FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
THE PATENTS RULE 2003
COMPLETE SPECIFICATION
(Section 10 and rule 13)
AN IMPROVED PROCESS FOR THE PREPARATION REMOGLIFLOZIN ETABONATE OR PHARMACEUTICALLY ACCEPTABLE SALT, SOLVATE, HYDRATE THEREOF
APPLICANT
GLENMARK PHARMACEUTICALS LTD
B/2, Mahalaxmi Chambers,
22 Bhulabhai Desai Road, Mumbai
Maharashtra, India - 400026
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED 5
2
AN IMPROVED PROCESS FOR THE PREPARATION REMOGLIFLOZIN ETABONATE OR PHARMACEUTICALLY ACCEPTABLE SALT, SOLVATE, HYDRATE THEREOF
RELATED APPLICATIONS 5
This application claims the benefit of Indian Provisional Application No. 201821013037 filed on April 5, 2018; which is hereby incorporated by reference in its entirety.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 10 Remogliflozin of formula (I), its prodrug Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate hydrate thereof.
OHOHOOOHOHNNO
Formula I
OHOOOOHOHNNOOO 15
Formula II
The present invention further relates to an improved process for preparation of Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate hydrate thereof, through formation of isopropyl alcohol solvate of Remogliflozin etabonate.
The present invention further relates to isopropyl solvate of Remogliflozin etabonate 20 and process for preparation thereof.
BACKGROUND OF THE INVENTION
Remogliflozin etabonate is a pro-drug of Remogliflozin, the active entity that inhibits the sodium dependent glucose transporter 2 (SGLT2). Remogliflozin etabonate is chemically 25 known as 5-methyl-4-[4-(1-methylethoxy)benzyl]-1-(1- methylethyl)-1H-pyrazol-3-yl 6-O-(ethoxycarbonyl)-β -D-glucopyranosid.
3
Remogliflozin etabonate is known to exhibit a strong inhibitory action for SGLT2 and is proposed for treatment of diabetic patients.
The process for preparation of Remogliflozin etabonate is disclosed in US Patent 7,084,123, US Patent 8,022,192 and WO2010127067.
It was observed that the processes provided in prior art suffers from following 5 disadvantages:
1. None of the processes disclosed in prior art is efficient and scalable to industrial scale. The processes disclosed in prior art require several purification steps to obtain pure intermediates and Remogliflozin etabonate to meet the requirements of ICH guidelines.
2. Multiple solvents are used at various stages of the processes, and thus a complete 10 removal of said solvents can be difficult.
3. Use of expensive Scandium or Copper catalysts is economically expensive and not feasible on industrial scale.
To overcome the prior-art problems the present inventors have now developed an improved process for the preparation of Remogliflozin etabonate or pharmaceutically 15 acceptable salt, solvate hydrate thereof, using industrially friendly solvents and reagents.
SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided an improved process
for the preparation of Remogliflozin etabonate of formula (II) 20
OHOOOOHOHNNOOO
Formula II
or pharmaceutically acceptable salt, solvate, hydrate thereof
comprising,
i) converting Remogliflozin of formula (I) 25
OHOHOOOHOHNNO
4
Formula (I)
to Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof,
ii) converting Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof to isopropyl alcohol solvate of Remogliflozin etabonate and 5
iii) converting isopropyl alcohol solvate of Remogliflozin etabonate to Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof.
According to another aspect of present invention, there is provided isopropyl alcohol solvate of Remogliflozin etabonate. 10
According to another aspect of the present invention, there is provided isopropyl alcohol solvate of Remogliflozin etabonate characterized by differential scanning calorimetric (DSC) thermogram.
According to another aspect of present invention, there is provided an isopropyl alcohol solvate of Remogliflozin etabonate characterized by powder X-ray diffraction (PXRD) pattern. 15
According to another aspect of present invention, there is provided isopropyl alcohol solvate of Remogliflozin etabonate characterized by a thermogravimetric analysis curve (TGA).
According to yet another aspect of present invention, there is provided a process for preparation of isopropyl alcohol solvate of Remogliflozin etabonate.
comprising, 20
i) mixing Remogliflozin etabonate or pharmaceutically acceptable salt, solvate, hydrate thereof with isopropyl alcohol or mixture of isopropyl alcohol and a suitable solvent and
ii) isolating isopropyl alcohol solvate of Remogliflozin etabonate.
25
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts differential scanning calorimetric (DSC) thermogram of isopropyl alcohol solvate of Remogliflozin etabonate
Figure 2 depicts powder X-ray diffraction (PXRD) pattern of isopropyl alcohol solvate of Remogliflozin etabonate 30
Figure 3 depicts TG thermogram of isopropyl alcohol solvate of Remogliflozin etabonate
DETAILED DESCRIPTION OF THE INVENTION
5
Those skilled in art will be aware that invention described herein is subject to variations and modifications other than those specifically described. It is to be understood that the invention described herein includes all such variations and modifications. The invention also includes all such steps, features, compositions and methods referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more said 5 steps or features.
Definitions:
For convenience, before further description of the present invention, certain terms employed in the specification, examples are described here. These definitions should be read in 10 light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. The terms used throughout this specification are defined as follows, unless otherwise limited in specific instances.
The terms used herein are defined as follows. 15
The term “hydrate” means a compound, in which water molecule/s is/are chemically bound to another compound or molecule or element. The term “hydrate” used herein is inclusive of hemihydrate.
The term “solution” used in the specification is intended to include mixture, suspension and other variations known in art and is not to be limited in scope by the specific embodiments 20 described herein, which are intended for the purposes of exemplification only.
As used in the specification and the claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. 25
The term “Remogliflozin” as used herein, includes Remogliflozin free base and is used interchangeably throughout the disclosure.
