Claims:We Claim:

1. An improved process for purification of Asenapine Maleate of formula (I) comprising of:

a) reacting crude Asenapine with maleic acid in presence of suitable solvent(s) to obtain pure Asenapine compound of formula (VI);
b) reacting pure compound of formula (VI) obtained in step (a) with maleic acid in presence of suitable solvent(s) to obtain trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino [4,5-c] pyrrole maleate compound of formula I (asenapine maleate).
2. The process according to claim 1 further comprises of:
a) Intermolecular cyclization of compound of formula (II) with N,N dimethyl glycine HCl in presence of suitable solvent(s) to obtain compound of formula (III);
b) insitu reaction of compound of formula (III) obtained in step (a) with suitable base and solvent(s) to obtain compound of formula (IV);
c) optionally seeding compound of formula (IV).
d) reducing compound of formula (IV) with palladium catalyst in presence of suitable solvent(s) to obtain compound of formula (V);
e) chlorinating compound of formula (V) with copper chloride in presence of suitable solvent(s) to obtain compound of formula (VI).
3. The process according to claim 2 step (a) further comprises of reacting cyclized product with fumaric acid in presence of suitable solvent(s) to obtain compound of formula (III).
4. The process according to claim 2 step (b) wherein base is selected from liquor ammonia, NaOH, KOH, carbonates and bicarbonates.
5. The process according to claim 2 step (d), wherein palladium catalyst is selected from 5% Pd/C or 10% Pd/C either in dry or wet form.
6. The process according to claim 2 step (d) further comprises of reacting reduced product with acid to form amine salt compound of formula (V).
7. The process according to claim 5, wherein acid is selected from hydrochloric acid, hydro bromic acid, phosphoric acid, nitric acid or sulfuric acid.
8. The process according to claim 2 step (e), wherein compound of formula (V) is diazotized using sodium nitrite and further reacted with copper chloride in presence of suitable solvent(s) to obtain compound of formula (VI).
9. The process according to any of the previous claims wherein suitable solvent(s) are selected from alcohols selected from methanol, ethanol, n-propanol, n-butanol, isopropanol; ethers selected from tetrahydrofuran, ethyl ether; water; hydrocarbons selected from cyclo hexane, cyclo pentane, cyclo heptane; halogenated hydrocarbons selected from methylene chloride, trichloroethylene or tetra chloro ethylene, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), pyridine, dioxane, toluene, xylene, diethyleneglycoldimethylether (Diglyme), 2-methyltetrahydrofuran, methanol, ethanol, propanol, isopropanol, butanol, acetone, butanone, propanone, water, methylene chloride (MDC), carbon tetrachloride or their mixtures.
10. An improved process for preparation of substantially pure form of Asenapine maleate of formula (I) free from process related impurities.

Dated this 16th day of June, 2017

, Description:FIELD OF THE INVENTION

The present invention relates to an improved process for the purification of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate) which is free from process related impurities.

BACKGROUND OF THE INVENTION

Trans-5-chloro-2- methyl-2,3,3a,12b- tetrahydro-1H-dibenz[2,3:6,7] oxepino [4,5-c] -pyrrole, which is commonly known as asenapine, is a compound having CNS-depressant activity and having antihistamine and anti-serotonin activities (US 4145434 to van den Burg).
Asenapine exhibits potential antipsychotic activity and may be useful in the treatment of depression (see international patent application WO 99/32108). A pharmaceutical preparation suitable for sublingual or buccal administration of asenapine maleate has been described in the international patent application WO 95/23600 (Akzo Nobel N.V.). A general methodology for the preparation of asenapine is disclosed in US 4145434. Physical-chemical properties of the drug substance Org 5222 have been reported (Funke et al. Arzneim. - Forsch/Drug.Res. 40, 536-539, 1990). Additional synthetic methods for the preparation of Org 5222 and radiolabelled derivatives thereof have also been described (Vader et al., J. Labelled Comp. Radiopharm. 34, 845-869, 1994).
A general methodology for the preparation of asenapine is described in the US ‘434 patent, the disclosure of which is incorporated herein for reference. Following the generalized method given in US ‘434 patent, asenapine can be prepared by the method depicted in scheme-1, given below.

