FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - "PROCESS FOR THE RESOLUTION."

2. Applicant(s)
(a) NAME :
(b) NATIONALITY
(c) ADDRESS:

EMCURE PHARMACEUTICALS LTD
Indian
ARC Plot No 2, IT-BT Park, Phase II, MIDC, Hinjwadi. Pune-411057 M Maharashtra, India

3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention

FIELD OF THE INVENTION
This invention relates to the resolution of a 2-aryl-alkanoic acid by making use of a chiral amino butanol. The process is novel and useful for large scale production.
BACKGROUND OF THE INVENTION
Alpha-aryl-alkanoic acid contains a chiral center, having an asymmetrically substituted carbon atom and therefore exists in two enantiomeric forms. Alpha-aryl-alkanoic acids of formula (I); apart from its major use as Non-Steroidal Anti Inflammatory Drugs (NSAIDs) are also known in various other biologically active compounds. Further, they are also used as precursors in the synthesis of biologically active compounds.

Ar is substituted or unsubstituted aromatic moiety. Ri is C1C6 alkyl
R2 is H, -OR3, halo
R3 is C1-C6 alkyl, H
(I)
A structural class of nonsteroidal antiinflamatory drugs are consisting of alpha-aryl
alkanoic acids bearing variously substituted aromatic groups. They are used for relief of symptoms of arthritis, primary dysmenorrhoea, fever, and as an analgesic, especially where there is an inflammatory component ref: 1) The Merck Index 13th Edition, Page 876 and 2) http://en.wikipedia.org/wiki/Ibuprofen.
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In the early twentieth century, the importance of chirality to the pharmaceutical
industry was established by the fact that one enantiomer of hyoscyamine possessed
greater pharmacological activity than the other. Today, most new drugs and those
under development consist of a single optically active isomer, and chirality is also
becoming an issue for the agrochemical and other industries. Regulatory agencies
throughout the world are currently reviewing the importance of chirality with regard
to pharmaceutical and agrochemical products. It is also seen that one of the isomer of
a racemate is more potent than the other. Ref:
http://as.wilev.com/WilevCDA/WilevTitle/productCd-0566Q84112,subiectCd-CH50,descCd-description.html
For instance, incase of 2-(4-isobutyl phenyl) propionic acid i.e. ibuprofen (II), the (+) form represented by (III) and the (-) form, represented by (IV). With regard to the physiological activity of optical isomers of this compound, it has been known that the (+) isomer is 160 times stronger than the (-) isomer in vitro ref: J. Pharm. Pharmakol.
28, 256-257.
Meanwhile it was experimentally proven with animals and human patients that the pharmaceutical composition of S (+)-ibuprofen is more potent. The same therapeutic action can be achieved with (S) ibuprofen with a substantially lower dose as compared with the racemate. Ref: US 4, 973, 745.
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CH3
H3C

(IN)

