ether  diisopropyl ether and 1 4-dioxane  hydrocarbons such as toluene  xylene  n-heptane  cyclohexane  n-hexane or mixtures thereof or their combination with water.

6. A process as claimed in claim 4  wherein said second organic solvent in step (b) is selected from ketones such as acetone  ethyl methyl ketone  methyl isobutyl ketone and diisobutyl ketone; esters such as niethyl acetate  ethyl acetate  n-propyl acetate  isopropyl acetate  n-butyl acetate and isobutyl acetate; chlorinated hydrocarbons such as methylene chloride  chloroform  carbon tetrachloride and ethylene dichloride; nitriles such as acetonitrile and propionitrile; alcohols such as methanol  ethanol  isopropyl alcohol and n-propanol; ethers such as diethyl ether  dimethyl ether  diisopropyl ether and 1 4-dioxane  hydrocarbons such as toluene  xylene  n-heptane  cyclohexane  n-hexane or mixtures thereof or their combination with water.

7. A process as claimed in claim 4  wherein said amine or indanamine base in step (b) is selected from amines having different stereoisomeric configuration selected from-

wherein  n = 1  2  3  4  5  or any multiple of 1;and
wherein said amine is indanamine when n=1.

8. A process as claimed in claim 4  wherein said temperature in step (d) is 20 to 300 C  preferably 25 to 270 C.

9. A process as claimed in claim 4  wherein said reaction mixture in step (d) is stirred for 12-17 hours  preferably for 12 to 15 hours  more preferably for 15 hours.

10. A process as claimed in claim 4  wherein said reaction mixture in step (e) is cooled to 00 C.

11. A process as claimed in claim 4  wherein said stirring in step (e) is done for 1 hour.

12. A process as claimed in claim 4  wherein said third organic solvent is selected from ketones such as acetone  ethyl methyl ketone  methyl isobutyl ketone and diisobutyl ketone; esters such as methyl acetate  ethyl acetate  n-propyl acetate  isopropyl acetate  n-butyl acetate and isobutyl acetate; chlorinated hydrocarbons such as methylene chloride  chloroform  carbon tetrachloride and ethylene dichloride; nitriles such as acetonitrile and propionitrile; alcohols such as methanol  ethanol  isopropyl alcohol and n-propanol; ethers such as diethyl ether  dimethyl ether  diisopropyl ether and 1 4-dioxane  hydrocarbons such as toluene  xylene  n-heptane  cyclohexane and n-hexane or a combination thereof.

13. A process as claimed in claim 4  wherein said washing of rosuvastatin amine or indanamine precipitate in step (g) is done with a third organic solvent or with a combination of two or more third organic solvents.

14. A pharmaceutical composition comprising rosuvastatin calcium obtained from the rosuvastatin indanamine salt as claimed in claim 1.

15. A rosuvastatin amine and indanamine salts and a process for preparing the same such as herein described in the description with reference to the examples.