CHAUHAN AJAY DAYAJI (IN)
DESHPANDE PANDURANG BALWANT (IN)
CHAUHAN AJAY DAYAJI (IN)
| EP0483932A1 | 1992-05-06 | |||
| US4567264A | 1986-01-28 |
| 1. | Novel polymorhic FormA of Ranolazine dihydrochloride characterized by XRD (2Θ) ± 0.2 peaks at 521,9.20,10.26,11.83,12.14,12.97,14.21,15.81,17.96,18.52,19.03,19.45,20.1 2,20.28,20.66,21.81,22.18,22.78,22.92,23.53,23.95,24.50,25.25,25.78,26.28, 26.97,27.36,27.97,28.28,28.85,29.59,29.95,31.23,33.87,34.15 Differential Scanning Calorimetry (DSC) : Endotherm at around 225.79 0C 2 Novel amorphous Form of Ranolazine dihydrochloride characterized by XRD (2Θ) with a broad hump ranging from 740. Differential Scanning Calorimetry (DSC) : Exotherm at around 154155 0C followed by Endotherm at around 222223 0C I I 3. . Novel Crystalline Form of Ranolazine base characterized by XRD ( 2Θ ) ± 0.2 peaks at i' 483,9.80,10.16,1222.04,12.96,14.11,14.74,15.92,16.27,17.24,17.74,19.09,1 9.62,20.49,21.19,22.16,,23.20,23.97,24.43,25.27,26.27,27.21,30.02,31.04, 31.64 & 31.13 Differential Scanning Calorimetry (DSC) : Endotherm at around 118119 0C 4 Novel process for the preparation of crystalline (±)l[3(2 Methoxyphenoxy)2hydroxypropyl]4[N(2,6dimethylphenyl) carbamoylmethyl] piperazine dihydrochloride without the use of chromatographic methods comprising steps a) Reaction of l(2methoxyphenoxy)2,3epoxypropane with excess piperazine preferably in 4 to 20 molar proportion in the presence of water or, alcohol to obtain l[3(2methoxyphenoxy)2 hydroxypropyl]piperazine | b) Purification of l[3(2methoxyphenoxy)2 hydroxypropyl]piperazine by preparing a weak acid addition salt such as acetate, fumarate, or maleate etc. preferably acetate followed by its isolation as a solid and further conversion to the base for subsequent use i c) Condensation of' l[3(2methoxyphenoxy)2 hydroxyproρyl]piρerazine with [(2,6dimethylρhenyl aminocarbonyl inethyl)chloride in dimethylformamide as' a solvent anhydrous alkali carbonate as base and alkali halide as a catalyst. d) Extraction of (+)l[3(2Memoxyphenoxy)2hydroxypropyl]4 [N(2,6dimetliylphenyl)carbainoyhnethyl] piperazine in watej immiscible organic solvent followed by extraction in water usin^ aqueous hydrochloric acid. e) Isolation of Ranolazine base by neutralization of hydrochloride solution using aqueous ammonia or using a mixture of aqueous ammonia and water miscible solvent. f) Dissolution of Ranolazine ba(se in organic solvents and contacting with hydrochloric acid in water, alcoholic solvent and the mixture there of to isolate solid dihydrochloride. |
| 2. | A process for the preparation of crystalline polymorphic FormA of (+)■ l[3(2Methoxyphenoxy)2hydroxypropyl]4[N(2,6dimetliylphenyl) carbamoylmethyl] piperazine dihydrochloride wherein dihydrochloride is prepared as per claim 4, is dissolved in methanol at above 50 0C anc cooled to 10 0C to isolate a solid product which on drying at 60100 0C with or with out vacuum yields crystalline Form A containing 24 % water. |
| 3. | A process for the preparation of Amorphous from (+)l[3(2 Metlioxyphenoxy)2hydroxypropyl]4pSf(2,6dimetliylphenyl) carbamoylmethyl] piperazine wherein dihydrochloride prepared as in claim 4 and 5 is dissolved in water or aqueous water miscible solvent at above 50 0C followed by evaporation of solvent under vacuum to obtain the amorphous form of (±)l[3(2Methoxyphenoxy)2hydroxypropyl]4[N (2,6dimetliylphenyl)carbamoyl methyl] piperazine dihydrochloride containing 24 % water. |