The term “salt” or “pharmaceutically acceptable salt” as used herein, is intended to mean those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic 30 response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
The term “crystalline” as used herein, means having a regularly repeating arrangement of molecules or external face planes.
6
Unless stated otherwise, percentages stated throughout this specification are weight/weight (w/w) percentages.
The term “room temperature” unless stated otherwise, essentially means temperature in range of 25‐27 °C.
The present invention relates to an improved process for preparation of Remogliflozin 5 etabonate of formula (II)
OHOOOOHOHNNOOO
Formula II
or pharmaceutically acceptable salt, solvate, hydrate thereof
comprising, 10
i) converting Remogliflozin of formula (I)
OHOHOOOHOHNNO
Formula (I)
to Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof, 15
ii) converting Remogliflozin etabonate or pharmaceutically acceptable salt, solvate, hydrate thereof to isopropyl alcohol solvate of Remogliflozin etabonate and
iii) converting isopropyl alcohol solvate of Remogliflozin etabonate to Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof.
According to an embodiment of present invention, converting Remogliflozin of formula 20 (I) to Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof comprises reacting Remogliflozin of formula (I) with ethyl haloformate. In an embodiment, ethyl haloformate is ethylchloro formate. The reaction may be carried out in the presence of base and suitable solvent. Suitable base may be organic or inorganic base. The organic base used in the step (i) of the process may be selected from 2,6-lutidine, pyridine, 2,4.6 25 trimethyl pyridine, triethylamine, diisopropylamine, diisopropylethylamine or mixture thereof.
7
The suitable solvent used in step (i) may be selected from the group consisting of toluene, xylene, benzene and acetone. According to another embodiment of the present invention, said reaction may be carried out at a suitable temperature. In a preferred embodiment, the reaction may be carried out at temperature ranging from 0 to -20° C. The reaction mixture may be stirred for suitable period of time till the completion of the reaction. The product may 5 be isolated by the conventional technique such as extraction using suitable solvent or mixture of solvents. In another embodiment, the residue may be directly used in the next step.
In step (ii), Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof of step (i) is converted into isopropyl alcohol solvate of Remogliflozin etabonate. The conversion of Remogliflozin etabonate or pharmaceutically acceptable salt, 10 solvate, hydrate thereof to its isopropyl solvate may be carried out by mixing Remogliflozin etabonate or pharmaceutically acceptable salt, solvate, hydrate thereof by treatment with isopropyl alcohol or mixture of isopropyl alcohol and a suitable solvent. A suitable solvent may be a hydrocarbon solvent.
In an embodiment, the step (i) product is treated with isopropyl alcohol at suitable 15 temperature. The reaction mass may be stirred for a suitable period of time. The solid may be collected by known techniques such as filtration.
In another embodiment, the product of step (i) is mixed with a mixture of isopropyl alcohol and n- heptane. The reaction mixture may be stirred at a suitable temperature for a suitable time. In an embodiment, the mixture may be stirred at room temperature or at an 20 elevated temperature such as 500 to 900 C. The reaction mass may be, if required, gradually cooled to room temperature. The solid may be collected by known techniques such as filtration and dried. In another embodiment, the solid may be further crystallized from isopropyl alcohol.
In step (iii), isopropyl alcohol solvate of Remogliflozin etabonate is converted to Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate hydrate 25 thereof. In an embodiment, the obtained Remogliflozin etabonate of step (iii) is in a hydrate form. According to yet another embodiment, Remogliflozin etabonate obtained in step (iii) is Remogliflozin etabonate hemihydrate.
In an embodiment, isopropyl alcohol solvate of Remogliflozin etabonate of step (ii) is treated with a mixture of solvents such as mixture of water and a suitable solvent. In an 30 embodiment, isopropyl alcohol solvate of Remogliflozin etabonate of step (ii) is treated with a mixture of solvents such as mixture of water and acetonitrile. The reaction mass may be stirred at a suitable temperature for a suitable period of time. The reaction mass may be filtered to remove undesired impurities. The solution may be further treated with suitable amount of water
8
and stirred. The obtained solid may be washed and collected by known techniques such as filtration.
The present process for preparation of Remogliflozin etabonate or pharmaceutically acceptable salt, solvate or hydrate thereof is advantageous as it allows Remogliflozin etabonate to be prepared in high yield and good quality via isopropyl alcohol solvate of Remogliflozin 5 etabonate. The preparation of isopropyl alcohol solvate of Remogliflozin etabonate ensures removal of maximum impurities. Additional merits of the process for preparation of Remogliflozin etabonate or pharmaceutically acceptable salt, solvate or hydrate thereof are high reproducibility and scalability.
According to a further embodiment of the present invention, Remogliflozin etabonate 10 of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof obtained is substantially pure. For the purpose of the present invention, the term “substantially pure” as used herein includes reference to purity of, or greater than, 98%, more preferably 99%, more preferably 99.5%, more preferably 99.9% purity as determined, for example by HPLC.
According to another embodiment, the present invention relates to substantially pure 15 Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof having purity greater than 98% as determined by HPLC.
According to another embodiment, the present invention relates to substantially pure Remogliflozin etabonate hemihydrate having purity greater than 98% as determined by HPLC.
According to another embodiment, the present invention relates to substantially pure 20 Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof having purity greater than 99% as determined by HPLC.
According to another embodiment, the present invention relates to substantially pure Remogliflozin etabonate hemihydrate having purity greater than 99% as determined by HPLC.
According to another embodiment, the present invention relates to substantially pure 25 Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof having purity greater than 99.5% as determined by HPLC.
According to another embodiment, the present invention relates to substantially pure Remogliflozin etabonate hemihydrate having purity greater than 99.5% as determined by HPLC. 30
According to another embodiment, the present invention relates to substantially pure Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof having purity greater than 99.9% as determined by HPLC.