Scheme-I

For preparing Asenapine from the acid (2), the carboxyl group is first transformed into the corresponding acid chloride by treatment with thionyl chloride. Coupling with sarcosine methyl ester provides for an ester (3). Treatment of the ester (3) with potassium tert-butoxide in toluene yields the cyclic Dione (4), which is subjected to further ring closure to an enamide (5) by treatment with poly phosphoric acid.
The step of reducing the enamide (5) with magnesium in methanol gave a mixture of cis and trans-lactam (6). Both isomers must be separated by column chromatography. It appears that the formation of the cis-lactam (6) is predominant (approx. 4:1 cis/trans). After separation, reduction of the cis or trans-lactam (6) with LiAlH4 /AlCl3 finally furnished the cis amine (1a) or desired trans-amine (Asenapine), respectively. Because the cis isomer is predominant, the synthesis is not optimal.
It seems from the disclosure that this reaction exhibits good yields, but it also predominantly provides the unwanted process impurities and cis-isomer of the compound (6a) upon subsequent work up, which leads consequently to the cis- asenapine (1a).
Additional synthetic methods for the preparation of asenapine or salts thereof are known from WO 2006/106136, WO 1998/54186 and EP 0,569,096 patent applications. Vader et al. (Labelled Comp. Radiopharm., 34(9), 845-869, 1994) discloses synthetic methods for the preparation of radiolabelled ORG 5222 and derivatives thereof. Orthorhombic crystal form of asenapine maleate is disclosed in WO 2006/106135.
A method of preparation of (5-chloro-2-phenoxyphenyl) acetic acid has been disclosed by J. Med. Chem. 25, 855 (1982). The method employed is Willegerodt-Kindler reaction whose synthetic utility is seriously limited by the necessity of elevated reaction temperature and use of frequently high pressure. The yield of the acid obtained by the method is less (46%) that is not commercially viable for pharmaceutical industries.
A generalized method for one step synthesis of methyl (monosubstituted)arylacetates from acetophenones is disclosed in Synthesis 126-127 (1981). According to this disclosure, for example, when a mixture of acetophenone, methanol and boron trifluoride etherate is added in one lot to a stirred suspension of lead (IV) acetate in benzene at room temperature, it leads to the formation of methyl phenyl acetate in good yields. This article does not disclose preparatory methods for the phenoxyphenyl acetic acid compounds of the present invention, particularly (disubstituted)phenylacetates, more particularly (5-chloro-2-phenoxyphenyl)acetic acid or esters thereof and their further conversion to asenapine or salts thereof.
US 7750167 disclose process for the preparation of Asenapine. This process involves the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino[4,5-c]pyrrole characterised in that an E-stilbene derivative is reacted with an azomethine ylide to provide a trans-pyrrolidine derivative is treated under conditions which effect an intramolecular ring closure reaction to produce trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino-[4,5-c]pyrrole.

Scheme-II

IN 3008/MUM/2011 Indian patent application discloses process for the preparation of Asenapine. This process involves the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (Asenapine) of formula (I). It also relates to novel intermediates i.e. 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII), 5-nitro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole of formula (VIII) and 5-amino-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole of formula (IX).

Scheme-III

There is a need for synthetic procedures for the preparation of asenapine which can reliably be carried out on an industrial scale.
When reproducing the procedure of US 4145434, WO 2006/106136, WO 1998/54186 and EP 0,569,096 patent applications. Vader et al. (Labelled Comp. Radiopharm., 34(9), 845-869, 1994) we found out, that the intermediate compounds as prepared by this method required subsequent chromatographic purification as it was an oily substance with a relatively high content of process impurities. It is difficult to manage to find a solvent that would enable purification of this substance by crystallization.
However, the method in accordance with the prior art does not make it possible to prepare Asenapine maleate with high purity, which is required in the case of a pharmaceutical substance, and in a yield acceptable in the industrial scale. The reason is mainly low purity of the intermediate products, which are moreover produced in forms requiring complicated purification with the use of chromatographic methods.
Several methods for the preparation of Asenapine maleate have been described. Like any synthetic compound, Asenapine maleate can contain process impurities, unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. It is also known in the art that impurities present in an active pharmaceutical ingredient (“API”) may arise from degradation of the API, for example, during storage or during the manufacturing process, including the chemical synthesis.
However the present inventors surprisingly came up with an improved process for removing or minimizing the process related impurities by using simple and milder reagents. This not only helped to remove tedious column purification technique but also made overall process easy to handle on large scale synthesis.