9H3

OH


Predominantly, ibuprofen is sold commercially as the racemic compound; however, since the (S) ibuprofen is described as being the more active enantiomer ref: US 4,851,444, development of (S)-ibuprofen is well advanced.
It has been seen that the side effects observed when applying the racemate in the the therapeutic doses do not occur or occur to a substantially lower extent with the S (+) ibuprofen. Also, it has been found that when the (-) isomer is converted to (+) isomer in vivo, the thioester of the (-) isomer, is formed as an intermediate. It is accumulated in adipose tissues in a form of a mixed triglycerides, the same as in the case of metabolism of fatty acids in vivo. Ref: Pharmacia, vol 25, page 2069, 1989 as mentioned in US 5,321,154. In order to eliminate such a side effect and to ensure the safety of the drug, there is a strong demand of only the (+) isomer.
It is also known that S (+)-flurbiprofen is the active agent. R (-)-flurbiprofen is not converted into (S)-enantiomer in humans, although it has been suggested that R (-)-flurbiprofen has analgesic activity only (WO 92/04018).
Ibuprofen and flurbiprofen have been marketed previously as the racemic mixture. However, in certain circumstances it may be advantageous to administer substantially one enantiomer only. Therefore, it is desirable to provide improved processes for
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production of a product enriched in a desired enantiomer of such aryl propionic acids. Consequently, there is now a strong demand for a practical and industrial method of producing optically active alpha aryl alkanoic acids (I).
WO 96/19431 teaches the resolution of racemic ibuprofen by making use of N-alky-D-glucamine as a resolving agent. As per this application, the racemic mixture of ibuprofen and an appropriate quantity of N-alkyl-D-glucamine were heated till solids were dissolved. The solution was then slowly cooled to precipitate the desired (S)-ibuprofen N-alkyl-D-glucamine salt. During the cooling process, the solution was preferably seeded with the (S)-ibuprofen N-alkyl-D-glucamine salt.
However, this process has certain disadvantages. The separation of the (S) ibuprofen from the (S) ibuprofen N-alkyl-D-glucamine salt depends on whether the N-alkyl-D-glulcamine is water soluble. If the N-alkyl-D-glucamine is not water-soluble, the salt is taken in water and cleaved with a strong base such as an aqueous alkali metal hydroxide. Thus, the only and hence the best mode of resolution referred in WO '431 is by using N-octyl-D-glucamine as resolving agent. The said salt is not soluble in water and cleaved by using KOH. The time and temperature of treatment needs to be chosen critically else there might be excessive racemization of the (S)-ibuprofen or degradation of N-alkyl-D-glucamine thus resulting in loss in yields and making the process costly.
US 4,209,638 discloses a process for increasing the proportion of the desired enantiomer from racemic arylpropionic acids by a partial dissolution resolution technique. A mixture comprising an inert liquid organic diluent and a salt of the 2-aryl-propionic acid with an enantiomer of a chiral organic nitrogenous base. The preferred bases are (-)-alpha-methylbenzylamine and (-)-alpha—(2-methoxyphenyl)ethylamine. The process makes use of multiple crystallizations to
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achieve the desired enantiomeric purity thus decreasing the yields. Further the recovery of (S)-alpha methyl benzyl amine becomes a difficult task.
In US 4,983,765, it is disclosed that ibuprofen is dissolved in a suitable solvent. Phenylethylamine is dissolved in the mixture. The mixture is stirred and the precipitated diastereomer is separated with enantiomeric purity of 80%. The product is crystallized thrice using ethanol and the enantiomeric purity obtained is 98%. Thus, (a) the enantiomeric purity obtained is comparatively less making the process less efficient, (b) the process makes use of more recrystalliztion steps thus making use of more amount of solvents and decreasing the yields and (c) the use of ethanol is also restricted from Government agencies. The license needs to be obtained for the same.
