Field of the invention:
The invention relates to an improved method for the preparation of (S)-Pregabalin useful for treating epilepsy and neuropathic pain. (S)-Pregablin is S-(+)-3-(aminomethyl)-5-methylhexonic acid, a compound having the chemical structure of formula (I)
(S)-Pregabalin, is a gamma-amino butyric acid or (S)-3-isobutyl (GABA) analogue. (S)-Pregabalin has been found to activate GAD (L-20 glutamic acid decarboxylase). (S)-Pregabalin has a dose dependent protective effect on-seizure, and is a CNS-active compound. (S)-Pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity (S)-Pregabalin is marketed under the name LYRICA.RTM. by Pfizer, Inc., in tablets of 25, 50, 75, 150, 200, and 300 mg doses.
The present invention also relates to an improved method for the preparation of the intermediate, namely (±)-3- (carbomoylmethyl)-5methylhexanoic acid of the formula (III) useful for the preparation of (S)-Pregabalin (±)-3-(carbomoylmethyl)-5methylhexanoicacid having the formula (III) given below
Further the present invention also relates to an improved process for the preparation of another intermediate (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid of the formula (IV) useful for the preparation of (S)-pregablin (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid having the formula (IV) given below
Further the present invention also relates to an improved process for the preparation of yet another intermediate (±)-4- isobutyl pyrrolidine -2 -one of the formula (V) useful for the preparation of pregablin (±)-4-isobutylpyrrolidine-2-one having the formula (V) given below
(V)
In addition the present invention also relates is an improved process for the preparation of still another intermediate(S)-4-isobutylpurrolidine-2-one of the formula (VI) useful for the preparation of (S)-pregablin (I). (S)-4-isobutylpurrolidine-2-one of the formula (VI) given below
In addition the present invention also relates also relates is an improved process for the preparation of still another intermediate (±)-pregabalin of the formula (VII) useful for the preparation of (S)-pregabalin(I). (±)-Pregabalin of the formula (VII) given below
• Prior art:
The process for the preparation of S-(+)-3-(aminomethyl)-5-methylhexonic acid ((S)-Pregabalin) of the formula (I) has been described in many literatures. The relevant prior art information are given below
(S)-3-(aminomethyl)-5-methylhexanoic acid can be prepared, as disclosed in U.S. Pat. No. 5,616,793, and in the corresponding publication in Drugs of The Future, 24 (8), 862-870 (1999).
The process comprises condensing 3-methylbutanal of the formula (1) with Ethylcyanoacetate of the formula (2 ) Diethylmalonate and Di-n-propylamine by refluxing in hexane, followed by refluxing 6Nhydrochloric acid of the formula (II). This compound is converted into the corresponding anhydride of the formula (a) by treatment with refluxing acetic anhydride. The reaction of the anhydride of the formula (a) with aqueous ammonia affords the glutaramic amide of the formula (III) which is subjected to optical resolution with(R)-(+)-l-phenylethylamine of the formula (IVA),yielding the (S)-enatiomer of the formula (IV). Finally, this compound is subjected to a hoffmandegradation with bromine sodiumhydroxide,to give the (S)-Pregabalin of the formula (I) , This process is shown in the scheme-1 given below
Scheme-I
The disadvantage of the above mentioned process is the difficultly of handling bromine, which is a hazardous chemical.
(R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid can be prepared, as disclosed in U.S. Pat. No. 2007/0293694A1
The Asymmetric ring in 3-isobutylglutaricanhydride is opened with cinchonaalkolides(quinidine, cinchonine and their derivatives') to form (S)-chiral ester. Then the (S) Chiral ester amidated at -70°C to form R-CMH of the formula (IV).