Object of the invention

The object of present invention is to provide an improved process for the purification of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino[4,5-c]pyrrole maleate (Asenapine maleate).
In another object, the present invention purification process is achieved by using simple and milder reagents which are easy to handle even at large scale synthesis. It eliminates use of tedious column chromatography required for removing process related impurities.
In another object, the present invention provides an improve process for the purification of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino[4,5-c] pyrrole maleate (Formula I) comprising of:
a) reacting crude Asenapine with maleic acid in presence of suitable solvent(s) to obtain pure Asenapine compound of formula (VI);
b) reacting pure compound of formula (VI) obtained in step (a) with maleic acid in presence of suitable solvent(s) to obtain trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino [4,5-c] pyrrole maleate compound of formula I (asenapine maleate).

In yet another object, the present invention further provides overall improved process for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino[4,5-c] pyrrole maleate (Formula I) comprising of:
a) Intermolecular cyclization of compound of formula (II) with N,N dimethylglycine HCl in presence of suitable solvent(s) to obtain compound of formula (III);
b) insitu reaction of compound of formula (III) obtained in step (a) with suitable base and solvent(s) to obtain compound of formula (IV);
c) optionally seeding compound of formula (IV).
d) reducing compound of formula (IV) with palladium catalyst in presence of suitable solvent(s) to obtain compound of formula (V);
e) chlorinating compound of formula (V) with copper chloride in presence of suitable solvent(s) to obtain compound of formula (VI).
f) purifying crude Asenapine using maleic acid and suitable solvent(s) to obtain pure Asenapine compound of formula (VI);
g) reacting pure compound of formula (VI) obtained in step (a) with maleic acid in presence of suitable solvent(s) to obtain trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino [4,5-c] pyrrole maleate compound of formula I (asenapine maleate).
The process for the preparation of Asenapine maleate is shown in below scheme:

DETAILS DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides an improved process for the purification of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino[4,5-c]pyrrole maleate of formula (I) (Asenapine maleate).
In another embodiment, the present invention provides purification process is achieved using simple and milder reagents which are easy to handle even at large scale synthesis. It eliminates use of tedious column chromatography required for removing process related impurities.
In another embodiment, the present invention provides an improve process for the purification of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino[4,5-c] pyrrole maleate (Formula I) comprising of:
a) reacting crude Asenapine with maleic acid in presence of suitable solvent(s) to obtain pure Asenapine compound of formula (VI);
b) reacting pure compound of formula (VI) obtained in step (a) with maleic acid in presence of suitable solvent(s) to obtain trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino [4,5-c] pyrrole maleate compound of formula I (asenapine maleate).
In yet another embodiment, the present invention provides following overall improved process for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino[4,5-c] pyrrole maleate (Formula I) comprising of:
a) Inter molecular cyclization of compound of formula (II) with N,N dimethylglycine HCl in presence of suitable solvent(s) to obtain compound of formula (III);
b) insitu reaction of compound of formula (III) obtained in step (a) with suitable base and solvent(s) to obtain compound of formula (IV);
c) optionally seeding compound of formula (IV).
d) reducing compound of formula (IV) with palladium catalyst in presence of suitable solvent(s) to obtain compound of formula (V);
e) chlorinating compound of formula (V) with copper chloride in presence of suitable solvent(s) to obtain compound of formula (VI).
f) purifying crude Asenapine using maleic acid and suitable solvent(s) to obtain pure Asenapine compound of formula (VI);
g) reacting pure compound of formula (VI) obtained in step (a) with maleic acid in presence of suitable solvent(s) to obtain trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino [4,5-c] pyrrole maleate compound of formula I (asenapine maleate).