US 5,015,764 and US 6,093,830 provide a process for increasing the amount of the desired enantiomer by forming a salt solution of a racemic mixture, treating the salt solution with a chiral organic nitrogenous base and an inorganic base, precipitating from the reaction solution, the less soluble distereomeric salt and separating the said diastereomeric salt. The chiral base used is (S)-alpha-methylbenzylamine. WO 93/15040 discloses an improvement to that process, where an inorganic or organic salt, soluble in the salt solution of the resolution process, is added to enhance the separation. US 5,235,101 describes the resolution of racemic ibuprofen by using (S)-methyl-benzyl-amine by floation process. US 5,235,100 also describes the resolution by (S)-methyl-benzyl-amine without making use of solvent. US 5,235,905 also describes the resolution by making use of (S)-methyl-benzyl-amine. JP 0714968 also describes the resolution of 2-arylpropionic acids by making use of (+)-alpha-phenylethylamine. The enantiomeric purity obtained by making use of (S)-methyl-benzyl amine is low. Multiple crystallizations are required. Further the recovery process of (S)-methyl-benzyl-amine is tedious.
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US 5,302,528 describe the resolution of alpha-substituted carboxylic acids by making use of micro-organisms. WO 9220812 also describes the resolution of Ibuprofen by making use of micro-organisms. US 5,283,193 also describes the resolution of alpha substituted organic acids by making use of Corynebacterium nitrilophilus. JP 2007029017 describes the resolution of carboxylic acids with luciferase. KR 2004071488 describes the resolution method using Candida rugosa lipase. US 2006003428 describes the resolution of alpha substituted carboxylic acids by papaya lipase. JP 06292598 describes the resolution of ibuprofen by making use of lauryl alcohol and biological catalysts such as lipase. KR 2001073740 describes the kinetic resolution of racemic esters of ketoprofen, ibuprofen, naproxen, phenoprofen or related compounds by making use of pseudomonas species. ES 2159232 describes the process for the resolution of Ibuprofen catalyzed by lipase or mixture of lipases. US 5,077,217 describes the preparation of optically active ibuprofen by enantioselective enzymatic hydrolysis, while making use of extractive membrane reactor containing a hemofilter prepared from polyacrylonitrile, microporous, ultrafiltration type hollow fibers. These reactors containing such extractive membranes are very costly and this process is industrially not feasible due to demand of specific design of the reactor. However, the use of micro-organisms in the process makes the process costly and industrially unfeasible. The microbial-enzyme reactions are highly sensitive to forces of a mechanical nature as well as temperature and pH conditions. The careful control over pH and temperature and well defined conditions are required to achieve the desired microbial activity. Hence, the monitoring of reaction conditions become very critical and tedious, http://www.freepatentsonline.com/4566469.html.
The use of other resolving agents has also been described in US 4,994,604 which discloses the use of (S)-lysine in a preferential crystallization method for the formation of the (S)-ibuprofen (S) lysine salt. US 5,332,834 discloses an improvement on that process including the racemization and recycle of the (R) -ibuprofen. However, (S) lysine is comparatively costly making the process
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industrially unfeasible. The reaction conditions make use of ethanol as a solvent. The use of ethanol is also restricted from Government agencies. The license needs to be obtained for the same.
US 4,246,164, US 4,246,193, US 4,501,727, KR 2006041061 and 4,515,811 disclose the use of N-alkyl-D-glucamines as resolving agents. However, these resolving agents are very costly.
US 5,599,969 discloses the process for the production of the enantiomer of ibuprofen which comprises the following stages:
(a) reaction of racemic ibuprofen with (S)-alpha-methylbenzylamine in presence of toluene and methanol to obtain (S)-alpha-methylbenzylamine salt of (S)-enriched-ibuprofen of an enantiomeric purity of 89.3% by weight.
(b) Recrystallisation of the (S) enriched ibuprofen salt to obtain (S) enriched ibuprofen salt with an enantiomeric purity of 94.1 % by weight.
(c) Second recrystallization step of the above enriched (S) ibuprofen salt to obtain 98.5% purity by weight and
(d) Liberation of the (S) enriched ibuprofen in Toluene by making use of cone. HC1 acid to yield (S) enriched ibuprofen of 98.5% enantiomeric purity by weight.
However, this method has following disadvantages. The process involves multiple recrystallization steps to obtain the required purity of the (S) ibuprofen salt. This process thus decreases the yield of the final product. Further this process makes use of more amounts of solvents thus making the process industrially unfeasible. Also, for (S)-alphamethylbenzylamine, the recovery becomes difficult.
