CLIAMS:0 ,TagSPECI:FORM – 2

THE PATENTS ACT, 1970
(39 of 1970)

PROVISIONAL SPECIFICATION
(SECTION 10, RULE 13)

“A PROCESS FOR SYNTHESIS OF PREGABALIN”

DISHMAN PHARMACEUTICALS & CHEMICALS LIMITED
A Company Incorporated Under The Indian Companies Act
Bhadr-Raj Chambers, Swastik Cross Roads,
Navrangpura, Ahmedabad-380 009,
Gujarat State, India

The following specification particularly describes the nature of this invention: -

FIELD OF INVENTION

The present invention relates to a process for synthesis of pregabalin. More particularly, the present invention relates to an improved process for synthesis of S (+) pregabalin in high yield and high optical purity.

BACKROUND AND PRIOR ART OF THE INVENTION

S (+)-Pregabalin or S- (+)-(amino methyl)-5-methyl hexanoic acid is represented in formula (I) as:

S-(+)-3-(amino methyl)-5-methyl hexanoic acid is also called ß-isobutyl-?-amino butyric acid or isobutyl GABA. Pregabalin is a structural derivative of the inhibitory neurotransmitter GABA.

Pregabalin is also found to exhibit analgesic, anticonvulsant, anxiolytic and sleep modulating activities and it is involved in regulation of brain neuronal activity. It exhibits anti seizure activity discussed in U.S patent U.S 5,563,175 and anti nociceptive activity discussed in U.S patent U.S 6,001876.

However, the racemic pregabalin is a inactive for anti convulsant but its S-isomer shows better activity than R-isomer, Yuen et, al in bioorganic and medicinal chemistry letters 1994, 4, 823.

It has also been found to be more active than Gabapentin in potential models of epilepsy. Thus it would be more beneficial to have an efficient process for the synthesis of S (+) pregabalin.

Presently, S (+)-Pregabalin is prepared in different ways, a common method involves the resolution of Pregabalin final product, a recemic compound into its R&S enentiomers or resolution of an earlier intermediate into its R&S enentiomers. Such methods involve Hoffman reaction. (EP 2225198B1, WO 2009/068967, WO 2008/004044, U.S 8,071,808B2).

Another process of synthesis of the Pregabalin reported in the Drugs of the Future, 24 (8), 860-870 (1999) and in US patent No 5,616,793; the 3-(carbamoylmethyl)-5-methyl hexanoic acid is resolved by using (R)-(+)- alpha phenylethylamine in chloroform as a solvent, to get R-(-)-3-(carbamoylmethyl)-5-methyl hexanoic acid. In many of the processes disclosed in various patents or patent applications, chloroform is reported for the resolution which is very toxic solvent. Further, the racemic Pregabalin obtained in this manner is subjected to Hoffman rearrangement in presence of bromine and alkali to get S-(+)-3-(aminomethyl)-5-methyl hexanoic acid or Pregabalin (I).

Several patents and published patent applications (e.g, U.S. Patent No.5,616,793 and international publication Numbers WO 2006/122258, WO 2006/ 22255 and WO 2006/121557 disclose a more convenient preparation of (±) pregabalin by means of Hoffman rearrangement of (±) 3-Carbomoyl methyl -5-methyl hexanoic acid , a compound of formula II, in the presence of bromine and an alkali hydroxide. (±) -3-Carbomoyl methyl -5-methyl hexanoic acid and (±)- 3-(amino methyl) -5-methyl hexanoic acid are represented in formula II and formula III respectively.

The synthesis route involving bromine is not suitable for industrial implementation, since it requires the use of bromine, which is very toxic and corrosive. These processes generally involve formation of undesired by products. It is known that presence of impurities may cause adversely effect in final product. Hence the above synthetic route was not suitable to prepare racemic pregabalin in commercially.

Further, Hoekstra et al, in organic process research & development 1997,1,26-38 reported the use of sodium hypochlorite as an alternative to the use of bromine but it gives the poor yield.

