DESC:FIELD OF THE INVENTION
The present invention relates to a process for preparing pure pentazocine of Formula 1 and its pharmaceutically acceptable salts.

Formula 1
In the particular aspect of present invention relates to an improved process for the preparation of pentazocine pharmaceutically acceptable salts and their conversion to pure pentazocine.

BACKGROUND OF THE INVENTION
Pentazocine has the chemical name (2RS,6RS,11RS)-1,2,3,4,5,6-hexahydro-6,11- dimethyl-3-(3-methyl-2-butenyl)-2,6-methylene-3-benzazocine-8-ol and it is represented by compound of Formula 1.

Formula 1
Pentazocine was developed by the Sterling Drug Company, Sterling-Winthrop Research Institute, of Rensselaer, New York. The analgesic compound was first made at Sterling in 1958. U.S. testing was conducted between 1961 and 1967. It was approved by the Food and Drug Administration in June 1967 after being favorably reviewed following testing on 12,000 patients in the United States. By mid-1967 pentazocine was already being sold in Mexico, England, and Argentina, under different trade names.
The lactate salt of pentazocine has been used in the development of formulations for parenteral administration selected from subcutaneous injection, intravenous injection, intramuscular injection, epidural injection, intracisternal injection and Infusion, etc. The aqueous injection preparation has certain limitations in stability, transportation, storage conditions and is easy to introduce impurities. Therefore, it is necessary to develop a freeze-dried drug that is stable in storage for a long time, has high safety, and is less irritating preparation.

US patent no. 4,105,659 first time discloses a process for preparing pentazocine by reacting racemic cis 1,2,3,4,5,6-hexahydro-6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocine with 1-bromo-3-methyl-2-butene in presence of sodium bicarbonate and dimethylformamide (DMF) at reflux temperature.

SCHEME-1

Further, the said patent discloses that recrystallization of crude pentazocine with a mixture of methyl alcohol and water.
During the reaction, alkaline sodium bicarbonate is usually added to neutralize the hydrobromic acid generated during the reaction. The speed of the reaction is determined by the reaction of hydrobromic acid with sodium bicarbonate. Therefore, a sufficient amount of hydrobromic acid is required to complete the reaction in a timely manner. It is difficult to achieve this goal in production because the solubility of sodium bicarbonate in DMF is very low and even if heated at a temperature in the range of 133°C to 137°C, the solubility is not enhanced significantly.
A Chinese application publication no. 112079779 discloses a process for preparing pentazocine by reacting 1,2,3,4,5,6-hexahydro-6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocine with 1-bromo-3-methyl-2-butene in presence of tetramethylcarbonate ammonium hydride and dimethylformamide (DMF).
SCHEME-2

Further, the said patent application discloses recrystallization of crude pentazocine with isopropyl acetate and n-heptane.
A Canadian application publication no. 1026330 discloses a process for preparing pentazocine by reacting 1,2,3,4,5,6-hexahydro-6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocine with 3-methyl-2-butenal-diethylacetate in the presence of 90% formic acid and dimethylformamide (DMF) at 110~130°C to give a reaction mixture. After completion of the reaction, a crude pentazocine is isolated by basification of the reaction mixture with aqueous ammonia.
SCHEME-3

Further, the said patent application discloses purification of crude pentazocine comprises acid-base treatment by using dilute acetic acid as an acid and aqueous ammonia as a base. Finally, the resulting product is recrystallized with mixed solvent of ethyl alcohol and water.
The pentazocine prepared by the above prior art references does not meet the norms of regulatory as individual unknown impurity could not be removed by purification of crude pentazocine with crystallization or recrystallization or acid-base treatment as reported in the prior art.
The presence of impurities can completely alter a formulation and make it something else entirely because chemicals react differently. For example, the undesired individual unknown impurity in a drug formulation can make a drug dangerous to human beings. Therefore, the quality of drug substance or drug product plays an important role in meeting the norms of regulatory.
Therefore, in view of the above prior art references, there is an urgent need to develop an economical process for preparing pure pentazocine and/or pharmaceutically acceptable salts thereof.
The present inventors have investigated an economical process for preparing pure pentazocine and/or pharmaceutically acceptable salts thereof, which meets the norms of regulatory viz. any individual unknown impurity is not more than 0.1% by high performance liquid chromatography (HPLC).