| 4. | The aqueous water miscible solvent is selected from aqueous ethanol, aqueous methanol, aqueous tetrahydrofuran, aqueous 1,4 dioxane, aqueous acetone containing 5 to 95 & 95 to 5 % v/v of water. |
| 5. | A process for the preparation of Ranolazine dihydrocnloride polymorphic Form A, by dissolving the Ranolazine hydrochloride in alcoholic solvent at reflux and cooling gradually to room temperature and filtering to produce the Form A. , :. |
| 6. | Novel process for the preparation of crystalline (±)~l[3(2 Memoxyphenoxy)2hydroxypropyl]4βNT(2,6 ; ' dimethylphenyl)carbamoyhnethyl] piperazine base without the use of chromatographic methods comprising steps f) Reaction of l(2methoxyphenoxy)2,3epoxypropane with excess piperazine preferably in 4 to 20 molar proportion in the presence of water or alcohol to obtain l'ς[3(2Jmethoxyphenoxy)2 hydroxypropyl]piperazine g) Purification of l[3(2rmethoxyphenoxy)2 hydroxypropyl]piperazine by preparing a weak acid addition salt such as acetate, fumarate, or maleate etc. preferably acetate followed by its . isolation as a solid and further conversion to the base for subsequent use. h) The condensation of l[3(2methoxyphenoxy)2 hydroxypropyljpiperazine with. . [(2,6dimetliylphenyl) aminocarbonyl methyl)chloride in dimethylformamide as a solvent and anhydrous alkali carbonate as base and alkali halide as a catalyst. i) Extraction of (±)l[3(2Metlioxyphenoxy)2hydroxypropyl]4 [N(2,6dimethylphenyl)carbamoylmethyl] piperazine in water immiscible organic solvent followed by extraction in water using aqueous hydrochloric acid. j) Isolation of Ranolazine base by neutralization of hydrochloride solution using aqueous ammonia or a mixture of aqueous ammonia and water miscible solvent, filtration and drying to get the crystalline Ranolazine base as characterized in claim no. 3. 10. |
| 7. | Ranolazine dihydrochloride as described in Claims 1, 2,4,5, 6 & 8 is with the moisture content up to 5 % and preferably from 24 %. |
| 8. | A novel process for the preparation of crystalline Ranolazine base as claimed in claim 4 and 9 wherein the base used is selected from anhydrous potassium carbonate, sodium carbonate, cesium carbonate and ammonium carbonate. The alkali halide used as catalyst is selected from sodium iodide, potassium iodide, sodium bromide and potassium bromide. |
| 9. | Water immiscible solvents used in the claim no. 4 and 9 is selected from •methylene chloride, toluene, ethylene dichloride, ethyl acetate. |
| 10. | Water miscible solvents used in the claim no. 4 and 9 is selected from methanol, ethanol, Isopropyl alcohol, 1,4 dioxane, Tetrahydrofuran, Dimethyl formamide, Acetone and acetonitrile. |
| 11. | A process for the purification of l[3(2rriethoxyphenoxy)2 hydroxypropyl ] piperazine by forjning a week acid salt & neutralizing the acid salt with aqueous ammonia. |
| 12. | The weak acid salt of l[3(2methoxyphenoxy)2hydroxypropyl ] piperazine used in purification as claimed in claim 14 is selected from acetate, fumarate, maleate, succinate and lactate. |
Field of the Invention _
The present invention relates to crystalline polymorph of (±)-l-[3-(2- Metlioxyphenoxy)-2-hydroxypropyl]-4-psr-(2>6-diirietliylp henyl)carbamoyl methyl] piperazine dihydrochloride and its base (Ranolazine base) and new amorphous (+)- 1 - [3 -(2-Methoxyphenoxy)-2-hydroxypropyl] -4- [N-(2 ,6- dimethylphenyl) carbamoyl methyl] piperazine dmydrochloride (Ranolazine dihydrochloride) and process for the preparation there of.