Hence, there is an unmet need to provide improved processes for preparing (S+) pregabalin which is suitable for industrial implementation, and avoids the use of bromine while the using of sodium hypochlorite produce pregabalin in high yields and with low amounts of undesired by-products.

DISADVANTAGES OF THE PRIOR ART

• Many of them fail to provide high yield and high optical purity.

• Many of them involve resolution of R&S enentiomers using Hoffman reaction.

• In many of the processes disclosed, chloroform is reported for the resolution which is very toxic solvent.

• The synthesis route involving bromine is not suitable for industrial implementation, since it requires the use of bromine, which is very toxic and corrosive.

• Many of the processes generally involve formation of undesired by-products.

• Many of the process use sodium hypochlorite as an alternative to the use of bromine but it gives the poor yield.

OBJECTS OF THE PRIOR ART

The main object of the present invention is to provide a process for synthesis of pregabalin which results in S (+) pregabalin in high yield and high optical purity.

Another object of the present invention is to provide a process for synthesis of pregabalin which is suitable for industrial implementation.

Yet another object of the present invention is to provide a process for synthesis of pregabalin which avoids the use of bromine.

Yet another object of the present invention is to provide a process for synthesis of pregabalin which produce pregabalin in high yields.

Yet another object of the present invention is to provide a process for synthesis of pregabalin which produce low amounts of undesired by-products.

Yet another object of the present invention is to provide a process for synthesis of pregabalin which is economical.

Yet another object of the present invention is to provide a process for synthesis of pregabalin which uses non toxic chemicals that are easy to handle.

BREIF DESCRIPTION OF INVENTION

The present invention provides process for synthesis of pregabalin which results in S (+) pregabalin in high yield and high optical purity.

The process involves preparation of racemic pregabalin formula III:

by reacting the (±)-3-(carbamoylmethyl)-5-methylhexanoic of Formula II:

with a Hofmann reagent sodium hypochlorite in amounts less than about 1.3 molar equivalents at a temperature of about 50 0C - 600C. (±)-3-carbamoylmethyl-5-methylhexanoic acid racemate with mandelic acid formed pregabalin mandalate of formula IV.

Finally mandelic acid and S(+)-pregabalin of formula I is separated by alkaline medium.

In one of the embodiments of the present invention, the process involves preparation of racemic pregabalin by

• combining an alkali hydroxide and water;
• adding (±) -3-(carbamoylmethyl)-5-methylhexanoic acid (referred to as Racemic CMH) at a temperature of about 0°C to 10°C;
• adding alkaline sodium hypochlorite, in a drop wise manner, at a temperature of about 0°C to 20°C;
• heating at a temperature of about 50°C to 60°C for one hour;
• after completion of reaction the material is precipitated with a strong mineral acid at pH 5 to 6
• The product is further purified by crystallization from a mixture of C1 to C4 alcohols and water.
• The process is schematically is represented in reaction scheme 1

In this embodiment, the present invention provides a process for the preparation of (±)-pregabalin of formula III comprising the following steps:
• combining water and an alkali hydroxide selected from a group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide;
• adding (±)-CMH of formula II at a temperature of about 0°C to 10°C;
• adding alkaline sodium hypochlorite, in a drop-wise manner, at a temperature of about 0°C to 20°C;
• heating to a temperature of about 50°C to 60°C for one hour;
• after completion of reaction the material is precipitated with a strong mineral acid at pH 5 to 6 selected from a group consisting of sulphuric acid, hydrochloric acid, acetic acid.

In a further embodiment, the present invention provides a process for the preparation of racemic pregabalin at neutral pH. The most preferable pH was 5.5. In this embodiment,
• the crude racemic pregabalin is dissolved in a mixture of C1 to C4 alcohol and water mixture and heated to a temperature of about 75°C to about 80°C for one hour.
• after that the reaction mixture is cooled to a temperature of about 0°C to about 10°C and maintaining 3 – 4 hrs to give pure racemic pregabalin of formula III.
• Preferably, the preparation of racemic pregabalin of formula III may be done by combining water and an alkali hydroxide is selected from a group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide; preferably the alkaline hydroxide is sodium hydroxide,

In a further embodiment, the process involves following steps:
• adding racemic CMH of formula II at a temperature of about 0°C to about 10C;
• adding alkaline sodium hypochlorite, in a drop-wise manner, at a temperature of about 0°C to about 20°C;
• heating to a temperature of about 50°C to about 60C; and
• precipitated with a strong mineral acid selected from a group consisting of sulphuric acid, hydrochloric acid, acetic acid., preferably the mineral acid is hydrochloric acid and cooling to a temperature of about 0°C to about 10°C.

