FIELD OF INVENTION:

The present invention relates to an improved process for the preparation of (1R, 2R)-2-[(dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexanol hydrochloride (Tramadol hydrochloride) of Formula I.

BACKGROUND OF THE INVENTION:

Tramadol is the common chemical name for the compound 2-[(dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexanol. (CAS Registry No. 27203-92-5) The empirical formula of tramadol is C16H25NO2 and its molecular weight is 263.37. The molecular structure of tramadol is represented by Formula I.

2-[(dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexanol (Tramadol) is a typical opioid which is a centrally acting analgesic, used for treating moderate to severe pain and most types of neuralgia, including trigeminal neuralgia. It is a synthetic agent and appears to have actions on the u-opioid receptor as well as the noradrenergic and serotonergic systems.

Tramadol in the form hydrochloride salt is widely used as an analgesic. Tramadol hydrochloride assumes a special position among centrally acting analgesics since this active pharmaceutical ingredient acts as a strong inhibitor of pain without the side effects which are known for opioids.

The preparation of tramadol has been mainly carried out with the aid of a Grignard reaction. The reactive bromides are usually employed for the preparation of Grignard compounds. From an economic point of view, the replacement of bromides with
chlorides in the preparation of Grignard reagents has advantages over the bromides. The chlorides are firstly less expensive and secondly give rise to smaller amounts of salts on account of their lower molecular weights. Moreover, the effluent amount will be less when chlorides are used.

The synthesis of Tramadol was first described in U.S. Pat. No. 3,652,589 and in British Pat. No. 9,92,399. The process involves the Grignard reaction of 2-[(dimethylamino)methyl]cyclohexanone with 3-methoxyphenylmagnesium bromide, yields an isomeric mixture of cis & trans 2-[(dimehtylamino)methyl]cyclohexanol. The isomers were separated by forming a hydrochloride salt of both isomers and selectively isolating the cis-2-[(dimethylamino)methyl]-1 -(3-methoxyphenyl)cyclohexanol hydrochloride by crystallizations from 1,4-dioxane.

This process has the disadvantage of usage of toxic solvent and also repeated crystallizations were required to get the pharmaceutically acceptable isomeric purity.

US 5,414,129 describes a process for the improved purification and separation of trans 2-[(dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexanol hydrochloride from a reaction mixture containing trans isomer and its cis isomer and Grignard reaction side products comprising treating the the mixture with a solution of HC1 in a low molecular weight alcohol or with gaseous HC1 in the presence of an organic solvent selected form medium molecular wweight alcohols, ketones, esters and ethers or aromatic ethers, to effect the selective precipitation of trans 2-[(dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexanol hydrochloride.

US 5,672,755 provides a process for the purification and isolation of (RR,SS)-2-dimethylaminomethyl-l-(3-methoxyphenyl)cyclohexanol from mixtures also containing the (RS,SR) isomer comprising reacting the above mixture in a solvent at elevated temperature under acidic conditions, thereby selectively dehydrating the unwanted trans-isomer to the corresponding alkene compound and the cis-isomer is isolated. One of the advantages of this process is during the dehydration process about 50% of the trans-isomer converted to the cis-isomer, thereby achieving a higher cis-isomeric ratio. Still
the unwanted isomer is a contaminant in the product, which has to be purified by forming a hydrochloride salt and crystallizing from IPA.

US 5,852,216 describes a method for the preparation of (3-alkoxyphenyl)magnesium chlorides and its further use in the preparation of 2-[(dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexanol.

A process for the separation of (RR,SS)-2-dimethylaminomethyl-l-(3-methoxyphenyl)cyclohexanol from a mixtures consisting of (RR,SS)- tramadol and (RS,SR)-tramadol has been described in US 5,874,620. The process comprises of reacting the mixture with electrophilic reagents such as thionyl chloride and acetic anhydride, thereby selectively reacting with the hydroxyl group of (RR,SS)-tramadol, leaving most of the (RR,SS)- tramadol intact, and precipitating the remaining practically pure (RR,SS)- tramadol from the mixture.

WO 99/61405 & WO 99/36390 describes the separation of isomers by forming an acid salt and crystallizing these salts from solvents such as nitriles and alcohols. This process ends with the repeated crystallizations which subsequently results in low yields.
US 6,469,213 describes a method for the preparation of cis-tramadol hydrochloride, through the formation of Mannich hydrochloride, liberating the Mannich base, reacting Mannich base with a Grignard reagent to form a base hydrate of cis-tramadol. This process also claims the use of base hydrate of cis-tramadol as a medicament.

WO2003029186 describes the use of transition metal complexes for achieving enhanced isomer selectivity of 2-[(dimethylamino)-methyl]-cyclohexanone during the Grignard reaction process. The process results in transition metal salts of the (±)-cis/trans tramadol isomeric mixture with cis/trans ratio of about 98:2, which were protonated to get the cis-tramadol base.