Background of the invention: -
Ranolazine dihydrochloride ( Formula-I) is a novel anti-anginal agent which has been reported to protect against biochemical electrophysiological and mermodynamic consequences of transient myocardial ischmia in the pentobarbitone-anesthetized dog, |jwithout inducing overt hemodynamic effects. *•
Formula-I
Prior Art :
US Patent 4567264 describes the preparation of Ranolazine base from basic stages by condensing [(2,6-dimethyphenyl) amino; carbonyl methyl] - chloride (II) with l-[3-(2-metlioxyphenoxy)-2- hydroxypropyl]piperazine.(III) The base was purified by column chromatography and isolated as oil. The hydrochloride salt was prepared in methanol using hydrochloric acid and the salt was isolated by addition of ether.
Ranolazine Base
EP 0483932 describes the preparation of Ranolazine base by condensation of α-[ N3N -bis (2-cWoroetiiyl)-amino]-2,6-dimetliylacetanilide hydrochloride (IV) with l-[3-(2-methoxy phenoxy)-2-hydroxy]-propylamine (V). The base was purified using column chromatography and hydrochloride was formed by treating with metholic hydrochloric acid and crystallized by addition of diethyl ether as co solvent to obtain a product with melting point 229- 230 0C.
Ranolazine base
It is a long standing need to avoid the formation of oil and obtain the product directly as solid there by eliminating laborious and expensive column chromatographic methods and achieving the higher yields of Ranolazine diliydrochloride. More over the prior art does not teach, any features such as polymorphic forms of the drug which may have varying pharmacological effects ''
Summary of the invention :
The main object of invention is to provide an industrially feasible process for preparation of (+)-l-[3-(2-Metlioxyphenoxy)-2-hydroxypropyl]-4-[N- (2,6-dimethylphenyl)carbamoyl methyl] piperazine base and dihydrochloride as a solid without the use of column chromatographic methods.
It is an another object of the invention to provide process for purification of l-[3-(2-methoxyphenoxy)-2-hydroxypropyl ] piperazine It is yet another object of the invention is to provide process for preparation and characterization of amorphous and crystalline forms of (±)-l-[3-(2- Methoxyphenoxy)-2-hydroxypropyl]-4-pST-(236-dimetliylphenyl) carbamoyl methyl] piperazine dihydrochloride. ,••*' '
It is yet another object of the invention is to provide process for preparation and characterization of crystalline form of (+)-l-[3-(2-Methoxyphenoxy)-2- liydroxypropyl]-4-[N-(2,6-dimetliylphenyl)carbamoyl methyl] piperazine base.
It is another object of the invention is to provide a process for preparation of Ranolazine base from its hydrochloride salt.
Thus in accordance with this invention the crystalline form-A of (+)-l-[3-(2- Memoxyphenoxy)-24iydroxypropyl]-4-[N-(256-dimemylphenyl)carb ainoyl methyl] piperazine dihydrochloride is prepared by dissolving Ranolazine base in organic solvent and reacting it with hydrochloric acid in water or water miscible solvent, followed by dissolution of the crude (+)-l-[3-(2- Memoxyphenoxy)-24iydroxypropyl]-4-[N-(2,6-dimetliylphenyl)ca rbainoyl methyl] piperazine dihydrochloride in alcoholic solvent at reflux and crystallizing the product by slow cooling to room temperature.
The amorphous form of (+)-l-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4- [N-(2,6-dimetliylphenyl)carbamoyl methyl] piperazine dihydrochlofide is obtained by dissolving Ranolazine dihydrochloride in water and drying it under vacuum. Optionally the amorphous foπn is also obtained by dissolving the crystalline product in large excess of a mixture of water and water miscible solvent (in the ratio of 5 to 95 & 95 to 5 v/v) more preferably in aqueous ethanol and evaporation under vacuum.