US 5,321,154 provides various optically active resolving agents like 2-(4-methylphenyl)-3-methyl butyl amine, (-)-alpha-tolylethylamine, (^-alpha-
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ethylbenzylamine, (+)-3-methyl-2-phenyl-butylamine etc for the resolution of ibuprofen. The yields and enantiomeric purity obtained by making use of these resolving agents is comparatively low.
WO 9602521 describes the resolution of aryl-substituted aliphatic carboxylic acid by formic a salt with an optically active oxazolidinone. US 4,940,813 describes the resolution of ibuprofen by making use of S-ethyl lactate.
US 5,302,751 describes that the achiral and racemic amine salts of racemic ibuprofen can be resolved with no use of optically active substances by means of direct crystallization method. The salts are prepared by treating a solution of ibuprofen in a suitable solvent with the amine solution and isolating the precipitate by filtration. The amines used are octyl amine, isopropyl amine, n-amylamine, n-propylamine, t-butylamine, alpha-methylbenzylamine etc.
HU 67809 describes the resolution of racemic carboxylic acids. In the process the racemic acids are treated with (+)-alpha-phenylethylamine in a solvent. The distereomeric residue is extracted with a super critical solvent. Evaporation of extract produces an enantiomer of the acid, and the second enantiomer is obtained from the extracted residue. The technique of super critical extraction makes the process costlier and industrially non viable.
US 4,973,745 and CN 1336921 describes the process of converting the racemate of 2-arylpropionic acid with an optically active form of threo-l-p-nitrophenyl-2-aminopropane-1,3 diol, preferably the D(-)-form, into the diastereomeric salts, separating these salts and converting the thus obtained obtained pure diastereomers into the free acids of the enantiomer forms of the 2-arylpropionic acid. The optical purity obtained after the reaction is comparatively low. Multiple crystallizations are required to increase the optical purity which results in the loss in yields and more
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amount of solvents is required. US 5,677,469 describes the resolution of chiral acids by making use of l-aminoindan-2-ols. CN 1318537 describes that the (S) ibuprofen is prepared via the optical resolution of racemic ibuprofen with L-(+)-2-amino-l-(4-nitrophenyl)-l,3-propaniediol ketal as resolving agent.
IN 183618 (Chemical Abstract 141:370652) describes the separation of optically active enantiomers from racemic mixture by making use of Tween-80 and Span-60.
US 5,189,208 discloses an ibuprofen resolution process using a non racemic ibuprofen as its starting material obtained from an enantioselective synthesis process.
IN 181369 describes the use of N-alkyl, N-cycloalkyl, or N-aralkyl D-glucamines in particular N-sec-butyl-, N-octyl- and N-benzyl-D-glucamines as resolving agents in the preparation of S-(+)-ibuprofen.
IN 178474 describes the preparation of optically active alpha-aryl propionic acids via esterification of ketenes with optically active alcohols.
WO 96/34842 discloses the process for selective preparation of (S) (+) ibuprofen, or salts thereof, from racemic ibuprofen, comprising the following steps:
(a) reacting racemic ibuprofen with the appropriate enantiomer of an optically active alcohol to produce a mixture of diastereomeric esters;
(b) distilling said mixture under suitable conditions such that the diastereomer incorporating the S-form of ibuprofen selectively distills off into the distillate;
(c) racemizing the benzylic carbon in the distillation residue under suitable conditions to regenerate a 1:1 mixture of distereomer esters; and
(d) optionally hydrolyzing the distillate of step (b) to (S) ibuprofen.
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This process is a multistep synthesis involving two chemical reactions viz esterification and hydrolysis. Further, this process makes use of and hence, requires longer time. Further this process makes use of fractional distillation assembly. US 5,278,337 describes that the racemic ibuprofen was resolved using n-octylamine. Ibuprofen with 58% (S) optical purity was dissolved in hexane at 50-60°C, n-octylamine was added, solvent was evaporated.
CN 1314336 describes the resolution of racemic ibuprofen by allowing it to react with chiral resolution agent A in mixed solvent under refluxing for 0.5 to 3 h, allowing to react with chiral resolution agent B under refluxing for 0.5 to 2 h. This process makes use of two chiral resoluting agents, thus (a) the process involves two chemical reactions, which demand more utilities, man power etc and (b) making the process economically less feasible. Further the recovery of the chiral regents from the mixture of two also becomes challenging.