U. S. Pat. No. 7,030,276 claims to get better selectivity of the desired isomer by carrying out the Grignard reaction in the presence of lithium salt and an alkoxy alkane. The
resulting alcohol is purified by converting into its hydrochloride forms and separated by crystallization from dioxane/water.

U. S. Pat. No. 6,399,829 provides an imporoved process for the for the preparation of (RR,SS)-2-dimethylaminomethyl-1 -(3-methoxyphenyl)cyclohexanol hydrochloride. This process comprises of synthesizing a Grignard reaction in the presence of an additive resulting in a higher transxis ratio of product than is obtained in the absence of additive. This is further converted to its hydrochloride forms and recrystallizing the hydrochloride forms from a nitrile solvent.

A process for the purification of (RR,SS)-2-dimethylaminomethyl-l-(3-methoxyphenyl)cyclohexanol has been described in EP 0940385. The separation of cis isomer from the cis/trans mixture by crystallizing cis-tramadol base as a solid using the combination of water & water-miscible organic solvents.

WO03078380 discloses the process of recovering the cis-isomer of tramadol from an isomeric mixture, comprising the crystallization of the cis-tramadol base from the isomeric mixture in presence of water. As the tramadol base exists in an oily form and it is practically difficult to crystallize selectively on a large scale.

U. S. Pat. No. 5,723,668 describes the separation of isomers of tramadol using an organic
acid, which results in four diastereomeric mixtures and therefore the corresponding yield is low. And even the use of chiral organic acids is not economically viable.

The preparation and the use of o- and p-anisylmagnesium chloride is known earlier in U. S. Pat. No. 2,959,596.

Whereas the preparation and the use of (w-methoxyphenyl)magnesium chloride has been disclosed in U.S. Pat. No. 5,852,216.The preparation of (3-alkoxyphenyl)magnesium chlorides containing one to five carbon atoms in their alkoxy radical can be obtained in high yields by the reaction of the corresponding 3-alkoxyphenyl chorides with activated magnesium. Activated magnesium can be obtained by the reduction of magnesium
halides, in particular magnesium chloride, with lithium, sodium or potassium. Reduction is usually effected with a 1 to 5 % molar excess of magnesium halide in a solvent or solvent mixture such as THF, DME or dimethyl diglycol at a temperature ranging from 65 °C to 162 °C. The reaction can be better conducted in the presence of alkali and alkaline earth metal salts such as alkali iodides, alkali sulphates and/or alkaline earth metal sulphates.

The activated magnesium which is obtained by the reduction is preferably reacted, without being isolated, with a 3-alkoxyphenyl chloride containing one to five carbon atoms in its alkoxy radical to form the corresponding Grignard compound.

The magnesium chloride compounds can be prepared in high yields and without the formation of by-products using activated magnesium. In contrast, the reaction of 3-alkoxyphenyl chlorides with magnesium which is not activated and in the presence of traces of dibromomethane, or in presence of ethyl bromide results in unsatisfactory yields. Moreover, the formation of by-products occurs to a considerable extent.
The preparation of 2-[(dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexanol using (3-methoxyphenyl)magnesiumchloride also has been disclosed in U.S. Pat. No. 5,852,216.The yield of 2-[(dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexanol is only 60% of the theoretical yield.

WO 99/36389 provides a process for the preparation of Tramadol, which involves the Grignard reaction of 2-[(dimethylaminomethyl)cyclohexanone with the Grignard reagent 3-methoxyphenylmagnesium halide to form crude Tramadol base.

EP 1785412 also describe the use of (3-methoxyphenyl)magnesium chloride for the synthesis of tramadol.

However, there is a scope and need to develop a better process using cheaper raw materials for the upturn of required tramadol isomer in higher yield on large scale production.

We have now developed an efficient method for the synthesis of (RR,SS)-2-[(dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexanol hydrochloride of formula I

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an improved process for the recovery of (RR,SS)- 2-[(dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexanol hydrochloride, which is simple, industrially applicable and economically viable.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of
(RR,SS)-2-[(dimethylamino)methyl]-l -(3-methoxyphenyl)cyclohexanol Tramadol
hydrochloride) of Formula I.

b) treating Grignard compound of formula III with 2-[(dimethylamino)methyl]-
cyclohexanone of formula IV at 40-78 ° C, in a suitable solvent to afford 2-[(dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexanol of formula V,

c) which is further subjected to the treatment of nitric acid, neutralization with
hydrochloric acid to give Tramadol HCl(Formula I).