The above process is described below in the scheme (II) given below
Scheme-II
A method for the preparation of pregabalin is published by Yuen PW et al. in Bioorganic & Medicinal Chemistry Letters [1994, 4 (6) 823-826].The synthetic route is shown in the scheme-(III) given below
(I)
Scheme-Ill
Refluxing 4-methylpentanoic acid of the formula (c) with SOCl2 in chloroform gives the acylchloride of the formula (d) which is condensed with the chiral oxazolidinone of the formula (e) by means of BuLi in THF, yielding the corresponding N-acyl derivative of the formula (f). The regioselective alkylation of the formula (f) with benzylbromoacetate of formula (g) by means of LDA in THF affords the (S)-adduct of the formula (I) with >95%e.e. purity .The elimination of chiral auxiliary with LiOH and H2O2 gives the glutaric acid monoester of the formula (i), which is reduced with BHs/SMez in THF,yielding compound Ester of the formula 0). The reaction of Ester of the formula (j) with tosyl chloride in pyridine yield the tosylate of the formula (k), which is treated with sodium azide in DI^SO, affording the azide of the formula (L). Finally this compound of the formula (L) is reduced and debenzylated with H2 over Pd/C in THF, to give (S)-Pregabalin of the formula (I).
The above method has the following disadvantages
1. Lengthy synthetic routes, use of expensive butyl lithium and Hazardous materials like sodium azide,BH3.SMe2 in the process
2. The process is not useful for mass production because of non viability, high cost and the use of highly flammable catalyst like Pd/C and H2.
3. The process employs the reaction that require n-butyl lithium and each step has to be carried out at low temperatures (< -35ºC.) under carefully controlled conditions.
The preparation of (±)-Pregabalin was reported for the first time by Ryszard Andruskiewicz et al. in Synthesis, page 953, 1989. The synthetic route is shown in the scheme-IV given below .
(±)-Pregabalin (t) was first synthesized by Silverman and Andruskiewiez in 1989. It first involved a conjugate addition of nitro methane (n) to ethyl 5-methylhexanoate of the formula
(m) to give nitro ester pf the formula (o) which was hydrogenated to give lactam of the formula (V).Hydrolysis of the lactam of the formula (V) under acidic condition gave racemic Pregabalin of the formula (VII). The synthetic route is as shown in the following
scheme-(IV)
The above method has the following disadvantages
1. Lengthy synthetic routes, use of expensive tetramethylguanidine and nitromethane Hazardous materials like Nitro methane in the process
2. The process is not useful for mass production because of non viability due f cost and use of highly flammable catalyst like Pd/C and H2.
Many processes of preparing (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid of the formula (I) is published by Marvin S.Hoekstra et al. In organic Process Research &Development (1997, 1,26-38),
In one of the methods disclosed, L-leucine (p) could be converted to brmoacid (q) and transesterified to give ester(r) using tert-butyl acetate. Displacement of bromide with diethylsodiomalonate gave the compound in good yield. This intermediate was not easily purified and was carried into the next step as a mixture with diethylmalonate. The chiral lactone (t) was opened with trimethylsilyl iodide and elaborated to the formula (I) via the azide.
The above mentioned synthetic route is as shown in the following scheme-(V)
Scheme-V
Draw back for the above method are the following :
The primary attraction of this route in comparison to the other routes under consideration was that the chirality is built right into the starting substance. However, in spite of the initially favorable outlook for this reaction sequence,L-leucine was found not to be low enough in cost to compensate for the relatively long synthesis (nine step).After exploring this rought to the point of preparing gram quantities of (I),it was set aside in favor of other, more advantageous sequences.
In the another method published is based on Stobbe condensation of Isobutyraldhyde of the formula (1) with diethylsuccinate of the formula (w) was worked out through the same chiral lactone (t) intermediate as was used in the method-a.The key chirality inducing step in this rought was classical resolution of the mono ester(y) withL-ephdrine.with the addition of the four step conversion of lacton of the formula (t) to the formula (I), the overall sequence consisted of nine steps. The length of the synthesis, in combination with an unsatisfactory overall yield, caused us to set it aside to expolore others.
The synthetic route is as shown in the following scheme-(VI)
Scheme-VI
(v)
still another process disclosed comprises dehydrating and forming 3-Isobutylglutaric acid of the formula (a) with acetic anhydride to obtain 3-isobutylglutaric anhydride acid of the formula (b)using ammonia&water, chiral separation of (±)-3-(carbamoylmethyl)-5-hexanoic acid of the formula (c) to obtain R-(-)-3-(carbamoylmethyl)-5-hexanoic acid of the formula(f),and subjecting the R-(-)-3-(carbamoylmethyl)-5-hexanoic acid of the formula(f) to Hoffman rearrangement reaction to obtain (S)-Pregabalin of the formula (I).