In first step, the inter-molecular ring closure reaction to form the 7-membered oxepine ring of asenapine can be performed with an Ullman-type reaction, i.e. treatment of a compound of Formula (II) in a solvent with copper(0) powder, with a copper(I) salt or with a copper (II) salt in the presence of a base at elevated temperatures (Organic Letters, 5, 3799-3802, 2003; Buck, E., et. al, Organic Letters 4, 1623-1626, 202; Sawyer, J. S., Tetrahedron 5045-5065, 2002) to provide trans-5-nitro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino-[4,5-c]pyrrole. An additive, such as N,N-dimethylglycine, N-methylglycine, 2,2,4,4-tetramethyl-3,5-heptanedione (TMHD) or 8-hydroxyquinoline, may be used to increase the solubility of the copper ions. Suitable bases include Cs2CO3, K 2 CO 3 , pyridine, NaOH, KOH or CsF. Useful copper sources include Cu-powder, Cul, CuBr, CuCl, Cu(CO)3 (copper(II)carbonate, Cu(OAc)2 (copper(II)acetate), Cu(OTf)2 (copper(II)trifluoromethanesulfonate), Cu2O or CuSO4 .
Suitable conditions for complete conversion of a compound of 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII) of Formula (VII) to trans-5-nitro -2-methyl-2,3,3a,12b -tetrahydro- 1H-dibenz [2,3:6,7]oxepino-[4,5-c] pyrrole of Formula (VIII) are the use of CuI, N,N-dimethylglycine and Cs2CO3. Solvents for use in the Ullman cyclisation reaction on an industrial scale are dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), pyridine, dioxane, toluene, xylene, diethyleneglycoldimethylether (Diglyme), 2-methyltetrahydrofuran, and the like.
Preferred reaction conditions for the Ullman cyclisation reaction at industrial scale are the use of dimethylacetamide or mixtures thereof with toluene as the solvent system, the use of Cs2CO3, NaOH, KOH or K2CO3 as the base, and the use of dimethylglycine in combination with Cu(I) salts such as copper(I)iodide or copper(I)chloride as the catalyst.
In further step, trans-5-nitro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino-[4,5-c]pyrrole is reacted with fumaric acid in presence of solvent(s), to obtain the compound of formula (III), optionally without being isolated for further reaction step. The solvent(s) preferably are selected from ketones or alcohols or their mixtures. More particular solvents are selected as methanol, ethanol, propanol, isopropanol, butanol, acetone, butanone, propanone or their mixtures.
In second step, compound of formula (III) either isolated or unisolated from previous step is reacted with base such as liquor ammonia in presence of suitable solvent(s) to obtain compound of formula (IV). Other suitable base includes but not limited to NaOH, KOH, carbonates and bicarbonates. Suitable solvent(s) are selected from water, halogenated hydrocarbons, alcohols or their mixtures. More particular solvents are selected as methanol, ethanol, propanol, isopropanol, butanol, water, methylene chloride (MDC), carbon tetrachloride or their mixtures. The process step optionally may require seed material for formation of compound of formula (IV).
In third step, compound of formula (IV) is reduced using suitable palladium catalyst in presence of hydrogen gas and suitable solvent(s) to obtain amine compound which is further treated with acid to obtain desired salt compound (V).
Suitable palladium catalyst is range of palladium catalysts selected from 10% Pd/C or 5% Pd/C. The catalyst may either be in dry or wet form. Suitable solvent(s) are selected from water, alcohols selected from methanol, ethanol, propanol or butanol; ethers selected from tetrahydrofuran.
Suitable acids are selected from hydrochloric acid, hydro bromic acid, phosphoric acid, nitric acid or sulfuric acid.
Suitable inorganic base are selected from NaOH, KOH, liquor ammonia, carbonates, bicarbonates.
In fourth step, the salt compound of formula (V) is chlorinated or diazotized using sodium nitrite in water and further reacted with cuprous chloride in hydrochloride solution to provide crude compound of formula (VI).
In further step, the crude compound of formula (VI) is purified by treatment with acid preferably maleic acid in suitable solvent(s) at suitable reaction conditions for removing process related impurities to provide pure Asenapine compound of formula (VI). Suitable solvent(s) include but not limited to water, methanol, ethanol, butanol, isopropanol, cyclo hexane, cyclo pentane, cyclo heptane, methylene chloride, trichloroethylene or tetra chloro ethylene or their mixtures.
In final step, the purified Asenapine compound of formula (VI) is treated with maleic acid in suitable solvent(s) at suitable temperature to provide Asenapine maleate compound of formula (I). The suitable solvent(s) are selected from water, halogenated hydrocarbon, hydrocarbons, alcohols or their mixtures. More particularly solvents include but not limited to water, methanol, ethanol, butanol, isopropanol, cyclo hexane, cyclo pentane, cyclo heptane, methylene chloride, trichloroethylene or tetra chloro ethylene or their mixtures.
Suitable techniques for isolation of product used in present invention process steps includes but not limited to such as distillation, distillation under reduced pressure or vacuum, evaporation, solvent-antisolvent, acid-base and filtration.
The following Examples serve to illustrate a synthesis process carried out by way of example. They are intended solely as examples of possible procedures without restricting the invention to their contents.