9
According to another embodiment, the present invention relates to substantially pure Remogliflozin etabonate hemihydrate having purity greater than 99.9% as determined by HPLC.
According to an embodiment of present invention, the substantially pure Remogliflozin etabonate of formula (II) is stable hemihydrate form of Remogliflozin etabonate. 5
According to another aspect of present invention, there is provided an isopropyl alcohol solvate of Remogliflozin etabonate.
According to another aspect of present invention, there is provided an isopropyl alcohol solvate of Remogliflozin etabonate characterized by differential scanning calorimetric (DSC) thermogram, a powder X-ray diffraction (PXRD) pattern or a thermogravimetric analysis curve 10 (TGA).
According to an embodiment of present invention, the isopropyl alcohol solvate of Remogliflozin etabonate characterized by differential scanning calorimetric (DSC) thermogram represented by figure 1.
According to an embodiment of present invention, the isopropyl alcohol solvate of 15 Remogliflozin etabonate characterized by differential scanning calorimetric (DSC) thermogram having endotherm at about 91.71°C and 109.39°C.
According to another embodiment of present invention, the isopropyl alcohol solvate of Remogliflozin etabonate characterized by an X-ray powder diffraction pattern represented in figure 2. 20
According to another embodiment of present invention, the isopropyl alcohol solvate of Remogliflozin etabonate characterized by an X-ray powder diffraction pattern comprising reflections at 6.74° , 9.42°, 11.70°, 18.24°, 19.41°, 19.79° and 22.13° ± 0.2° 2Ɵ.
According to another embodiment of the present invention, the isopropyl alcohol solvate of Remogliflozin etabonate characterized by an X-ray powder diffraction pattern 25 comprising reflections at 6.74 °, 9.42 °, 11.06°, 11.70 °, 13.40°, 13. 80°, 15.88°, 17.01°, 18.24°, 18.79°, 19.09°, 19.41°, 19.79°, 22.13°, 22.53° and 27.99°± 0.2° 2Ɵ.
According to another embodiment of present invention, the isopropyl alcohol solvate of Remogliflozin etabonate characterized by thermogravimetric analysis curve (TGA) represented in figure 3. 30
According to yet another aspect of the present invention, there is provided process for preparation of isopropyl alcohol solvate of Remogliflozin etabonate
comprising,
10
i) mixing Remogliflozin etabonate or pharmaceutically acceptable salt, solvate, hydrate thereof with isopropyl alcohol or mixture of isopropyl alcohol and suitable solvent, and
ii) isolating isopropyl alcohol solvate of Remogliflozin etabonate.
In step (i), Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, 5 solvate, hydrate thereof is mixed with isopropyl alcohol or mixture of isopropyl alcohol and suitable solvent. A suitable solvent may be a hydrocarbon solvent.
In an embodiment, Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof is mixed with isopropyl alcohol at suitable temperature.
The reaction mass may be stirred for a suitable period of time. The solid may be 10 collected by known techniques such as filtration. The obtained sold may be optionally further washed with isopropyl alcohol.
In another embodiment, Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof is mixed with a mixture of isopropyl alcohol and suitable solvent such as n- heptane. The reaction mixture may be stirred at a suitable 15 temperature for a suitable time. In an embodiment, the mixture may be stirred at room temperature or at an elevated temperature such as 500 to 900 C. The reaction mass may be, if required, gradually cooled to room temperature. The solid may be collected by known techniques such as filtration. In another embodiment, the solid may be further crystallized from isopropyl alcohol. In another embodiment, the solid may be further washed with isopropyl 20 alcohol.
According to an embodiment of present invention, the isopropyl alcohol solvate of Remogliflozin etabonate obtained is substantially pure.
The term “substantially pure” as used herein includes reference to purity of, or greater than, 98%, more preferably 99%, more preferably 99.5%, more preferably 99.9% purity as 25 determined, for example by HPLC.
According to yet another embodiment, there is provided a process for preparation of Remogliflozin of formula (I)
OHOHOOOHOHNNO
11
Formula I
comprising steps of
a) reacting 4-(hydromethyl)phenol with 2-halopropane in presence of a base and a suitable solvent to obtain compound of formula (IV)
OHOCH3CH3OHOHCH3CH3XBase4-(hydroxymethyl)phenolFormula IV 5
wherein X is halogen selected from Cl, Br, I or F
b) reacting the compound of formula (IV) with a chlorinating agent in suitable solvent to obtain compound of formula (V)
OHOCH3CH3ClOCH3CH3Chlorinating agentFormula IVFormula V
c) reacting the compound of formula (V) with methyl acetoacetate in presence of a base 10 and a suitable solvent to obtain compound of formula (VI)
H3COOCH3OMethyl acetoacetateOCH3CH3OCH3OCH3OClOCH3CH3BaseFormula VFormula VI
d) reacting the compound of formula (VI) with hydrazine in presence of suitable solvent to obtain compound of formula (VII)
OCH3CH3NHNHOCH3OCH3CH3OCH3OCH3ONH2 NH2 H2OFormula VIFormula VII 15
e) reacting the compound of formula (VII) with sulfonyl halide in presence of base and suitable solvent to obtain compound of formula (VIII)
12
OCH3CH3NHNHOCH3RSClOORSOOOOCH3CH3NHNCH3BaseFormula VIIFormula VIII
wherein R is Mesyl or tosyl,
f) reacting compound of formula (VIII) with haloalkane followed by desulfonation to obtain compound of formula (IX)
RSOOOOCH3CH3NHNCH3CH3CH3XOOCH3CH3NNHCH3CH3CH3BaseFormula VIIIFormula IX 5
g) reacting compound of formula (IX) with glucose derivative of formula (X) in presence of base and suitable solvent to obtain Remogliflozin formula (I)
OHNNOOHOHOOOHOHNNOOPGOPGOBrOPGOPGFormula X1.2. DeprotectionFormula IXFormula I
wherein PG is protecting group
h) optionally converting Remogliflozin of formula (I) to Remogliflozin etabonate of 10 formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof.