Scheme-VII
The above described processes have the following disadvantages
1. Acetic anhydride used to form intermediate of the formula (b) is harmful and hazardous chemical. .
2. The difficultly of handling bromine, which is hazardous chemical.
3. The optical resolution is done using a mixture of ethanol and Chloroform which is problematic because use of chloroform in larger quantities would be toxic.
A process for the resolution of (±)-pregabalin using (S)-(+)-mandelic acid is disclosed in the US pat no 5840956.
Isovaleraldehyde of the formula (l)is reacted with diethyl malonate by Knoevenagel condensation to obtain ethyl 2-carboxyethyl-5-methylhex-2-enoate of the formula ( 3 ), which on reaction with potassium cyanide afforded ethyl
2-carboxyethyl-3-cyano-5-methylhexanoate.(4) Ethyl 2- Carboxyethyl-3-Cyano -3 cyano -5-methylhexanoate of the formula ( 4) on heating with sodium chloride in dimethyl sulfoxide under Krapcho conditions yielded ethyl 3-cyano-5-methylhexanoate of the formula ( 5 ), which on treatment with potassium hydroxide afforded the corresponding potassium salt. Catalytic hydrogenation of the potassium salt solution using sponge Nickel provided the racemic pregabalin of formula-(VII). The racemic pregabalin on resolution with S-(+)-r^andelic acid gave S-(+)-pregabalin of the formula (I)
The above synthesis route is shown in the scheme -VIII given below
The main drawbacks of the above process are the following :
1) The reduction catalyst(Raney nickel) used is hazardous and easily flammable and also is expensive.
2) The use of highly hazardous potassium cyanide(KCN)
3) The resolving agent((S)-Mnadelic acid ) used is in large excess.
4) The process is not feasible in commercial mass production
5) Recovery and re-use of resolving agent is tedious
The preparation of (S)-(+)-3-(aminomethyl)-5-hexanoic acid (pregabalin) is described in W02006/136087.The process starts from3-Isobutylglutaric acid of the formula (II), which is converted into 3-Isobutylglutrayl imine of the formula (7). 3-Isobutyglutraylimine of the formula (7) is converted into recemic pregabalin by Hoffman rearrangement to obtain racemic pregabalin of the formula(VII), the recemic pregabalin of the formula (VII) is resolved in the chiral reagent (S)-mandelic acid, then treated with THF and water to give (S)-Pregabalin of the formula (I).
The above synthesis route is shown in the scheme -IX given below
The following are the disadvantages of the above process
1. The process involves use of higher temperature like 180ºC, which requires the use of specially designed reaction vessels.
2. The isolation of the intermediate 3-Isobutylglutarimine of the formula (II) by adding alcohol /water mixture of solvent. The recovery of the unused solvent is not possible which makes the process uneconomical
3. A diaseteromeric salt of pregabalin with (S)-Mandelic acid was obtained by heating to 50-60ºC a solution of racemic pregabalin(lmol) and an excess of (S)-Mandelic acid(1.8mol) batch heating and temperature are kept to the minimum necessary to dissolve solid in to order to minimize acid catalyzed decomposition of recemic pregabalin to the corresponding lactam. The lactam is an impurity which is difficult to remove, consequently the process does not yield pure compound.
4. Removal of (S)-Mandelic acid from the diasteromeric salt to give to enriched (S)-Pregabalin of the formula (I) was done using THF which is an extremely flammable liquid and may form explosive peroxides.
Pregabalin has become very popular for the treatment of epilepsy and neuropathic pain. The hitherto known processes described above have one or the other disadvantages. Considering the importance gained for pregablin clinically as well as considering its commercial importance, there is a need for developing an improved process, which will avoid the usage of hazardous chemicals and is industrially viable with product of high purity and yield. In addition it would be advantageous to provide an improved method for the preparation of pregablin which would be simple , convenient ,cost-efficient and is suitable for commercial production assuring the quality of pregablin prepared.