While the resolution of racemic mixtures with chiral auxiliaries is known, generally such known processes lead to a 50% yield of enantiomer. To get higher yields of one enantiomer, the other enantiomer typically must be separated from the chiral auxiliary prior to racemization and recycle. Such separation of chiral auxiliary requires extra processing steps and equipment and often consumes chemicals and generates wastes in stoichiometric quantities. Furthermore, additional process equipment and energy are often needed to alternate between radically different conditions (temperature, solvent, pH, etc) for racemization and resolution.
Thus, to obtain enantiomerically pure isomer of alpha aryl alkanoic acid on industrial scale, there is a continuous interest in finding methods to resolve racemic compound in good yields of each highly enriched enantiomer, based on total racemate feed.
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This task is challenging in light of the number of problems from literature processes for resolution of racemic ibuprofen:
a) Poor yields in the process.
b) Recovery of the resolving agents.
c) Multiple crystallizations.
d) Limitations due to enzymatic reactions.
e) Specific design of the reactor.
f) Longer reaction time.
g) Critical reaction conditions.
h) More than one chiral resolving agents, i) more than one crystallization processes.
In view of the above shortcomings, it was necessary to develop an alternate resolving agent, which would give S-(+)-ibuprofen i.e. compound of formula (III), by a process, which is industrially feasible and viable.
SUMMARY OF THE INVENTION
The present inventors have developed a chiral resolving agent which provides alpha-aryl propionic acid with more than 90% chiral purity, without much repetitive crystallization.
The present inventors have developed a process for the preparation of alpha-aryl propionic acid by making use of a resolving agent, L-3-nitrobenzyl-2-amino-butanol, which can be prepared easily. The chiral resolving agent can be recovered easily.
The present inventors have developed a process for the preparation of (S) (+) ibuprofen in which the chiral resolving agent can be easily recovered.
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Accordingly, a method for preparation of alpha-aryl propionic acid which is easy, requires less manpower is developed. The process is also cost effective and industrially feasible.
The method is implemented for the preparation of (S) (+) Ibuprofen. OBJECT OF THE INVENTION
First object of the present invention is to provide an improved process for the preparation of alpha-arylpropionic acid of formula (I) by a synthetic route, which is simple and industrially feasible.
Second object of the invention is to provide alpha-arylpropionic acid of formula (I) in pharmaceutically acceptable yields.
Third object of the invention is to provide alpha-arylpropionic acid of formula (I) by making use of resolving agent, which can be prepared from the less expensive chemicals, in simple steps.
Fourth object of the invention is to provide alpha-arylpropionic acid of formula (I) in pharmaceutically acceptable enantiomeric purity without carrying out multiple recrystallizations.
Fifth object of the invention is to provide alpha-aryl-propionic acid of formula (III) by a process which is simple, economical, and requires less man power and specially designed equipments.
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DETAILED DESCRIPTION OF THE INVENTION:
Alpha-aryl propionic acid of formula (I), can be resolved.
R1^.R2 Ar-^^COOH
wherein Ar is substituted or unsubstituted aromatic moiety. Substituted means that
the aromatic ring is substituted by one or upto 3 substituents selected from halo (CI,
Br or I), hydroxy, alkyl, alkoxy, amino, amino alkyl, nitro, aryl, aryloxy or arylthio
group.
Alkyl are CI to C6 straight chain or branched or cyclic alkyl groups including 4-
isobutyl-phenyl, 3-phenoxy-phenyl, 3-benzuyl-phenyl, 2-fluoro-4-biphenylyl, 6-
methoxy-2-naphthyl, 2-(4-chlorophenyl)-5-benzoxazole, [4-(l -oxo-2-
isoindolinyl)phenyl], phenyl, {p-(l-oxo-2-isoindolinyl)phenyl], 6-chloro-9-H-
carbazole, 4-(2-thienylcarbonyl)benzene, 5-benzoyl-2-thienyl, 3-chloro-4-(2,5-
dihydro-lH-pyrrol-l-yl)benzene, 9-H-fluorene-2-yl and alike.
Rl is C]-C6 alkyl, R2 is hydrogen or hydroxy, -OR3, halo, R3 is C1-C6 alkyl or
hydrogen.
The following table illustrates the compounds of the present invention.