OBJECTIVE OF THE INVENTION
The principal object of the present invention is to provide an economical process for preparing pure pentazocine and/or pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide an improved process for the preparation of crystalline acid addition salt of pentazocine and its conversion to pure pentazocine of Formula 1.

SUMMARY OF THE INVENTION
The present invention provides an economical process for preparing pure pentazocine of Formula 1 or pharmaceutically acceptable salts thereof,

Formula 1

comprises:
i) reacting a compound of Formula 2,

Formula 2

with a compound of Formula 3,

Formula 3
in presence of organic base at a suitable temperature to give a reaction mixture;
ii) isolating a crude pentazocine and
iii) purifying the crude pentazocine to obtain pure pentazocine of Formula 1.

One aspect of the present invention provides an economical process for preparing pure pentazocine of Formula 1 or pharmaceutically acceptable salts thereof,

Formula 1

comprises:
i) reacting oxalate salt of pentazocine having Formula 1a

Formula 1a

with aqueous ammonia in presence of suitable solvent to give a reaction mixture;
ii) isolating a crude pentazocine from the reaction mixture and
iii) purifying the crude pentazocine to obtain pure pentazocine of Formula 1.

In another aspect, the present invention provides a crystalline oxalate salt of pentazocine having Formula 1a.

Formula 1a

In another aspect, the present invention is to provide a process for preparing crystalline oxalate salt of pentazocine having Formula 1a,

Formula 1a
comprises:
i) reacting pentazocine with oxalic acid at a suitable temperature in the presence of suitable solvent to give a reaction mixture and
ii) isolating crystalline oxalate salt of pentazocine having Formula 1a from the reaction mixture of step i).

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline pentazocine oxalate of Formula 1a.
Figure 2 shows differential scanning calorimetry (DSC) thermogram of crystalline pentazocine oxalate of Formula 1a.

DETAILED DESCRIPTION OF THE INVENTION
The term "pure" used herein means pentazocine of Formula 1 or pharmaceutically acceptable salts thereof having any individual unknown impurity not more than 0.1% by high performance liquid chromatography (HPLC).
The term “pharmaceutically acceptable salts” means salts of pentazocine selected from but not limited to lactate, hydrochloride and alike.
The instant invention relates to an economical process for preparing pure pentazocine of Formula 1 or pharmaceutically acceptable salts thereof.