According to an embodiment, in step (a) 4-(hydromethyl)phenol is alkylated with 2-halopropane such as 2-chloropropoane, 2-bromopropane and 2-iodopropane.
According to an embodiment of the present invention, the chlorinating agent used in step (b) include, but is not limited to, oxalyl chloride, thionyl chloride, phosphorous trichloride, 15 phosphorous pentachloride, phosphorous oxychloride. The preferred chlorinating agent is oxalyl chloride or phosphorous oxychloride.
The base used in the step (a) and (c) are selected from organic or inorganic base. The organic base is selected from, but not limited to, triethylamine (TEA), N,N-diethylisopropylamine, Ν,Ν-diisopropylethylamine (DIPEA), diethylamine, tripropylamine 20
13
and trioctylamine. Preferably Ν,Ν-diisopropylethylamine (DIPEA) is used. The inorganic base is selected from, but not limited to, alkali metal alkoxide such as potassium tert. butoxide, an alkali metal hydride such as sodium hydride or potassium hydride or alkali metal carbonates such as potassium carbonate or sodium carbonate. The preferred inorganic base is potassium tert-butoxide. 5
According to an embodiment of the present invention, step (c) is carried out in presence of an alkali metal halide. The alkali metal halide used in step (c) is selected from, but not limited to, a group consisting of lithium bromide, lithium chloride, sodium iodide and potassium iodide.
The suitable solvents used in steps (a), (b), (c) or (d) is selected from polar or non-polar solvents. The polar solvent is selected from C1-C5 alcohols such as methanol, ethanol, n-10 propanol, isopropyl alcohol and the like, N,N-dimethylformamide, acetonitrile, dichloromethane, ethyl acetate, tetrahydrofuran and the like. The non-polar solvent is selected from C5-12 aromatic hydrocarbons such as toluene, xylene and the like, C2-8 ethers or mixtures thereof.
According to an embodiment of present invention, step (d) provides reaction of 15 compound of formula (V) with hydrazine, preferably hydrazine hydrate, to obtain a cyclized compound of formula (VII).
According to an embodiment of present invention, step (e) illustrates the tosylation or mesylation of compound of formula (VII) to give sulfonated compounds. Tosylation of compound of formula (VII) can be carried out by reaction with tosyl chloride in presence of a 20 base and solvent. The reaction may be carried out at a suitable temperature such as 10-30°C. Suitable solvents include, but not limited to, N,N-dimethylformamide, acetonitrile, dichloromethane, and ethyl acetate . Bases which may be utilized include, but are not limited to, cesium carbonate, potassium carbonate, pyridine, and triethylamine. Mesylation of the compound of formula (VII) may be performed by reaction with methanesulfonyl chloride or 25 methanesulfonic anhydride optionally in the presence of a base in a suitable solvent. Suitable solvents include, but are not limited to, N,N-dimethylformamide, acetonitrile, and n-methyl pyrrolidinone. Bases which may be utilized include, but are not limited to, pyridine, triethylamine and lithium hydroxide. Accordingly, in one embodiment, the tosylation or mesylation may be carried out in the presence of a base, preferably pyridine. 30
The compound of formula (VIII) is alkylated and then is desulfonated to form a compound of formula (IX). The alkylation of compound of formula (VIII) is carried out by reaction with alkyl halide, such as 2-chloropropoane, 2-bromopropane and 2-iodopropane, in presence of a base and solvent. The base used is selected from lithium hydroxide, sodium
14
hydroxide, potassium hydroxide, potassium tert-butoxide, cesium carbonate, potassium carbonate, sodium tert-butoxide, lithium tert-butoxide, lithium carbonate, and sodium carbonate, 1 ,8- diazabicyclo [5.4.0 ]undec-7-ene, triethylamine, pyridine, preferably lithium hydroxide is used. Suitable solvents include N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane and the like, preferably N-methyl-2-5 pyrrolidone is used.
Desulfonation is carried out using a base such as sodium hydroxide or potassium hydroxide to obtain compound of formula (IX).
In an embodiment of present invention, the alkylation reaction of step (f) is quenched with base such as triethanol amine prior to desulfonation step. 10
According to another embodiment of present invention, in step (g) compound of formula (IX) is reacted with protected glucose derivative in presence of base in suitable solvent. After the completion of the reaction, the residue is hydrolyzed in presence of base such as sodium hydroxide to cleave the protecting group and obtain Remogliflozin of formula (I). The protecting group may be selected from, but are not limited to, acetyl group, pivaloyl group, 15 benzoyl group or a benzyl group.
The base may be selected from organic or inorganic base. Preferably, inorganic bases which may be utilized include, but are not limited to, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium tert-butoxide, sodium tert-butoxide, 20 potassium tert-butoxide and the like.
The solvent may be selected from, but are not limited to toluene, acetone, 2-butanone, methyl-isobutyl ketone, ethanol, methanol, isopropanol, butanol, tert-butanol, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether, and dichloromethane
The present process for preparation of Remogliflozin of Formula (I), provides 25 substantially pure Remogliflozin of Formula (I). For the purpose of the present invention, the term “substantially pure” as used herein includes reference to purity of, or greater than, 98%, more preferably 99%, more preferably 99.5%, more preferably 99.9% purity as determined, for example, by HPLC.