Example 1: Preparation of 5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole
To a mixture of 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol (100 g) and toluene (400 ml) were added under a nitrogen atmosphere cesium carbonate (107.93 g), N,N dimethylglycine HCl (18.49 g), N,N-dimethylacetamide (200 ml) and cuprous chloride (13.12 g). The reaction mixture was heated to reflux, stirred for about 15 hours at reflux temperature and azeotropically reflux in dean stark column. The reaction mixture was cooled and charged with liquor ammonia (100 ml) and process water (200 ml) and stirred for 30 minutes. The reaction mixture was filtered through hyflo bed and washed with toluene (150 ml). The organic layer was separated and evaporated under vacuum to obtain reaction mass.

Example 2: Preparation of fumaric acid salt of 5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole
The reaction mass from example-2 was dissolved in mixture of methanol (250 ml) & acetone (1 ml) and Fumaric acid (25 gm) was added at 30-35°C. The reaction mixture was stirred at for 60-90 minutes. The obtained solid was filtered, washed with methanol to obtain wet cake.
Example 3: Preparation of 5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole
The wet cake obtained in example-2 was added to solution of methylene chloride (500ml) at 25-35°C. The mixture was stirred at 10 minutes and process water (100 ml) was added to it. liq. Ammonia (50 ml) was added to it slowly along with stirring. The organic layer was separated and distilled off under vacuum to obtain solid. The solid was dissolved in methanol and optionally seeded and allowed to precipitate slowly. Process water (200 ml) was added to the reaction mass and stirred for 120-180 minutes. The product was filtered and washed with methanol and water and dried to obtain desired product.
Example 4: Preparation of 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole
5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole (100 gm) were dissolved in methanol (300 ml). Palladium on charcoal (2 gm) in methanol (50 ml) was added to this reaction mixture. The reaction mixture was hydrogenated using hydrogen gas for about 4-5 hour at about 40-45oC. The reaction mixture was cooled to room temperature and filtered over hyflo bed and washed with methanol (100 ml). The solvent was distilled off under vacuum. Methylene chloride (500 ml) & process water (300 ml) was added to this reaction mass and aqueous sodium hydroxide (5 gm in 50 ml process water) was added and stirred for about 30 minutes. The organic layer was separated and used for further reaction step. The crude 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole was obtained in nearly quantitative yield (268 mg, 1.0 mmol) and used without further purification.
Example 5: Preparation of Asenapine
To solution of 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole in methylene chloride as obtained in example-4 was added process water (600 ml) and conc. hydrochloric acid (72 ml) and stirred for 30 minutes. The aqueous layer was separated and cooled to 0-5oC. The reaction mass was filtered and washed with mixture of 5 ml Conc. Hydrochloric acid and 20 ml Process water at 0-5ºC and dried to obtain crude amine salt of formula (V).
Crude product (V) (100 g) was taken in flask and process water (1500 ml) and conc. hydrochloric acid (200 ml) were added to it along with stirring. 24.5 gm sodium nitrite dissolved in 100 ml process water was added and the mixture was stirred for 30 minutes at 0-5°C. The reaction mixture was added to flask containing Copper chloride (67 g) in hydrochloric acid (400 ml) at 60-65°C and stirred for about 60-70 minutes. Decant the aqueous layer to separate sticky mass. Add liq. ammonia solution (700 ml) and ethyl acetate (500 ml) to the stick mass and stir for about 30 minutes. The organic layer was separated and was distilled off under vacuum to obtain product.
Example 6: Preparation of Asenapine Maleate
The asenapine obtained in example-4 was dissolved in cyclo hexane (1000ml) and stirred for 15 minutes at 50-55oC. To this solution was added a solution of maleic acid (10 gram) in process water (4000 ml) and stirred for 30 minutes at 50-55oC. The organic solvent was separated and distilled off and n-butyl alcohol (125 ml) was added to the residue below 60oC. Activated carbon was added to the reaction mass, stirred and filtered through hyflo bed. 27.7 g Maleic acid was added to the filtrate and stirred for 45-60 minutes till clear solution obtained. The reaction mixture was cooled and optionally seeded. The precipitated solid was filtered and washed with n-butyl alcohol and dried to obtain desired product.

Dated this 16th day of June, 2017