Formula 1

wherein the process comprises preparation of crude pentazocine followed by its purification.
The crude pentazocine can be prepared by reaction of 1,2,3,4,5,6-hexahydro-6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocine (known as norpentazocine or normetazocine) of Formula 2 with 1-chloro-3-methyl-2-butene (known as prenyl chloride) of Formula 3 in presence of organic base at a suitable temperature to give a reaction mixture.
The inventors of the present invention have observed that prenyl chloride is advantageous to use over prenyl bromide (commonly used in prior art) because of the following reasons:
• the use of prenyl chloride makes the process economical as it is cheaper than prenyl bromide.
• prenyl chloride is easy to handle as it is less lachrymatory w.r.t. prenyl bromide.
The suitable temperature for the reaction is in the range of 10°C to 40ºC or preferably in the range of 10°C to 30ºC and the organic base used in the said reaction is selected from but not limited to ethylamine, diethylamine, triethylamine, triethanolamine and alike or combination thereof.
The said reaction is carried out in the presence of suitable solvent. The suitable solvent can be selected from an aprotic solvent. The aprotic solvent can be selected from but not limited to dimethylformamide (DMF), n,n-dimethylacetamide (DMAc), dimethyl-sulfoxide (DMSO), ether solvent and alike or mixture thereof.
After completion of the reaction, the crude pentazocine can be isolated from the reaction mixture by using any technique known in the prior art such as extraction, distillation, crystallization or combination thereof.
In one embodiment after completion of the reaction, water immiscible solvent can optionally be added and the resulting mixture is filtered to remove suspended particles.
To the clear filtrate or the preceding reaction mixture, water, water immiscible solvent and optionally an acid are added at a temperature of 30°C to 80°C. Then, the layers are separated.
Wherein an acid is added to clear filtrate or the preceding reaction mixture, the organic layer is discarded and aqueous layer containing product is cooled to a temperature 10°C to 40°C and basified with a base in presence of water immiscible solvent. The temperature of the resulting mixture is raised to 30°C to 80°C and layers are separated. The organic layer is washed with alkali metal solution and solvent is distilled to give a crude product.
The optionally added acid is acetic acid and alike and the base used during the extraction is aqueous ammonia.
Wherein an acid is not added to clear filtrate or the preceding reaction mixture, the organic layer is carried forward for product isolation and from the aqueous layer product is extracted to organic layer by using a base and water immiscible solvent. The combined organic layers is washed with aqueous alkali metal solution such as aqueous sodium chloride and solvent is distilled and the resulting product is purified with a mixture of solvents to give a crude pentazocine.
The water immiscible solvent is selected from but not limited to ethyl acetate, methyl acetate, toluene or mixture thereof and alike.
Further purifying the crude pentazocine to obtain pure pentazocine of Formula 1.
The crude pentazocine is purified by acid-base treatment and followed by recrystallization with suitable solvent.
The solvent used in purification viz. recrystallization is selected from ethyl acetate, methyl acetate, toluene, acetone, butanone, methyl isobutyl ketone, ethyl isopropyl ketone, water and alike.
In one embodiment, oxalic acid can be used as an acid and aqueous ammonia can be used as a base for acid-base purification.
In a preferred embodiment, a pure pentazocine of Formula 1 can be prepared by preparing pentazocine oxalate salt of Formula 1a;

Formula 1a

followed by neutralization with a base.
The said process can be proceeded in the following manner.
The oxalate salt of pentazocine is prepared by reacting crude pentazocine with oxalic acid in the presence of suitable solvent at suitable temperature in the range of 50 °C to 70 °C to give a reaction mixture. After completion of the reaction, cooling the reaction mixture at a temperature in the range of -10 °C to 10°C to obtain oxalate salt of pentazocine. The said oxalate salt of pentazocine is filtered, washed and dried.
The oxalic acid used in the present invention may be in the form of anhydrous, hydrate or dihydrate. Preferably, the oxalic acid used in the present invention is in the form of dihydrate.
The inventors of the present invention have observed that methanol is a preferable suitable solvent over the other solvents such as ethanol, isopropanol, acetone and acetonitrile to prepare oxalate salt of pentazocine.
Further, the resulting oxalate salt of pentazocine is neutralized by using aqueous ammonia in presence of water and solvent selected from but not limited to ester solvent such as ethyl acetate, methyl acetate, isopropyl acetate and alike.
The neutralization reaction is carried at a temperature in the range of 25°C to 80°C and preferably 40°C to 80°C.
The crude product can be isolated with extraction method followed by layer separation, washing of organic layer and distillation of organic solvent to give pentazocine.
In a preferred embodiment, the layers are separated after neutralization and the pentazocine is extracted in ester solvent. The ester solvent layer is washed with water and distilled the ester solvent to give a crude pentazocine.
Further, the resulting pentazocine is purified with a mixture of solvents selected form but not limited to water, acetone, butanone, methyl isobutyl ketone, ethyl isopropyl ketone, ethyl acetate, methyl acetate, toluene and alike to give pure pentazocine of Formula 1.
One aspect of the present invention provides a pure pentazocine of Formula 1 by preparing pentazocine oxalate salt of Formula 1a and followed by neutralization with a base. The base used for neutralization is aqueous ammonia.
The preparation of pentazocine oxalate salt of Formula 1a and its neutralization with a base can be proceeded by the process as discussed herein above.
Further, the resulting pentazocine, obtained after neutralization, can be purified with mixture of solvents selected form but not limited to water, acetone, butanone, methyl isobutyl ketone, ethyl isopropyl ketone, ethyl acetate, methyl acetate, toluene and alike to give pure pentazocine of Formula 1.
The inventors of the present invention have observed that individual unknown impurity cannot be removed with solvent purification only and results . They surprisingly observed that individual unknown impurity can be removed by preparing salt of crude pentazocine followed by neutralization and recrystallization with solvent or mixture of solvents.