30
EXAMPLES
The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. The examples provided below are merely illustrative of the invention and are not intended to limit
15
the same to disclosed embodiments. Variations and changes obvious to one skilled in the art are intended to be within the scope and nature of the invention.
Methods
Differential scanning calorimetry (DSC) thermogram was measured by a Differential scanning calorimeter (DSC 822, Mettler Toledo) having temperature range of 30 to 350 °C with 5 heating rate of 10°C/min.
X‐ray powder diffraction method (XPRD) pattern was collected on Phillips X‐ray diffractometer model XPERT‐PRO (PANalytical) Detector Xcelerator. The radiation source used was copper (Cu, 15 Kα1=1.54060Å and Kα2=1.54443Å) at a constant temperature within 2Ɵ range of 2.0°‐5.0°. 10
Example 1
Preparation of [4-(propan-2-yloxy)phenyl]methanol of formula (IV)
300 g of para-hydroxy benzyl alcohol was added to 900 ml of DMF and the reaction mass was cooled to 10-15 °C, followed by the addition of 352.54 g of potassium t-butoxide lot wise over a period of 40 minutes. The reaction mass was stirred for 10-15 minutes and 594.53 15 ml of isopropyl bromide was added slowly over a period of 60 minutes. The reaction mixture was warmed to 25-30 ° C and was maintained for 12-15 hrs. 3.0 L of water and 3.0 L ethyl acetate were added to the reaction mixture and it was stirred for 30 minutes. The layers were separated. The organic layer was washed sequentially with 5 % Sodium hydroxide solution and brine solution. The organic layer was then distilled out under vacuum to obtain 340 - 370 g of 20 oily product.
Example 2
Preparation of [4-(propan-2-yloxy)phenyl]methanol of formula (IV)
500 g of para-hydroxy benzyl alcohol was added to the mixture of 1500 ml methanol and 396 g of potassium hydroxide. The reaction mass was stirred for 2 hours at 30° C and 1487 25 g of isopropyl bromide was added slowly at about 40° C. The reaction mixture was maintained at 40-45° C for 25 hours. Water and toluene were added and the reaction mixture was stirred for 30 mins. The layers were separated. The organic layer was distilled under vacuum to obtain 615 g of oily product.
Example 3 30
Preparation of 1-(chloromethyl)- 4-(propan-2-yloxy)benzene of formula (V)
To the mixture of 213.94 g of oxalyl chloride and 700 ml of acetonitrile was added slowly 141.6 g of dimethyl formamide. The reaction mixture was cooled and stirred for 30 min. To the mixture was added 140 g of [4-(propan-2-yloxy)phenyl]methanol and 140 ml
16
acetonitrile. The reaction mixture was stirred for 2.0 h at 25-35 °C. After the completion of reaction, the reaction mass was concentrated under vacuum at 50-55 °C to obtain the residue. To the residue was added 1400 ml toluene and 1400 ml water. The reaction mixture was stirred for 30 min and layers were separated. The organic layer was washed with sodium bicarbonate solution followed by brine solution. The organic solvent was distilled off under vacuum at 55-5 60 °C.
Example 4
Preparation of 1-(chloromethyl)- 4-(propan-2-yloxy)benzene of formula (V)
To the mixture of 830.25 g of phosphorus oxychloride and 2000 ml of acetonitrile was added slowly 440 g of dimethyl formamide. The reaction mixture was cooled to 10 °C and 10 stirred for 2 hours. To the reaction mixture was added 500 g of [4-(propan-2-yloxy)phenyl]methanol and 500 ml acetonitrile. The reaction mixture was stirred for 5 hours at 25-35 °C. After the completion of the reaction, the reaction mass was concentrated under vacuum to the obtain 650 g of oily mass.
Example 5 15
Preparation of methyl 3-oxo-2-[4-(propan-2-yloxy)benzyl]butanoate of formula (VI)
To the mixture of 121.22 g of potassium carbonate and 405 ml of DMF was added 93.35 g methyl acetoacetate. The reaction mixture was stirred for 15 min, followed by slow addition of 135 g of 1-(chloromethyl)- 4-(propan-2-yloxy)benzene. The reaction mixture was stirred for another 15 mins and then the temperature of reaction mass was raised to 70-80°C and stirred at 20 that temperature for a period of 3 to 4 hours. After the completion of the reaction, 675 ml of water and 675ml of toluene was added. The mixture was stirred, organic layer was separated and washed twice with 675 ml of water. The organic layer was then subjected to distillation under vacuum to obtain 165 g of oily product.
Example 6 25
Preparation of methyl 3-oxo-2-[4-(propan-2-yloxy)benzyl]butanoate of formula (VI)
To the mixture of 900 ml toluene and 900 ml of DMF was added 1-(chloromethyl)- 4-(propan-2-yloxy)benzene from example 4, followed by addition of 126.22 g of lithium chloride and 55 g of sodium iodide. To the reaction mixture was added 346 g of methyl acetoacetate and 546 g of diisopropyl ethyl amine. The reaction mixture was heated to 55°C and stirred for 5 30 hours. After the completion of the reaction, the reaction mass was extracted with toluene. The organic layer was separated and washed with dilute hydrochloric acid and saturated sodium chloride solution. The organic layer was then subjected to distillation under vacuum to obtain the 620 g of oily product.
17
Example 7
Preparation of 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one of formula (VII)
To the mixture of 640 ml of toluene and 164g of methyl 3-oxo-2-[4-(propan-2-yloxy)benzyl]butanoate was added 62.12 g of hydrazine hydrate. The reaction mass was heated 5 to 70-75 °C and maintained for about 14 hrs. After the completion of the reaction, the product was filtered and dried under vacuum at 50-55°C for 10 hours to provide 85 g of product.