Objectives of the present invention:
Therefore the main objective of the present invention is to provide an improved method for the preparation of pregablin of the formula (I)
Another objective of the present invention is to provide an improved method for the preparation of (S)-pregablin of the formula (I) which is simple, convenient, cost-efficient and is also suitable for commercial production assuring the quality of(S)- Pregablin prepared
Yet another objective of the present invention is to provide an improved process for the preparation of the intermediate, namely (±) - 3- (carbomoylmethyl)-5methylhexanoic acid of the formula (III) useful for the preparation of(S) - Pregabalin
Still another objective of the present invention is to provide an improved process for the preparation of another intermediate(R)-3-(Carbamoylmethyl)-5-methylhexanoic acid of the formula (IV) useful for the preparation of (S)-Pregablin
Still another objective of the present invention is to provide an improved process for the preparation of yet another intermediate (±) 4- isobutyl pyrrolidine 2 - one of the formula (V) useful for the preparation of pregablin
still another objective of the present invention is to provide an improved process for the preparation of still another intermediate (S) 4- isobutyl pyrrolidine 2 - one of the formula (VI) useful for the preparation of pregablin
Yet another objective of the present invention is to provide an improved process for the preparation of still another intermediate (±)-Pregabalin of the formula (VII) useful for the preparation of(S)-pregabalin
The above objectives of the present invention have been achieved based on our findings based on extensive R&D initiated that the intermediate (±) - 3- (carbamoylmethyl)-5methylhexanoic acid of the formula (III) can be prepared by treating the compound of the formula (II) with nitrogen containing compounds, alkali and water when (±) - 3- (carbamoylmethyl)-5methylhexanoic acid is produced., The compound of the formula III obtained can be converted to (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid of the formula IV which can be converted directly to (S)-Pregabalin of the formula I vis ,the intermediates (±) 4- isobutyl pyrrolidine 2 - one of the formula V , S- (+)-4-Isobutylpyrolidine-2-one Formula VI & (±)-pregabalin of the formula (VII) By this method there is no necessity of resolution at the last stage of the process , consequently the (S)-Pregabalin of the formula I is obtained in more purer form. Such a process has not been reported so far and hence is novel
• Summary of the invention
Accordingly the present invention relates to an improved process for the preparation of the intermediate, namely (±) 3 (carbomoylmethyl)-5methylhexanoic acid of the formula
(±)-3-(carbamoylmethyl)-5-methylhexanoic acid
Which is an important intermediate for the preparation of (S)-Pregabalin of the formula I
Which comprises
(a) Condensing commercially available 3-isobutylglutaric acid of the formula (II)
With nitrogen containing reactant selected from alkaline ammonium salts, urea or thiourea, preferably urea at a temperature in the range of 100-160®C, preferably at a temperature in the range of about 130 to 160ºC
(b) Cooling the resulting reaction mixture to a temperature in the range of 100°C to 120°C .
(c) adding water to the reaction mass obtained in step (b) thereby bringing the temperature which brings down to temperature to about 60°C, adding an alkaline solution and heating the mixture to a temperature in the range of 60-90®C, and cooling to a temperature in the range of 0-10°C and
(d) Neutralizing the resultant reaction mixture with an inorganic acid selected from HCI or sulfuric acid, to obtain the compound of the formula (III)
According to another feature of the present invention there is provided an improved process for the preparation of another intermediate(R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid of the formula
Useful for the preparation of (S)-pregablin of the formula I
Which comprises
(a) Condensing commercially available 3-isobutylglutaric acid of the formula (II)
With nitrogen containing reactant selected from alkaline ammonium salts, urea or thiourea, preferably urea at a temperature in the range of 100-160®C, preferably at a temperature in the range of about 130 to 160°C
(b) Cooling the resulting reaction mixture to a temperature in the range of 100°C to 120°C .