DETAILED DESCRIPTION OF THE INVENTION:

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
Experiments:

ILLUSTRATIVE EXAMPLES OF THE INVENTION

Example 1: Charge in a overflow design reactor 3.0 M of magnesium turnings followed by THF 40 ml and agitate the mass with addition of 4ml of Et Br and 0.5 gm Iodine. Stir the reaction mass till decolourisation of Iodine and exotherm leads to about reflux. To the reaction mass is now added 5g of 3-Chloroanisole (MCA) in 20 ml of THF and the mass heated to reflux and maintained for 30 min. To this reaction mass is added a solution of 137.5 g MCA and 200 ml of THF over 5 hrs. The mass is heated for 1 hour further at reflux until the formation Grignard is completed. The reaction mass is cooled
and the Grignard solution over flown with the help of Nitrogen gas to a GRIGNARD COLLECTION VESSEL and stored under nitrogen @ 0.5 kg/cm2.

Example 2: To the residual magnesium having a activity ratio of 98.5% + in the above reactor is added 1.0 M of magnesium turnings and the mass agitated to activate the fresh magnesium for about 20 min . Now 60 ml of THF is added to the magnesium magma over 30 mins, while vigorously agitating the reaction mass. The mass is now heated to reflux and 142.5 gm of MCA in 200 ml of THF is dropped over 4 hours . The mass is further cooked at reflux for 1 hour and the reaction mass cooled .The reaction mass is overflown with Nitrogen gas to the GRIGNARD COLLECTION VESSEL and stored under nitrogen @0.5kG/cm2. THE ABOVE RECTION CYCLE IS REPEATED INDEFINITELY FOR GENERATION OF 97.5% PURE GRIGNARD .

Example 3: 1 mol equivalent of the MCA Grignard solution is transferred to a suitable kettle and the mass heated to 75°C. To the reaction mass is added 1 mol equivalent Mannich base, (2-dimethylamino)methylcyclohexanone ~ 40% solution in toluene. The mass is added at refux to completely exhaust the Grignard. On completion of reaction the mass is cooled to 30°C.

Example 4: To a kettle is charged 350 ml of water and the reaction mass is quenched at 10°C with agitation. To the kettle is now charged 2.02 mole H CI as 30 % solution and the organic layer separated for solvent recovery. To the aqueous mass is added 200 ml Toluene and the mass neutralized with 1.05 mol 20% NH3 solution. The organic layer is separated and the aqueous is discarded.

Example 5: To the organic layer is added Nitric Acid as al0% solution and the crude mass is isolated by filtration. The crude mass is suspended in 300 ml of methanol pulped and filtered to obtain 165 to 170 gms of the CRUDE TRAMADOL SALT.

Example 6: Into areactor is charged 250 ml of toluene and 75 ml of 15% NH3 solution and the wet cake of the salt is charged over lhr. The mass is heated to 50°C and the
organic layer collected. The organic mass is washed with IN alkaline base solution at 50°C. The organic mass is washed with DM water till free of salts.

Example 7: The organic mass is stripped of toluene under vacuum. To the residual mass is added 150 ml of IP A and activated carbon 5 g and the mass filtered through a micron filter bed. The organic solution is treated with 72 g of 24% solution of HC1 in IPA. The mass is cooled, filtered and dried to obtain 150 g of pure 99.8% TRAMADOL HYDROCHLORIDE, conforming Pharma EP specifically.

We Claim:

1. An improved process for the preparation of (RR,SS)-2-[(dimethylamino)methyl]-l -(3-methoxyphenyl)cyclohexanol Tramadol
hydrochloride) of Formula I.

which comprises:

a) treating 3 -chloroanisiole of formula II,
with activated magnesium in anhydrous organic solvent 'or' a mixture of organic solvents to give a compound of formula III,

b) treating Grignard compound of formula III with 2-[(dimethylamino)methyl]-
cyclohexanone of formula IV at 40-78 °C, in a suitable solvent to afford 2-[(dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexanol of formula V, which is further subjected to the treatment of nitric acid, neutralization with hydrochloric acid to give Tramadol HCl(Formula I).

2. A process according to claim 1, the (3-methoxypheny)magnesium chloride is reacted with the (2-dimethylamino)methylcyclohexanone.

3. A process according to claim 1, in which the (3-methoxypheny)magnesium chloride is prepared from magnesium.

4. A process according to claim 1-3, in which the (3-methoxypheny)magnesium chloride is prepared from activated magnesium obtained from fresh magnesium by repeating cycle.

5. A process according to claim 1, solvent or mixture of solvent selected from aliphatic ethers and / or aromatic hydrocarbons.

6. A process according to claim 5, preferred solvent is THF.

7. A process according to claim 1, in which (3-methoxypheny) magnesium chloride is prepared at 42°C-120°C.

8. A Process according to claim 1, in which mole ratio to magnesium to MCA is 2-5.

9. A process according to claim 1, in which temperature of coupling of Mannich base and (3-methoxypheny) magnesium chloride is 60-95°C.

10. A process according to claim 1, in which the (3-methoxphenyl) magnesium chloride is reacted with 2-dimethylamino)methylcyclohexanone to give crude tramadol salt.

11. A process according to claim 8, in which crude tramadol salt is purified to obtain pure tramadol through a standard methods.