Example 8
Preparation of 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one of formula (VII) 10
To the mixture of 1000 ml of methanol and 500 g of methyl 3-oxo-2-[4-(propan-2-yloxy)benzyl]butanoate was added 192 g of hydrazine hydrate. The reaction mass was maintained at 30°C. Water was added to the reaction mixture and the mixture was stirred for 5 hours. The solid obtained was filtered and dried under vacuum at 50-55 °C to obtain 360 g of product. 15
Example 9
Preparation of 5-methyl-4-[4-(propan-2-yloxy)benzyl]-2,3-dihydro-1H-pyrazol-3-yl methanesulfonate of formula (VIII)
40.92 g of methane sulfonyl chloride was added drop wise to the mixture of 400 ml acetonitrile and 80 g of 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-20 one. The reaction mass was cooled to 10-20 °C followed by addition of 33.39 g of pyridine. The reaction mixture was maintained at that condition till the completion of the reaction. 1200 ml of water was added and the reaction mixture was stirred. The product was filtered out. The wet cake obtained was dried in vacuum try drier for 10 hours at 65 °C to get 100 g of the product. 25
Example 10
Preparation of 5-methyl-4-[4-(propan-2-yloxy)benzyl]-2,3-dihydro-1H-pyrazol-3-yl methanesulfonate of formula (VIII)
To 1.0 kg of 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one and 0.417 kg of pyridine was added 5.0 lit. of acetonitrile at room temperature. The reaction 30 mass was cooled to about 20 oC under stirring. 0.558 kg of methane sulfonyl chloride was added drop wise. The temperature of the reaction mass was raised to about 35 oC, and maintained for about 3 hours. After the completion of the reaction, the reaction mass was quenched in to water.
18
The precipitated product was filtered and washed with water and dried to obtain 1.25 Kg of product.
Example 11
Preparation of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one of formula (IX) 5
23.18 g of lithium hydroxide monohydrate was added to mixture of 60 g of 5-methyl-4-[4-(propan-2-yloxy)benzyl]-2,3-dihydro-1H-pyrazol-3-yl methanesulfonate and 300 ml of N-methyl-2-pyrrolidone (NMP) at about 25-30 oC. To this mixture 66.91g of isopropyl bromide was added. The reaction mixture was stirred for 2 hours at about 25 oC. After the completion of the reaction, 33.61g of triethanolmine was added to reaction mixture and the mixture was 10 heated to 60-65°C and maintained at that temperature for 1 to 2 hrs. The reaction mixture was neutralized by the addition of sodium hydroxide and 300 ml of methanol. The mixture was maintained for 1-2 hours and after the completion of the reaction, the pH was adjusted to 7-8 by adding dilute hydrochloric acid. The reaction mixture was heated to 60-65 oC and maintained for 20-30 mins. The reaction mass was cooled to room temperature and stirred for about 18 15 hours. The product was collected by filtration. Wet cake obtained was dried at about 60-65 oC for 10 hours to obtain about 23 g of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one.
Example 12
Preparation of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-2,3-dihydro-1H-20 pyrazol-3-yl methanesulfonate
To 3000 ml of N-methyl pyrrolidone was added 177 g of lithium hydroxide and 600 g of 5-methyl-4-[4-(propan-2-yloxy)benzyl]-2,3-dihydro-1H-pyrazol-3-yl methane sulfonate with stirring at room temperature. 740 g of isopropyl bromide was added dropwise at about 15 oC and the reaction mass was stirred for about 12 hour at room temperature. After the 25 completion of the reaction, 6000 ml of water was added and the pH of reaction mass was adjusted to about 8.0 with conc. hydrochloric acid. The reaction mass was stirred for about 2 hours and filtered to and dried under vacuum at about 55 oC, to get 620 g of product.
Example 13
Preparation of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy) benzyl]-1,2-dihydro-3H-30 pyrazol-3-one
To 3000 ml of methanol was added 600 g of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-2,3-dihydro-1H-pyrazol-3-yl methanesulfonate at room temperature. Further to this mixture was added 1200 ml of 8.5% aqueous sodium hydroxide solution under stirring at
19
room temperature. The reaction mixture was maintained for about 12 hour below 35 oC. After the completion of the reaction, the pH of reaction mixture was adjusted to about 8 with conc. HCl. The obtained product was filtered and dried at 55 oC for about 10 hours to get 390 g of product.
Example 14 5
Preparation of Remogliflozin free base of formula (I)
3.64 g of lithium hydroxide monohydrate was added to the mixture of 100 ml of tert. butanol, 10 g of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one and 21.38 g of O-Acetyl D glucopyranosyl bromide. The reaction mass was stirred for about 5 hours at about 40 oC. After completion of reaction, sodium hydroxide 10 solution was added and the mixture was stirred for another 2 hours. The layers were separated and the organic layer was washed with 20 % brine solution. The organic layer was distilled out under vacuum and to it was added to 120 ml of water. The mixture was stirred for another 4-5 hours. The product obtained was filtered and washed with water. The wet cake was then dried in vacuum try drier at 40 oC for 8 to 10 hours to get 6 g of Remogliflozin free base having 15 HPLC purity of >99% by HPLC.
Example 15
Preparation of Remogliflozin free base of formula (I)
Step (i): Preparation of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 20
To 1000 ml of tert. butanol was added 100 g of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy) benzyl]-1,2-dihydro-3H-pyrazol-3-one followed by addition of 43.6 g of lithium hydroxide monohydrate and 268 g of O-Acetyl D glucopyranosyl bromide with stirring at room temperature. The reaction mass was heated to about 45 oC and maintained for about 5 hours. After completion of reaction, the reaction mass was concentrated to get oily mass of 5-methyl-25 1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside. The obtained oily mass as such was taken for the next stage.