(c) adding water to the reaction mass obtained in step (b) thereby bringing the temperature which brings down the temperature to about 60°C , adding an alkaline solution and heating the mixture to a temperature in the range of 60-90°C, and cooling to a temperature in the range of O-1OºC and
(d) Neutralizing the resultant reaction mixture with an inorganic acid selected from Hcl or Sulphuric acid to obtain the compound of the formula (III)
(e) Reacting (±)-3-(carbamoylmethyl)-5-methylhexanoic acid of the formula (III) obtained in step (d) with a Chiral base such as (R)-l-Phenylethylamine,l-(lnaphthyl)ethylamine,
(R)-phenyl glycinol, preferably (R)-l-phenylethylamine in the presence of solvent or mixture of solvents selected from chlorinated hydrocarbons such as dichloromethane, ethylene dichloride; Cl-C5alcohol such as methanol, ethanol, Isopropanol,l-butyl alcohol, 2 - butyl alcohol, tertiary butyl alcohol and isoamylalcohol ; Ketones such as acetone, 2-butanone, methyl isobutyl ketone and methylethylketone ;and mixtures thereof, the preferred solvent being a ketone most preferably acetone to obtain substantially pure chiral salt (R)-3-(Carbamoylmethy)-5-methylhexanoic acid of the formula IVA;
Wherein R1 represents chiraiamine
(f) Dissolving the salt of the formula IVA obtained in step (e) in water to form a solution and acidifying the solution with an inorganic acid selected from hydrochloric Sisulfuric acid to obtain solid (R)- (-)-3-(carbamoylmethyl)-5- methylhexanoic acid of the formula IV
According to yet another feature of the present invention involves an improved process for the preparation of another intermediate (±) 4-isobutyl pyrrolidine 2 - one of the formula (V)
Useful for the preparation of (S)-pregablin which comprises
(a) Condensing commercially available 3-isobutylglutaric acid of the formula (II)
With nitrogen containing reactant selected from alkaline ammonium salts, urea or thiourea, preferably urea at a temperature in the range of 100-160°C, preferably at a temperature in the range of about 130 to 160°C
(b) Cooling the resulting reaction mixture to a temperature in the range of 100®C to 120°C.
(c) adding water to the reaction mass obtained in step (b) thereby bringing the temperature which brings down the temperature to about 60°C , adding an alkaline solution and heating the mixture to a temperature in the range of 60-90®C, and cooling to a temperature in the range of 0-10°C
(d) Neutralizing the resultant reaction mixture with an inorganic acid selected from hydrochloric acid or sulfuric acid to obtain the compound of the formula (III)
(e) Adding the (±)-3-(carbamoylmethyl)-5-methylhexanoic acid of the formula(III) obtained in step ( d) in to an aqueous solution of an alkali, preferably sodium hydroxide then adding an alkali hypohalite such as sodium hypobromite, sodium hypochlorite, preferably sodium hypochlorite in to the solution , maintaining the temperature of the solution in the range of 45-50°C, the concentration of the alkali solution being maintained in the range of 10-30%. and
(f) Adding an inorganic acid to set the pH value between 7-13 and maintaining the solution at a temperature in the range of 30-120®C and extracting the (±)-4-isobutylpyrrolidine-2-one of the formula (V) formed using organic solvents such as aromatic hydrocarbon as benzene, methyl benzene, and toluene, and dichloromethane, dichloromethane preferably Toluene and Dichloromethane.
According to still another feature of the present invention there is provided an improved process for the preparation of still another intermediate S- (+)-4-Isobutylpyrolidine-2-one of the formula (VI)
Useful for the preparation of(S) - pregablin of the formula I
which comprises
(a) Condensing commercially available 3-isobutylglutaric acid of the formula (II)
With nitrogen containing reactant selected from alkaline ammonium salts, urea or thiourea, preferably urea at a temperature in the range of 100-160°C, preferably at a temperature in the range of about 130 to 160®C
(b) Cooling the resulting reaction mixture to a temperature in the range of 100°C to 120°C.
