The present invention relates to an environment friendly and direct one pot process for preparing highly pure Monomethyl Fumarate without isolating any intermediates.
BACKGROUND OF THE INVENTION
Monomethyl Fumarate is chemically known as (2E)-4- Methoxy-4-oxobut- 2-enoic acid having the following structure:

Monomethyl Fumarate has been identified as a nicotinic acid receptor agonist in vitro. Monomethyl Fumarate and prodrugs of monomethyl fumarate are useful for treating neurodegenerative, inflammatory, and autoimmune diseases including multiple sclerosis, psoriasis, irritable bowel disorder, ulcerative colitis, arthritis, chronic obstructive pulmonary disease, asthma, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
TECFIDERA i.e. Dimethyl Fumarate (DMF) is rapidly metabolized in vivo to monomethyl fumarate (MMF), and hence DMF is considered to be a prodrug of MMF.

In November 2018, USFDA has approved to Banner Life Sciences for its new drug application (NDA) for monomethyl fumarate (BAFIERTAM) delayed- release 95mg capsules, for the treatment of relapsing forms of multiple sclerosis.
Monomethyl fumarate is a novel bioequivalent of dimethyl fumarate (TECFIDERA). According to the FDA, monomethyl fumarate met the required safety, efficacy, quality, and bioequivalence standards for approval.

Zecher et al. in US4515974 discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using cis-trans catalysts like acetyl chloride, benzene sulphochloride, titanium tetrachloride, boron trifluoride etc.

Scheme-1: Process as per US4515974
Ishibashi Koji et al. in JP2850471 discloses the process of preparation of monomethyl fumarate by reacting a maleic acid monoester in the presence of a bromide salt and / or iodide salt catalyst.

Scheme-2: Process as per JP2850471
Raillard et al. in US9302977 discloses the preparation method of monomethyl fumarate (MMF) or a pharmaceutically acceptable salt thereof; comprising reacting monomethyl maleate acid chloride in presence of a solvent.

Scheme-3: Process as per US9302977

Ikebe Haruhiro et al. in JPH0359894 disclose preparation of monomethyl fumarate via isomerization of monomethyl maleate in the presence of quaternary ammonium bromide and organic peroxide.

Scheme-4: Process as per JPH0359894

Schweckendiek et al. in DE1165586 discloses the preparation of monomethyl fumarate via isomerization of monomethy1 maleate using oxalyl chloride as a catalyst.

Scheme-5: Process as per DE1165586
Journal of Organic Chemistry (1958), 23, 1559-60 discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using thiourea as a catalyst.

Scheme-6: Process as per Journal of Organic Chemistry (1958), 23, 1559-60
Organic Preparations and Procedure International (1983), 15 (4), 233-8, discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using HCl, AlCl3 or phthaloyl chloride as a catalyst.

Scheme-7: Process as per Organic Preparations and Procedure International
(1983), 15 (4), 233-8

The disadvantages of the prior disclosed processes observed includes the cis-trans conversion in the presence of cis-trans catalyst which is cumbersome and time consuming and has several repeated in process tests involved, which often makes difficult to handle on the large scale manufacturing in the industries. Besides this other prior disclosed processes resulting in impure material with process related impurities involving further purifications to get pharma grade material. Such several operations makes the process non-economically viable for the commercial scale.
Hence, there exists a need of process/es, which are not only industrially and economically feasible but also amenable to scale up and provide improved yields & quality.
The inventors of the present application provide a simple and industrially viable process without isolating any intermediates (cis/trans) for the preparation of highly pure 4-methoxy-4-oxobut-2-enoic acid (Monomethyl Fumarate) with consistent and uniform crystalline nature and form.
SUMMARY OF INVENTION

Particular aspects of the present application, relates to the process for preparation of highly pure 4-methoxy-4-oxobut-2-enoic acid. The application further relates to process for preparation of highly pure 4-methoxy-4-oxobut-2- enoic acid of formula (I) which is substantially free from process related isomeric impurities.
Different aspects of the present application are summarized herein below individually.
In one aspect of the present application, the present invention relates to a process for the preparation of highly pure 4-methoxy-4-oxobut-2-enoic acid of formula (I)

comprising the steps of:

(I)

a. reacting maleic anhydride with a halo compound in methyl alcohol;
b. adding another non polar solvent ranging between 2-5 times of the methyl alcohol;
c. heating the reaction mass of step b) upto a temperature range of 65- 80°C;
d. maintaining the reaction at a temperature range of 65-80°C for a time duration of about 12-18 hours;
e. cooling the reaction mass upto a temperature range of 0-10°C;
f. maintaining the reaction mass for time duration ranging between 60 min to 180 min at a temperature range of 0-10°C;
g. isolating the highly pure 4-methoxy-4-oxobut-2-enoic acid (Monomethyl Fumarate) of formula (I).

In another aspect of the present application, the present invention relates to a highly pure thermodynamically stable crystalline form designated as Form SMF characterized by:
a) X-ray powder diffraction peaks at about 6.4, 12.8, 19.3, 23.0, 25.8, 27.9, 42.5 and 45.9 ±0.2º 2?;
b) Differential Scanning Calorimetric thermogram having peak ranging between 144-152ºC;
c) IR spectra peaks at 3082, 2963, 2549, 1721, 1689, 1634, 1428, 1321, 1287, 1179, 998, 898, 778 ±5 cm-1.
In yet another aspect , the crystalline Form SMF of Monomethyl Fumarate obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules useful in the treatment of neurodegenerative, inflammatory, and autoimmune diseases including multiple sclerosis, psoriasis, irritable bowel disorder, ulcerative colitis, arthritis, chronic obstructive pulmonary disease, asthma, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
Further aspects of the present invention are demonstrated in detailed description section as well as in the examples.

BRIEF DESCRIPTION OF THE DRAWINGS
FIG.1: is an Illustration of a High performance Liquid Chromatography (“HPLC”) of Mono-Methyl Fumarate-Form SMF obtained according the present invention.
FIG.2: is an Illustration of a IR spectrum of Mono-Methyl Fumarate-Form SMF obtained according the present invention.
FIG.3: is an Illustration of a differential scanning clorimetric (“DSC”) curve of Mono-Methyl Fumarate-Form SMF obtained according the present invention.
FIG.4: is an Illustration of X-ray powder diffraction (XRPD) pattern of Mono-Methyl Fumarate-Form SMF obtained according the present invention.

DETAILED DESCRIPTION
As set forth herein, embodiments of the present invention provide an ecofriendly process for preparation of 4-methoxy-4-oxobut-2-enoic acid or monomethyl fumarate (I). The present invention provides with a simple and industrially amenable process for making the compound of formula (I), which exhibits various advantages over other processes reported in the state of arts. The advantages are discussed on the relevant places of further description. Individual embodiments of the present invention are detailed herein below separately.
In one embodiment according to the present application, it provides an environment friendly process for preparing high purity 4-methoxy-4-oxobut-2- enoic acid or monomethyl fumarate (I)
In another embodiment according to present application, it provides a stepwise one pot process for the preparation of 4-methoxy-4-oxobut-2-enoic acid of formula (I)

comprising the steps of :

(I)

a. reacting maleic anhydride with a halo compound in methyl alcohol;
b. adding another non polar solvent ranging between 2-5 times of the methyl alcohol;

c. heating the reaction mass of step b) upto a temperature range of 65- 80°C;

d. maintaining the reaction at a temperature range of 65-80°C for a time duration of about 12-18 hours;

e. cooling the reaction mass upto a temperature range of 0-10°C;

f. maintaining the reaction mass for time duration ranging between 60 min to 180 min at a temperature range of 0-10°C;

g. isolating the highly pure 4-methoxy-4-oxobut-2-enoic acid (Monomethyl Fumarate) of formula (I).

Individual steps of the embodiments are detailed herein below.