The reaction of sodium hypochlorite with a compound of formula II is exothermic, hence, in another embodiment, when sodium hypochlorite is added to a compound of formula II at a temperature of 0-15°C, the sodium hypochlorite is added over a period of time such that the reaction mixture was maintained at temperature of 5-10°C.

In an embodiment, the present invention provides a process for preparing racemic pregabalin of formula III, said process comprising reaction of (±)3-(carbamoylmethyl)-5-methyl hexanoic acid of formula II with sodium hypochlorite at temperature of from about 50°C to about 70°C.

Typically, the temperature at which processes of the invention are conducted range from 50°C to 70°C. And in preferred embodiments, processes of the present invention are conducted at a temperature of 55-60°C.

In other embodiments, the present invention provides (±)-pregabalin of formula III which is prepared by reacting of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid of formula II with less than about 1.3 molar equivalents of sodium hypochlorite, preferably from about 0.90 molar equivalents to 1.1 molar equivalents of sodium hypochlorite.

In a further embodiment, the present invention provides a process for the purification of racemic pregabalin of formula III comprising combining water and said alcohol is selected from a group consisting of C1-C4 wherein the purification process of racemic pregabalin is, preferably, isopropyl alcohol and methanol.

In a further embodiment, the present invention provides a process for the purification of racemic pregabalin comprising the cooling maintenance 3-4hrs to a temperature of about 0°C to about 10°C wherein the purification process of racemic pregabalin is, preferably, a temperature of about 5°C to 10°C.

In a further embodiment, the present invention provides a process for the purification of racemic pregabalin comprising the cooling maintenance 3 to 4hrs to a temperature of about 0°C to about 10°C wherein the purification process of racemic pregabalin is, preferably a maintenance time of about 2hrs to about 3hrs

In other embodiments, the present invention provides (±)-pregabalin of Formula III which is prepared by reacting of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid of Formula II with sodium hypochlorite wherein both the reaction temperature and amount of sodium hypochlorite is regulated as described herein.

In other embodiments, the separation of racemic mixture of compound of formula III by treating it with a optically active acid like madelic acid,camphor sulphonic acid and tartaric acid. Most preferable acid is mandelic acid. The formula of pregabalin mandalate is represented by formula IV.

In the present invention, compound of the Formula III is resolved into its (S) enantiomer by reacting it with chiral resolving agent, in an alcoholic solvent and water to get (S)-2-hydroxy-2-phenylacetic acid compound with (S)-3-(aminomethyl)-5-methylhexanoic acid (1:1) or (S)-Pregabalin Mandellate salt or compound of the Formula IV,

In the present invention, compound of the Formula IV is desalinated by an alkaline media such as Sodium hydroxide- water, Potassium hydroxide-water or Ammonia – water, prefereably in Ammonia-water to get pure Pregabalin (I) quality as per ICH standards.

ADVANTAGES OF THE PRESENT INVENTION

The present process for synthesis of pregabalin which results in S (+) pregabalin provides following advantages over the existing processes:

1. The present process synthesizes S (+) pregabalin in high yield and high optical purity.

2. The present invention is suitable for industrial implementation.

3. The present process avoids the use of bromine.

4. The present process produces pregabalin in high yields.

5. The present process is economical.

6. The present process uses non toxic chemicals that are easy to handle.

Dated this 21st day of December,2013.

________________________
GOPI J. TRIVEDI (Ms)
Patent Attorney
At Y. J. Trivedi & Co.
(Authorized Agent of the Applicant)

To,
The Controller of Patents,
Patent Office,
Mumbai