Step (ii): Preparation of Remogliflozin free base
To 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside was added 375 ml of 34% aqueous sodium hydroxide 30 solution and the reaction mass was stirred for 2 hours. The product layer was separated by adding about 100 ml of water followed by concentrating the product layer to get residue. To the residue was added 200 ml of methanol and 500 ml of water. The reaction mass was stirred for about 30 mins at room temperature and the pH of reaction mass was adjusted to about 7.5 with
20
acetic acid. The reaction mass was then extracted with ethyl acetate and the ethyl acetate layer obtained was washed with 5% brine solution and then concentrated to residual mass. To the obtained residual mass was added tert-butanol, ethyl acetate and n-hexane mixture and stirred for 15 hours to get slurry. The slurry was filtered and washed with n-hexane. The product was dried to get 150 g of Remogliflozin free base. 5
Example 16
Preparation of isopropyl solvate of Remogliflozin Etabonate
To mixture of 1350 ml of toluene, 135 g of Remogliflozin free base, 57.8 g of 2,6-lutidine and 1.35 g of pyridine was slowly added 45.51 g of Ethyl chloro formate and the reaction mass was cooled to about -10 oC and stirred for 3 to 4 hours. After the completion of 10 the reaction, 675 ml of water was added to reaction mass and the mixture was stirred. The layers were separated and the organic layer was washed with 675ml of dilute hydrochloric acid and 675 ml water. The organic layer was concentrated under vacuum. To the residue was then added mixture of 810 ml of ethanol and 810 ml of n-heptane and the mixture was heated to about 70 oC to obtain a clear solution. The clear solution was then cooled to 25 oC and stirred for 8 to 10 15 hours. The solid thus obtained was isolated by filtration and crystallized from 1350 ml of isopropyl alcohol to obtain isopropyl alcohol solvate of Remogliflozin etabonate.
Example 17
Preparation of Isopropyl solvate of Remogliflozin Etabonate
75 g of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy) benzyl]-1H-pyrazol-3-yl ß-D-20 glucopyranoside was condensed with 25.28 g Ethyl chloroformate in presence of 32.01 g of 2, 6, lutidine and 0.75 g of pyridine in 750 ml of toluene at 0-5°C for 2 hours. After the completion of the reaction, the reaction mixture was washed with 375 ml of aq. HCl solution. The organic layer was concentrated under vacuum to get a residue. The solid was isolated from residue by using mixture of 450 ml of ethanol 450 ml and 450 ml of n-heptane. The obtained solid was 25 further taken in 750 ml of isopropyl alcohol and the reaction mass was stirred at room temperature. The obtained solid was fileted and dried under vacuum at 45°C to give 53 g of isopropyl solvate of Remogliflozin Etabonate.
Example 18
Preparation of Remogliflozin Etabonate Hemihydrate of Formula (II) 30
Isopropyl alcohol solvate of Remogliflozin etabonate obtained in example 16, was subjected to conversion to stable hemihydrate Remogliflozin etabonate by dissolving in 1:1 acetonitrile and water mixture followed by addition of 18 volumes of water. The hemihydrate
21
Remogliflozin etabonate obtained was dried at 40 oC for 10 hours to get 81g (0.6 w/w) of final product having HPLC purity of > 99%.
Example 19
Preparation of Remogliflozin Etabonate Hemihydrate of Formula (II)
To 135 g of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1H-pyrazol-3-yl 5 ß-D-glucopyranoside was added 337.5 ml of acetone, 48.16 g of 2,6-Lutidine and 1.35 g of Pyridine at room temperature. The reaction mass was cooled to about -10 oC with stirring. 39.0 g of Ethylchloro formate was slowly added to the reaction mixture. The reaction mass was stirred for about 3 hours at temperature -5 oC to -10 oC. After the completion of the reaction, 675 ml of water and 1350 ml toluene were added. The reaction mass was stirred for 1 hour and 10 the layers were separated. The organic layer was washed with 675 ml dilute hydrochloric acid followed by washing with water. The organic layer was concentrated to get the residual mass. To the residual mass, 540 ml of isopropyl alcohol and 540 ml n-heptane was added. The mixture was heated to about 80 oC. The mixture was cooled to room temperature and stirred for 10 hour. The solid was filtered. The solid is washed with 135 ml of n-heptane. The obtained solid was 15 taken in 1080 ml of isopropyl alcohol and the reaction mass was heated to 75-80 oC. The reaction mass was cooled to room temperature. The solid, Remogliflozin etabonate isopropyl solvate was collected by filtration and dried.
Remogliflozin etabonate isopropyl solvate was mixed with 75 ml water and 75 ml acetonitrile. The reaction mass was stirred at room temperature for 30 minutes. The reaction 20 mass was filtered. The clear filtrate was taken in a flask and 1350 ml of water was added. The reaction mass was stirred at room temperature for 8-10 hours. The obtained solid was filtered, washed with 270 ml water and dried to obtain 97.2 g of Remogliflozin Etabonate Hemihydrate.
22
We claim:
1. Process for preparation of Remogliflozin etabonate of formula (II)
OHOOOOHOHNNOOO
Formula II
or pharmaceutically acceptable salt, solvate, hydrate thereof 5
comprising,
(i) converting Remogliflozin of formula (I)
OHOHOOOHOHNNO
Formula I
to Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, 10 hydrate thereof,
(ii) converting Remogliflozin etabonate or pharmaceutically acceptable salt, solvate, hydrate thereof to isopropyl alcohol solvate of Remogliflozin etabonate, and
(iii) converting isopropyl alcohol solvate of Remogliflozin etabonate to Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate 15 thereof.