In step a) process of preparation of 4-methoxy-4-oxobut-2-enoic acid of formula (I) from maleic anhydride is carried out with a halo compound at temperature ranging between 65-80°C in the presence of methyl alcohol solvent and a non-polar organic solvent.
In a particular embodiment according to the present invention, it provides a process of preparation of 4-methoxy-4-oxobut-2-enoic acid of formula (I) from maleic anhydride, which involved use of a halo compound selected from acetyl chloride, trimethylsilyl chloride or acetyl bromide.
In another particular embodiment according to the present invention, the halo compound used was acetyl chloride or acetyl bromide.
In step e) for the preparation of 4-methoxy-4-oxobut-2-enoic acid, maintain the temperature of the reaction at a temperature range of 65-80°C for time duration of about 12-18 hours. A lower time duration was found to result in unreacted starting material present in a significant amount and upto more than 5-10% (by HPLC).
In yet another embodiment, reaction of halo compound is carried out in step a) at temperature not exceeding 50°C and not less than 40°C.
The non-polar solvent used in the reaction range between 2 to 5 times with respect to the organic solvent methyl alcohol, wherein a non-polar organic solvent used in step b) is selected from toluene or xylene.
In a particular embodiment according to the present invention, the non-polar solvent used was toluene.
The reaction mass in the process was heated upto a temperature range of 65- 80°C. A lower temperature was not found suitable for the reaction, since reaction remained incomplete while higher temperature resulted in significant impurities formations.
The reaction mass was maintained at a temperature ranging between 65-80°C for a time duration of about 12-18 hours in order to complete the conversion into monomethyl fumarate. The step involves isomerisation as well as selectively favouring formation of the desired geometrical isomer as fumarate.
The reaction mass is cooled upto a temperature ranging between of 0-10°C. Once the reaction mass is cooled in the desired range of temperature, it was allowed to be maintained time duration ranging between 60 min to 180 min. Inventors of present application realized that such time duration of not less than 60 minutes was found significantly important both from equilibration and yield perspective besides high purity level of drug substance.
Isolated the highly pure crystalline 4-methoxy-4-oxobut-2-enoic acid of formula (I) was carried out by conventional means of filtration and drying.
The crystalline form was formed consistent reproducible and uniform in texture.
In a particular embodiment a process for the preparation of 4-methoxy-4- oxobut-2-enoic acid of formula (I) wherein isolating the highly pure 4-methoxy-4- oxobut-2-enoic acid in step g) comprising the further steps of filtering, washing with a non-polar organic solvent and drying the material under vacuum at temperature not exceeding 60°C.
In a particular embodiment, for the isolation of 4-methoxy-4-oxobut-2- enoic acid of formula (I) in step g), washing is carried out with non-polar organic solvent at temperature ranging between 5-10ºC.
More particularly non-polar organic solvent used during washing were selected from toluene or xylene.
In another embodiment of the present application, the present invention provides a highly pure thermodynamically stable crystalline form designated as Form SMF characterized by:
a). X-ray powder diffraction peaks at about 6.4, 12.8, 19.3, 23.0, 25.8, 27.9, 42.5 and 45.9 ±0.2º 2?;
b). Differential Scanning Calorimetric thermogram having peak ranging between 144-152ºC;
c). IR spectra peaks at 3082, 2963, 2549, 1721, 1689, 1634, 1428, 1321, 1287, 1179, 998, 898, 778 ±5 cm-1.
The samples of crystalline Monomethyl fumarate "Form SMF" were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source--Cu Ka radiation using the wavelength 1.5418°A.
The present application, provides the crystalline solid of Monomethyl Fumarate (referred to as `Form SMF`) that exhibits an X-ray powder diffraction pattern. The prominent and characteristic XRPD peaks (in Angle (2T°) ± 0.20) and their d spacing values (A°) of the crystalline Form –SMF are tabulated herein below:
Table-1
S. No. Angle (2T°)±0.20 d Spacing value (A°)
1. 6.40 13.79
2. 12.82 6.90
3. 19.27 4.6
4. 23.03 3.86
5. 25.80 3.45
6. 27.85 3.20
7. 39.68 2.29
8. 45.99 1.97
Differential Scanning Calorimetric analysis was performed using a Perkin Elmer Pyris 7.0 instrument.
The crystalline highly pure material was found thermodynamically stable, and the uniform crystalline Form (Designated as Form-SMF), is further characterized by DSC endothermic peak ranging between 144-152 ºC.
In a particular embodiment, the DSC endothermic peak was found to be at 149.60 ºC, while onset was observed at 147.17 ºC and end set at 150.95 ºC.
In another embodiment crystalline Form SMF, which has an Infra Red absorption spectrum having characteristic peaks 3082, 2963, 2549, 1721, 1689, 1634, 1428, 1321, 1287, 1179, 998, 898, 778 ±5 cm-1.
The IR spectral details are tabulated in the Table -2.
TABLE-2
Peak Number X (cm-1) (A)
1. 3427.10 0.22
2. 3082.24 0.73
3. 3016.27 0.62
4. 2963.98 0.61
5. 2920.99 0.54
6. 2881.04 0.55
7. 2687.82 0.44
8. 2596.67 0.39
9. 2549.43 0.42
10. 1894.64 0.25
11. 1721.79 1.78
12. 1689.48 1.88
13. 1634.18 1.34
14. 1554.18 0.29
15. 1439.85 0.98
16. 1428.95 0.83
17. 1321.46 1.72
18. 1287.33 1.15
19. 1265.87 1.25
20. 1201.25 0.81
21. 1179.24 1.56
22. 998.71 1.16
23. 958.68 0.54
24. 921.04 0.61
25. 898.69 0.66
26. 778.99 0.47
27. 744.99 0.20
28. 660.03 0.54
29. 653.84 0.57
30. 561.87 0.39