Name Rl R2 Ar
Ibuprofen CH3 H 0Ph (para substituted)
Fenoprofen CH3 H ^^^^ (meta substituted)
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Ketoprofen CH3 H o ^^ \^\ (meta substituted
Fulurbiprofen CH3 H F (meta substituted)
Naproxen CH3 H ^0xXJ
Benoxaprofen CH3 H cl^O^°Y^i
Indoprofen CH3 H odo
Atrolactic acid CH3 OH (X
Pheneturide CH2-CH3 H a
Indobufen CH2-CH3 H Odo
Carprofen CH3 H aJX€f
Suprofen CH3 H o ^^ \/^\ (pam substituted)
Tiaprofenic acid CH3 H 0
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Pirprofen CH3 H £>£>-
Cicloprofen CH3 H CxP~
Thus, alpha aryl propionic acids comprise ibuprofen, fenoprofen, ketoprofen, flurbiprofen, naproxen, benoxaprofen, indoprofen, atrolactic acid, pheneturide, indobufen, carprofen, suprofen, tiaprofenic acid, pirprofen, cicloprofen and minoxiprofen.
A mixture of (S)-alpha-aryl propionic acid and (R)-alpha-aryl propionic acid, typically a racemic mixture, and appropriate quantity of the resolving agent are heated in the inert solvent. The heating is carried till a clear solution is obtained. After the heating is completed the reaction mixture is cooled with stirring. The reaction mixture contains diastereomeric salts, which on crystallization(s) gives the salt in desired enantiomeric purity. Upon obtaining the desired enantiomeric purity the salt is broken into the respective alpha aryl propionic acid using acid and water. The acid is selected from the group comprising of hydrochloric acid, sulphuric acid, acetic acid etc. The preferable acid used is hydrochloric acid.
The resolving agent used is compound of formula (V).
X (V) l^
X is selected from chlorine, bromine, iodine and nitro. X can be anywhere in the ring. Preferably X is at meta position. X is preferably nitro.
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The resolving agent used in the current embodiment is L-3-substituted-benzyl-2-amino-butanol of formula (V). This resolving agent can be easily prepared from 3 substituted-benzaldehyde (VI) and L-2-amino butanol (VII). The imine (VIII), thus obtained, can be reduced by making use of sodium borohydride. The reaction is described in Scheme (I) below:


OH

NaBH4



OH
(L)
x-

(V)

Investigations were conducted on ibuprofen to determine a method of economically converting the racemate into an optically pure enantiomer. Accordingly, ibuprofen is frequently named throughout the invention. However, the process described is generally applicable to the separation of alpha-aryl-propionic acids.
Racemic alpha-aryl-propionic acid i.e. racemic ibuprofen is used as the substrate for the resolution. L-3-nitro-benzyl-2-amino-butanol is used as the resolving agent. After heating the substrate and resolving agent in an inert solvent till the clear solution is obtained, the reaction mixture was cooled and the solid of distereomeric mixtures was observed. The solid of (S) ibuprofen salt precipitates out at room temperature. The
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product enriched with (S)-ibuprofen salt is filtered and washed. The filtrate and the washings are saved for the racemization and recycle of the resolving agent as well as the solvent.
The separation of (S) ibuprofen from the (S) ibuprofen salt is carried in the presence of acid and water. The salt is added to water with stirring. The salt is separated by addition of an acid and cooling the reaction mixture to desired temperature. The temperature is further increased and the separated solid is filtered and dried.
The solvent used for the formation of (S) ibuprofen salt is selected from the group of organic solvents comprising of ethers, alcohols, esters, nitriles etc. The preferred solvents are selected from the group comprising of di-isopropyl ether, di-ethyl ether, dimethylether etc. The most preferred solvent is di-isopropyl ether.
The reaction of formation of the (S) ibuprofen salt is carried out at higher temperature. The temperature for the reaction is such that the solution becomes clear during the reaction. The temperature is preferably selected from a range of 50 to 80°C.
The reaction time is the time period required for the reaction in addition of the time required for forming clear solution and 1 to 4 hours longer than that. Preferable the reaction time is selected in the range of 0.5 to 5 hours.
The (S) ibuprofen is obtained from the salt by treating the aqueous solution of (S) ibuprofen with acid.
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The acid used to liberate (S) ibuprofen from its salt is selected from the group comprising of hydrochloric acid, sulphuric acid, acetic acid etc. The preferable acid used is hydrochloric acid.
Thus, the current embodiment makes use of a process, which is advantageous in achieving the following aspects:
a) Cost effective and industrially feasible process.
b) Makes use of a reagent for resolution, which can be easily synthesized.
c) Pharmaceutically acceptable yields.
d) Pharmaceutically acceptable enantiomeric purity.
e) The recycling of the resolving agent is easy, which reduces the overall cost of the synthesis.
f) Use of less steps for purification, thus increasing the overall yields of the final product.
The invention is described in detail here below with respect to the following examples, which are provided merely for illustration and are not intended to restrict the scope of the invention in any manner. Any embodiments that may be apparent to a person skilled in the art are deemed to fall within the scope of the present invention.
Examples:
Example 1: Preparation of imine from 3-nitro-benzaldehyde
In a multineck round bottom flask, toluene (500 ml) was charged. 3-Nitro-benzaldehyde (100 g) was added under stirring. The reaction mixture was slowly heated to 110°C. To the reaction mixture was added dropwise L-2-amino-butanol (88.4 g). The reaction mixture was further refluxed for an hour and gradually cooled to room temperature. The reaction was stirred for 3 hrs and then cooled to 5-10°C for an hour. The solid precipitated which was filtered and dried well. The product was
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dried. The filtrate was stirred overnight and then again chilled to 0-5 °C for 4-5 hours. The obtained solid was filtered and dried well. The filtrate is further concentrated and chilled. The solid obtained is filtered and suck dried well. Yield: 130 g
Example 2: Reduction of imine using sodium borohydride
To a 4 neck round bottom flask was charged methanol (395 ml). Imine from Example 1 (79 gm) was added under stirring. The reaction mixture was cooled to 20°C. NaBH4 was then added in small lots (portion wise) maintaining the temperature at 20°C to 25°C within an hour. After the addition of NaBH4 the reaction mixture was maintained at 20 to 25°C for an hour. The reaction mixture was concentrated. Water (800 ml) was added to the reaction mixture under stirring. The reaction mixture was stirred for 30 mins at room temperature. The reaction was filtered and suck dried well. The wet cake was taken in water (1600 ml) and concentrated hydrochloric acid (45 ml) was added to dissolve the reaction mixture completely. The reaction mixture was extracted with ethyl acetate (250 x 2) and the layer was separated. The pH of the aqueous layer was adjusted to 10 to 12 using 50% NaOH solution. The reaction mixture was filtered. The product was suck dried well and washed with water. Yield:-61 g
Example 3: Resolution of ibuprofen using L-3-Nitro benzyl 2-amino butanol
In a 500ml round bottom flask, di isopropyl ether (62.5 ml) was charged. Racemic ibuprofen (25 g) was added to the reaction flask. The reaction mixture was stirred and L-3-nitro benzyl-2-amino-butanol (27.2g) was added. The reaction mixture was heated to reflux. The mixture was refluxed for 2 hrs. The reaction mixture was gradually cooled to room temperature. The mixture was stirred at room temperature
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for 3 hrs. The solid was precipitated at room temperature. The solid was filtered and washed by 25 ml of di isopropyl ether. The solid was further dried. Yield: -17.8 gm Enantiomeric purity - 94.5%
Example 4: Purification of (S) Ibuprofen salt
(S) Ibuprofen salt (2.5 g) was added to diisopropyl ether (5.0 ml) and the reaction
mixture was heated to 60-65°C. The reaction mixture was maintained at 60-65°C for
1 hour and then cooled to 25-30°C. The reaction mixture was further stirred at 25-
30°C for 2 hours and filtered. The solid was washed with 2.5 ml diisopropyl ether and
dried.
Yield: - 2.0 gm
Enantiomeric purity - 98.9%
Example 5: Preparation of (S) ibuprofen:
To a 4-neck round bottom flask was added water (150 ml). The (S) ibuprofen salt (15 g) from Example 1 was added under stirring. The reaction mixture was cooled to 0 to 5°C. Concentrated hydrochloric acid (5 ml) was diluted in water in the ratio of (1:3) and slowly added to the reaction mixture at 0-5°C. The reaction mixture temperature was gradually increased to 20-25°C. The reaction mixture was further stirred. The reaction mixture was then filtered and dried well. The solids washed with water and dried. Yield: -7.2 g