(c) adding water to the reaction mass obtained in step (b) thereby bringing the temperature which brings down the temperature to about SO'C , adding an alkaline solution and heating the mixture to a temperature in the range of 60-90°C, and cooling to a temperature in the range of 0-10°C
(d) Neutralizing the resultant reaction mixture with an inorganic acid selected from hydrochloric acid or sulfuric acid to obtain the compound of the formula (III)
(e) Reacting (±)-3-(carbamoylmethyl)-5-methylhexanoic acid of the formula (III) obtained in step (d) with a Chiral base such as (R)-l-Phenylethylamine, l-(lnaphthyl)ethylamine,(R)-phenyl glycino I, preferably (R)-l-phenylethylamine, in the presence of solvent or mixture of solvents selected from chlorinated hydrocarbons such as dichloromethane, ethylene dichloride; Cl-C5alcohol such as methanol, ethanol, Isopropanol,l-butyl alcohol, 2 - butyl alcohol, tertiary butyl alcohol and isoamylalcohol ; Ketones such as acetone, 2-butanone, methyl isobutyl ketone and methylethylketone ;and mixtures thereof, the preferred solvent being a ketone most preferably acetone to obtain substantially pure chiral salt (R)-3-(Carbamoylmethy)-5-methylhexanoic acid of the formula IVA;
(f) Dissolving the salt of the formula IVA obtained in step (e) in water to form a solution and acidifying the solution with inorganic acids such as sulphuric acid and hydrochloric acid preferably hydrochloric acid to obtain solid (R)- (3)-(carbamoylmethyl)-5- methylhexanic acid of the formula IV
(g) Adding R-3-(carbamoylmethyl)-5-methylhexanoic acid of the formula (IV) obtained in step (f) to an aqueous solution of an alkali, then adding an alkali hypohalite at a temperature in the range of-10to-5°C to the solution maintaining the temperature under 45-50° and
(h) Adding an inorganic acid to set the pH value between 7-13, at a temperature in the range of 30-120°C and extracting with organic solvents such as aromatic hydrocarbon as benzene, methyl benzene, and toluene, and dichloromethane, dichloromethane preferably Toluene and Dichloromethane, to obtain (S)-4-isobutylpyrrolidine-2-one of the formula (VI).
In addition the present invention also relates also to an improved process for the preparation of still another intermediate (±)-pregabalin of the formula (VII)
Useful for the preparation of (S)-pregabalin which comprises
(a) Condensing commercially available 3-isobutylglutaric acid of the formula (II)
With nitrogen containing reactant selected from alkaline ammonium salts, urea or thiourea, preferably urea at a temperature in the range of 100-160°C, preferably at a temperature in the range of about 130 to 160°C
(b) Cooling the resulting reaction mixture to a temperature in the range of 100°C to 120°C
(c) adding water to the reaction mass obtained in step (b) thereby bringing the temperature which brings down the temperature to about 60°C , adding an alkaline solution and heating the mixture to a temperature in the range of 60-90°C, and cooling to a temperature in the range of 0-10°C and
(d) Neutralizing the resultant reaction mixture with inorganic acids such as sulphuric acid or hydrochloric acid preferably hydrochloric acid to obtain the compound of the formula (III)
(e) Adding (±)-3-(carbamoylmethyl)-5-methylhexanoic acid of the formula (III) to an aqueous solution of an alkali, then adding an alkali hypochlorite in to the mixture maintaining the temperature under 45-50°C
(f) Adding an inorganic acid selected from sulphuric acid and hydrochloric acid preferably hydrochloric acid to set pH value at 5.5-6.5, at a temperature in the range of 10-30°C ,then filtering the slurry mass formed to obtain (±)-pregabalin of the formula (VII)
According to another feature of the present invention there is provided an improved method for the preparation of (S)-Pregabrm of the formula (I) which comprises
(a) Condensing commercially available 3-isobutylglutaric acid of the formula (II)
With nitrogen containing reactant selected from alkaline ammonium salts, urea or thiourea, preferably urea at a temperature in the range of 100-160°C, preferably at a temperature in the range of about 130 to 160°C
(b) Cooling the resulting reaction mixture to a temperature in the range of 100®C to 120°C
(c) adding water to the reaction mass obtained in step (b) thereby bringing the temperature which brings down the temperature to about 60°C , adding an all