The crystalline form of (±)-l-[3-(2-Methoxyphenoxy)-2-hydroxyρropyl]-4- [N-(2,6-dimethylphenyl)carbamoyl methyl] piperazine base is obtained by treating the dihydrochloride salt with aqueous ammonia or in a mixture of aqueous ammonia 'and water miscible solvents at 20-60 0C, cooling to 30 0C, filtering and drying. Detailed description of invention :
l-(2-metlioxyphenoxy)-2,3-epoxypropane and [(2,6-dimethylphenyl) aminocarbonyl mctbyl)chloridc arc prepared using the process disclosed in US 4,567,264 . \ " ]
The process for preparing (+)-l-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]- 4-pS[-(2,6-dimethylphenyl)carbamoyl metliyl] piperazine dihydrochloride of present invention comprises the steps, . :
a) Reaction of l-(2-memoxyphenoxy)-2,3-epoxypropane with excess
c) l-[3-(2-methoxyphenoxy)-2-hydroxypropyl]piperazine is reacted with. [(2,6-dimethylphenyl) aminocarbonyl methyl)chloride in dimetliylformamide as a solvent, anliydrous alkali carbonate as base and alkali halide as a catalyst. The reaction mixture is < filtrated, water is added followed by extraction with water immiscible organic solvent in which the Ranolazine base is soluble! The organic layer is extracted with dilute hydrochloric acid, the layers are separated and the aqueous layer containing the product as hydrochloride is degassed followed by neutralization with a mixture of ammonia and water miscible solvents to obtain Ranolazine base which is filtered and dried under vacuum . Alternatively the Ranolazine base is also obtained by neutralizing the dihydrochloride salt in aqueous ammonia or in a mixture j of aqueous ammonia arid water miscible solvent. ; ! : I d) (±)-l-[3-(2-Metlioxyphenoxy)-2-hydroxypropyi]-4-[N-(2,6- dimethylphenyl)carbamoyl methyl] piperazine base is dissolved in organic solvents such as acetone, THF, Toluene is contacted with 1 . >' hydrochloric acid ( > 2 -4moles) in water, alcoholic solvent and the mixture there of ( in the ratio of 10-90 & 90- 10 % v/v followed by the separation of solid. i i '
The Ranolazine dihydrochloride obtained in previous step (d) is dissolved in methanol at above 50 C and cooled to 10 C to isolate a solid product which on drying at 60-100 C with or with out vacuum yields crystalline Form-A of (±)-l-[3-(2-Metlioxyphenoxy)-2-hydroxypropyl]-4-[N-(2,6- dimethylρhenyl)carbamoyl methyl] piperazine dihydrochloride containing 2- 4 % water as characterized by XRD as shown in Figure- 1 & DSC in Figure-II with characteristic endotlierm at around 225-226 0C
The Ranolazine dihydrochloride obtained in step (d) is dissolved in aqueous ethanol above 50 0C followed by evaporation of solvent under vacuum to obtain the amorphous form of (±)-l-[3-(2-Methoxyphenoxy)-2- hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbamoyl methyl] piperazine
followed by an endotlierm at around 222-226 0C. It may be further noted that the water content in solvent is very important. A mixture of amorphous & crystalline is obtained if the water content in solvent is below 5 %.
The invention also gives an alternate process for the preparation of (+)-l-[3~ (2-Methoxyphenoxy)-2-hydroxypropyl]-4-pS[-(2,6-drmethylpheny l) - carbamoyl methyl] piperazine base form its diliydrocliloride by neutralizing the diliydrochloride salt using a mixture of aqueous ammonia & water miscible solvent at 20-60 0C .
It may be further noted that the crystalline and amorphous Ranolazine di¬ liydrocliloride exhibit a broad endotherm below 100 0C in DSC.
The following examples will further illustrate the invention but not intended to limit the scope of the invention as defined herein above or as claimed below. Example-1:
Preparation of l-[3-(2-Metkoxyphenoxy)-2-hydroxypropyl ] piperazine
100 gms l-(2-methoxyphenoxy)-2,3-epoxypropane was added in a 60 min at 0-5 0C to 192 gms of anhydrous piperazine dissolved in 500 ml methanol. Reaction mixture is stirred further for 2 Hrs at 0-5 0C. It is quenched in 400 ml DMW & filtered. The product is obtained by extraction with MDC from the saturated aqueous layer with sodium chloride. 65 gms of acetic acid and 400 ml water is added in the MDC layer. Aqueous layers was separated and basified with 100 ml liquor ammonia. The product was extracted with 500 ml methylene dichloride and isolated by evaporation of solvent. The residue was used as such in the next reaction.