In another aspect, the present invention provides a crystalline oxalate salt of pentazocine having Formula 1a.

Formula 1a

In one embodiment, crystalline oxalate salt of pentazocine of Formula 1a, prepared by the present invention, may be characterized by analytical techniques known in the prior art are selected from but not limited to X-ray diffraction (XRD), differential scanning calorimetry (DSC), infrared spectroscopy (IR) and melting point.
The crystalline oxalate salt of pentazocine having Formula 1a can be characterized by X-Ray diffraction (XRD) as shown in Figure 1.
Further, the crystalline oxalate salt of pentazocine having Formula 1a having XRD °2-? (degree 2-theta) values comprises 8.6, 11.6, 12.8, 14.1, 15.4, 16.5, 17.2, 18.8, 21.5, 21.8, 23.0, 24.9, 27.1 + 0.5 °2-?.
The crystalline oxalate salt of pentazocine having Formula 1a can be characterized by differential scanning calorimetry (DSC) as shown in Figure 2 and having endothermic peak at 211.31 °C.
In another aspect, the present invention is to provide a process for preparing crystalline oxalate salt of pentazocine having Formula 1a by the process as discussed herein above in the preferred embodiment of the present invention.

The starting materials of the present invention viz. 1,2,3,4,5,6-hexahydro-6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocine of Formula 2 with 1-chloro-3-methyl-2-butene of Formula 3 can be prepared by any method known in the prior art.
The purity of final product/intermediates, reaction completion and monitoring of the reaction of the present invention can be checked by any analytical techniques known in the prior art such as high-performance liquid chromatography (HPLC), thin-layer chromatography (TLC), gas chromatography (GC) and alike.
In the present invention, the compound of Formula 1 is a mixture of two enantiomer viz. (2RS,6RS,11RS)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methylene-3-benzazocine-8-ol.
Having described the invention with reference to certain preferred aspects, other aspects will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail by an economical, efficient process for preparing pentazocine of Formula 1 or its pharmaceutically acceptable salts.
EXAMPLES
Example 1. Process for preparation of crude pentazocine
Method A: To a mixture of Nor pentazocine (50g) in DMF (150ml), triethyl amine (41.5g) was added at 25-30ºC. The temperature of the resulting mixture was lowered to 15-20ºC and prenyl chloride (40.5g) was added. After reaction completion, demineralized water, toluene and acetic acid was added and the temperature was raised to 50-70ºC. The layers were separated and the aqueous layer was carried forward for further reaction. The aqueous layer containing product was cooled to 20-30ºC and basified using aqueous ammonia solution in the presence of toluene. The temperature of the resulting mixture was raised to 50-70ºC and the product was extracted in toluene, washed with sodium chloride solution. Then, the toluene was distilled out completely at reduced pressure and the degas mass was crystallized with mixture of toluene and water to get crude pentazocine.