2. The process according to claim 1, wherein in step (i) Remogliflozin of formula (I) is reacted with ethyl haloformate.
3. The process according to claim 1, wherein in step (i) Remogliflozin of formula (I) is reacted with ethyl chloroformate. 20
4. The process according to claim 1, wherein in step (ii) Remogliflozin etabonate or pharmaceutically acceptable salt, solvate, hydrate thereof is treated with isopropyl alcohol or mixture of isopropyl alcohol and a suitable solvent.
23
5. The process according to claim 1, wherein in step (ii) Remogliflozin etabonate or pharmaceutically acceptable salt, solvate, hydrate thereof is treated with isopropyl alcohol.
6. The process according to claim 1, wherein in step (ii) Remogliflozin etabonate or pharmaceutically acceptable salt, solvate, hydrate thereof is treated with mixture of 5 isopropyl alcohol and n-heptane.
7. The process according to claim 1, wherein in step (iii) isopropyl alcohol solvate of Remogliflozin etabonate is mixed with a mixture of water and a suitable solvent.
8. The process according to claim 1, wherein in step (iii) isopropyl alcohol solvate of Remogliflozin etabonate is mixed with a mixture of water and acetonitrile. 10
9. The process according to claim 1, wherein in step (iii) Remogliflozin etabonate is obtained as hydrate form.
10. The process according to claim 1, wherein in step (iii) Remogliflozin etabonate is obtained as hemihydrate form.
11. The process according to claim 1, wherein Remogliflozin of formula (I) is prepared by 15 process which comprises:
(a) reacting 4-(hydromethyl)phenol with 2-halopropane in presence of a base and a suitable solvent to obtain compound of formula (IV)
OHOCH3CH3OHOHCH3CH3XBase4-(hydroxymethyl)phenolFormula IV
wherein X is halogen selected from Cl, Br, I or F 20
(b) reacting compound of formula (IV) with a chlorinating agent in suitable solvent to obtain compound of formula (V)
OHOCH3CH3ClOCH3CH3Chlorinating agentFormula IVFormula V
(c) reacting the compound of formula (V) with methyl acetoacetate in presence of a base and a suitable solvent to obtain compound of formula (VI) 25
24
H3COOCH3OMethyl acetoacetateOCH3CH3OCH3OCH3OClOCH3CH3BaseFormula VFormula VI
(d) reacting the compound of formula (VI) with hydrazine in presence of suitable solvent to obtain compound of formula (VII)
OCH3CH3NHNHOCH3OCH3CH3OCH3OCH3ONH2 NH2 H2OFormula VIFormula VII
(e) reacting compound of formula (VII) with a sulfonyl halide in presence of a base 5 and suitable solvent to obtain a compound of formula (VIII)
OCH3CH3NHNHOCH3RSClOORSOOOOCH3CH3NHNCH3BaseFormula VIIFormula VIII
wherein R is Mesyl or tosyl,
(f) reacting compound of formula (VIII) with haloalkane followed by desulfonation to obtain compound of formula (IX) 10
RSOOOOCH3CH3NHNCH3CH3CH3XOOCH3CH3NNHCH3CH3CH3BaseFormula VIIIFormula IX
(g) reacting compound of formula (IX) with glucose derivative of formula (X) in presence of base and suitable solvent to obtain Remogliflozin formula (I)
25
OHNNOOHOHOOOHOHNNOOPGOPGOBrOPGOPGFormula X1.2. DeprotectionFormula IXFormula I
wherein PG is protecting group.
12. The process according to claim 11, wherein in step (a) 2-halopropane is 2-brobopropane.
13. The process according to claim 11, wherein in step (b) the chlorinating agent is selected 5 from group consisting of oxalyl chloride, thionyl chloride, phosphorous trichloride, phosphorous pentachloride, and phosphorous oxychloride.
14. The process according to claim 11 wherein in step (e), sulfonyl halide is methane sulfonyl chloride.
15. The process according to claim 11, wherein in step (g), the protecting group is acetyl, 10 pivaloyl, benzoyl or a benzyl.
16. Isopropyl alcohol solvate of Remogliflozin etabonate.
17. The isopropyl alcohol solvate of Remogliflozin etabonate according to claim 16, is characterized by a differential scanning calorimetric (DSC) thermogram having endotherm at about 91.71°C and 109.39°C. 15
18. The isopropyl alcohol solvate of Remogliflozin etabonate according to claim 16, is characterized by an X-ray powder diffraction pattern comprising reflections at 6.74° , 9.42°, 11.70°, 18.24°, 19.41°, 19.79° and 22.13° ± 0.2° 2Ɵ.
19. The isopropyl alcohol solvate of Remogliflozin etabonate according to claim 16, is characterized by an X-ray powder diffraction pattern comprising reflections at 6.74 °, 20 9.42 °, 11.06°, 11.70 °, 13.40°, 13. 80°, 15.88°, 17.01°, 18.24°, 18.79°, 19.09°, 19.41°, 19.79°, 22.13°, 22.53° and 27.99°± 0.2° 2Ɵ.
20. Process to prepare isopropyl alcohol solvate of Remogliflozin etabonate comprising,
(i) mixing Remogliflozin etabonate or pharmaceutically acceptable salt, solvate, hydrate thereof with isopropyl alcohol or mixture of isopropyl alcohol and 25 suitable solvent, and
(ii) isolating isopropyl alcohol solvate of Remogliflozin etabonate.
26
21. The process according to claim 20, wherein in step (i) Remogliflozin etabonate or pharmaceutically acceptable salt, solvate, hydrate thereof is treated with isopropyl alcohol.
22. The process according to claim 20, wherein in step (i) Remogliflozin etabonate or pharmaceutically acceptable salt, solvate, hydrate thereof is treated with mixture of 5 isopropyl alcohol and n-heptane.