Yield =80 gms. HPLC purity = 96-$k %.
ExampIe-2 r-
Preparation of crude (+)-l-[3~(2-Methoxyphenoxy)-2-hydroxypropyl]-4- [N-(2,6-dimethylphenyl)carbamoylmethyl] piperazine dihydrochloride.
A mixture of 90 gms l-[3-(2-Memoxyphenoxy)-2-hydroxypropyl ] piperazine, 85 gms [(2,6-dimethylphenyl) aminocarbonyl methyl)chloride, 120 gms anhydrous potassium carbonate and 3.6 gms sodium iodide in 260 ml dimethyl formamide is stirred at room temperature (30-35 0C) for 18 Hrs. The reaction mixture is quenched in 1600 ml water and extracted thrice with 300 ml methylene dichloride each time . Combined methylene dichloride layer is treated with a mixture of 1100 ml aqueous hydrochloric acid ( 35 %) & 900 ml water. Acidic aqueous layer is basified with ammonia, extracted with methylene dichloride and solvent is evaporated to get Ranolazine base. ; Yield = 140 gms , The above Ranolazine base is taken in 2160 j ml j acetone and 100 hydrochloric acid gas dissolved in isopropyl alcohol is added at room temperature till pH is acidic. The precipitated dihydrochloride compound is Filtered, is washed with acetone to give the Ranolazine dihydrochloride Yield = 144 gm.
Example-3 :-
Preparation of Crystalline (+)-l-[3-(2-Methoxyphenoxy)-2- hydroxypropyl]-4-[N-(2,6-diniethylphenyl)carbamoylmethyl] piperazine dihydrochloride.
100 gms of Crude (+)-l-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4-[N- (2,6-dimemylplienyl)caitamoyhnetliyl] piperazine dihydrochloride is dissolved to get a clear solution in 500 ml methanol., The solution is cooled to room temperature and further cooled to 100C. The product is filtered, washed with 2 X 50 ml methanol and dried at 75 degree C for 10 Hrs. get crystalline Form -A of Ranolazine diliydrochloride] ;: characterized .by XRD & DSC as shown in Figure |I and II.
Example-4: -
Preparation of Amorphouse (+)-l-[3-(2-Methoxyphenoxy)-2- hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbamoylmethyl] piperazine dihydrochloride
100 gms Ranolazine diliydrochloride is added in 500 ml water and heated to get a clear solution. Water is distilled off under reduced pressure, the residue is cooled to room temperature to obtain, amorphous form characterized by a XRD pattern (Figure III ) and DSC (Figure IV) exhibiting a broad endotherm around 80 and exotherm bet 220-224 and followed by endotherm 150-156 0C.
Example-5: -
Preparation of Amorphouse ,(+)-l-[3-(J2-Methoxyphenoxy)-2- hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbampylitnethyl] piperazine dihydrochloride
100 gms Ranolazine dihydrochloride is added ;i| in 2000 ml ethanol containing 10 % water and heated to get a clear: solution. Solvent is distilled off under reduced pressure, the residue is cooled to room temperature to obtain amorphous form characterized by a XRD pattern (Figure m ) and DSC (Figure IV) exhibiting a broad endotherm around 80 and exotherm bet 220-224 and followed by endotherm 150-156 0C.
Example -6:~
Preparation of Ranolazine base from its di hydrochloride salt
20 gms Ranolazine dihydrohloride at room temperature is added to a mixture containing 150 ml water and 50 ml acetone and 20 ml liquor ammonia. It is stirred for two hrs. The precipitated base, was . filtered and dried under vacuum at 70 0C to get crystalline form of Ranolazine base characterized by XRD & DSC as shown in Figure V & VI. Yield = 12 gms. Figure. I XRD data of Crystalline form of Ranolazine dihydrochloride
Figure. V
XRD data of Crystalline form of Ranolazine Base.