Method B: To a mixture of Nor pentazocine (50g) in DMF (150ml), triethyl amine (41.5g) was added at 25-30ºC. The temperature of the resulting mixture was lowered to 15-20ºC and prenyl chloride (40.5g) was added. After reaction completion, ethyl acetate was added and reaction mixture was filtered and washed with ethyl acetate. To the clear filtrate, ethyl acetate and water were added and the temperature was raised to 50-70ºC. The aqueous and organic layers were separated and the aqueous layer was discarded after extracting product in organic layer by adding aqueous ammonia and ethylacetate in aqueous layer. The combined organic layer containing the product was washed with sodium chloride solution and solvent was distilled out completely at reduced pressure. The resulting degas mass was crystallized with mixture of acetone (90ml) and water (10 ml) to get crude pentazocine.

Example 2. Process for preparation of crystalline pentazocine oxalate salt
To a crude pentazocine, methanol (100 ml) and oxalic acid dihydrate (25g) were added at 25-30ºC to give a reaction mixture. The temperature of the reaction mixture was raised to 60-65ºC and the reaction mixture was stirred for 2 hours. Then, the reaction mixture was cooled to -5°C to -10ºC under stirring for 3 hours to obtain the product The product was filtered out, washed with methanol and dried to get pentazocine oxalate salt.

Example 3. Process for preparation of pure pentazocine
To a mixture of pentazocine oxalate salt in water (250 ml) and ethyl acetate (350 ml), aqueous ammonia was added to adjust pH more than 10 at a temperature 25-30°C. The temperature of the resulting reaction mixture was raised to 50-70°C and layers were separated. Then, the product is extracted in ethyl acetate, washed with demineralized water. Then, the ethyl acetate was distilled off and the degas mass was crystallized with mixture of acetone and water to get pentazocine of USP quality having 99.87% purity and 0.06% individual unknown impurity by HPLC.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents. ,CLAIMS:WE CLAIM
Claim 1. A process for preparing pure pentazocine of Formula 1 or pharmaceutically acceptable salts thereof,

Formula 1

comprises:
i) reacting a compound of Formula 2,

Formula 2

with a compound of Formula 3,

Formula 3
in presence of organic base at a suitable temperature to give a reaction mixture;
ii) isolating a crude pentazocine and
iii) purifying the crude pentazocine to obtain pure pentazocine of Formula 1.

Claim 2. The process as claimed in claim 1, wherein the organic base is selected from ethylamine, diethylamine, triethylamine, triethanolamine and alike or combination thereof.
Claim 3. The process as claimed in claim 1, wherein the suitable temperature for the reaction is in the range of 10°C to 40ºC.

Claim 4. A process for preparing pure pentazocine of Formula 1 or pharmaceutically acceptable salts thereof,

Formula 1

comprises:
i) reacting oxalate salt of pentazocine having Formula 1a

Formula 1a

with aqueous ammonia in presence of suitable solvent to give a reaction mixture;
ii) isolating a crude pentazocine from the reaction mixture and
iii) purifying the crude pentazocine to obtain pure pentazocine of Formula 1.

Claim 5. The process as claimed in claim 4, wherein the suitable solvent used at step i) is water and ester solvent selected from ethyl acetate, methyl acetate, isopropyl acetate and alike.

Claim 6. The process as claimed in claim 1 and claim 4, wherein the purification of the crude pentazocine comprises preparation of crystalline oxalate salt of pentazocine.

Claim 7. A process for preparing crystalline oxalate salt of pentazocine having Formula 1a,

Formula 1a
comprises:
i) reacting pentazocine with oxalic acid at a suitable temperature in the presence of suitable solvent to give a reaction mixture and
ii) isolating crystalline oxalate salt of pentazocine having Formula 1a from the reaction mixture of step i).

Claim 8. The process as claimed in claim 7, wherein the suitable solvent used at step i) is methanol.

Claim 9. The process as claimed in claim 7, wherein the suitable temperature is 50°C to 70 °C.
Claim 10. A crystalline oxalate salt of pentazocine having Formula 1a.

Formula 1a