In another embodiment of the present invention, it provides a highly pure 4- methoxy-4-oxobut-2-enoic acid having purity exceeding of 99.5% (by HPLC).
Highly pure Monomethyl fumarate "Form SMF" “can be analysed by HPLC method, using High Perform Liquid Chromatograph- make Waters series equipped with UV Detector operated at 225 nm and Hypersil BDS C18, 250 mm x 4.6 mm ID, 5 µm particle size column. Analyses were performed using the following mobile phase, at flow rate of 1.0 ml/minute, column oven temperature 40°C in gradient mode with below tentative Gradient program.

Time (min) Mobile phase A (Phosphate Buffer) Mobile phase B (Acetonitrile)
0.01 75 25
04.00 50 50
07.00 50 50
09.00 75 25
14.00 75 25

In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure that uniquely define that crystalline form, within any associated and recited margin of error, for purposes of identification.
As polymorphism has been given importance in the recent literatures owing to its relevance to the drugs having oral dosage forms due to its apparent relation to dose preparation/suitability in composition steps/ bioavailability and other pharmaceutical profiles, stable polymorphic form of a drug has often remained the clear choice in compositions due to various reasons of handling, mixing and further processing including bioavailability and stability.
The present invention provides an improved process for the preparation of substantially pure crystalline form of Monomethyl fumarate (Form SMF) wherein substantially pure material having a purity of greater than 99.5% by HPLC and meeting the quality of ICH guidelines. Monomethyl fumarate crystalline material obtained by the process of the present invention is chemically stable and has been found with good dissolution properties.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about normal pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" (open ended) means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. As used herein, "consisting essentially of" means that the invention may include ingredients in addition to those recited in the claim, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed invention. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The crystalline "Form SMF" of Monomethyl fumarate obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.
The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Mishra Manoj et al in WO2019079277A1 disclose an injectable pharmaceutical compositions comprising polymer conjugated of monomethyl fumarate, and methods for treating relapsing–remitting multiple sclerosis (RRMS) and psoriasis.
Pharmaceutically acceptable excipients used in the compositions comprising Crystalline Form-SMF of Monomethyl fumarate of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Pharmaceutically acceptable excipients used in the compositions of Crystalline Form-SMF of Monomethyl fumarate of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the below example, which is provided by way for illustration purpose only and should not be construed as limiting the scope of the invention in any manner.
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 present invention.
Examples
The process for preparation of 4-methoxy-4-oxobut-2-enoic acid of formula (I) according to the present invention is a one-pot ecofriendly procedure which is detailed in the stepwise demonstration mentioned herein below:

(I)

Example A:
Charged 100g Maleic Anhydride into round bottom flask. Added 40 ml methanol at 25-30°C. Heat the reaction mass to 45-50°C. Stirred the reaction mixture for 3.0 hr at 45-50°C to make the reaction mixture clear. Added 91.2 ml Trimethylsilyl Chloride in the course of 10 min at 45-50°C. Charged 150 ml of Toluene at 45-50°C. Heat the reaction mass to 70-75°C. Stirred the reaction mixture in course of for 17-18 hr at 70-75°C. Cool the reaction mass to 5-10°C. Maintained the reaction mass for 2.0 hr at 5-10°C. Filtered the reaction mass and washed with 100 ml toluene at 5-10°C. Suck dried in 2 hrs. Dried the material at 45°C under vacuum. Unload the material.
Yield [w/w] = 94.5 gm Purity = 99.59% (by HPLC)
Example B:
Charged 100g Maleic Anhydride into RBF. Added 40 ml methanol into above RBF at 25-30°C.Heat the reaction mass to 45-50°C.Stir the reaction mass for 3.0 hr at 45-50°C, to make the reaction mixture clear. Added 7.5 ml acetyl bromide in the course of 10 min at 45-50°C. Charged 150 ml Toluene at 45-50°C. Heat the reaction mass to 70-75°C.Stir the reaction mass for about 15-16 hr at 70-75°C. Cool the reaction mass to 5-10°C.Maintain reaction mass for 2.0 hr at 5-10°C. Filter the reaction mass at 5-10°C. Wash with 100 ml chilled toluene at 5-10°C. Suck dried the material in 2 hrs. Dry the material at 45°C under vacuum. Unload the material. Yield [w/w] = 73 gm, % Yield- 55.30% Purity = 99.67%

Example C:
100g of Maleic Anhydride is charged into Round bottom flask. Added 40 ml of methanol at 25-30°C and heat the reaction mass to 45-50°C. Stirred the reaction mass for 3hr at 45-50°C to get the reaction mass clear. Added 7.26 ml acetyl chloride at 45-50°C. Charged 150 ml Toluene at 45-50°C. Heat the reaction mass to 70-75°C. Stirred the reaction mass for 14-15 hrs at 70-75°C. Cool the reaction mass to 5-10°C. Maintain reaction mass for 2.0 hr at 5-10°C. Filtered the reaction mass and washed with 66 ml toluene at 5-10°C. Suck dried for 2 hrs. Dried the material at 60°C under vacuum. Unload the material. Yield [w/w] = 87.5gm Purity = 99.95% (by HPLC)
IR (KBr): 3082.24, 2963.98, 2549.43, 1721.79, 1689.48, 1634.18, 1428.95, 1321.46, 1287.33, 1179.24, 998.7, 898.69, 778.99 cm-1.

WE CLAIM

1. A process for the preparation of highly pure 4-methoxy-4-oxobut-2-enoic acid of formula (I)

comprising the steps of:

(I)

a. reacting maleic anhydride with a halo compound in methyl alcohol;
b. adding another non polar solvent ranging between 2-5 times with respect to methyl alcohol;
c. heating the reaction mass of step b) upto a temperature range of 65- 80°C;
d. maintaining the reaction at a temperature range of 65-80°C for a time duration of about 12-18 hours;
e. cooling the reaction mass upto a temperature range of 0-10°C;
f. maintaining the reaction mass for time duration ranging between 60 min to 180 min at a temperature range of 0-10°C;
g. isolating the highly pure crystalline 4-methoxy-4-oxobut-2-enoic acid (Monomethyl Fumarate) of formula (I).

2. A process for the preparation of 4-methoxy-4-oxobut-2-enoic acid of formula
(I) according to claim 1, wherein halo compound used in step a) are selected from trimethyl silyl chloride, acetyl bromide or acetyl chloride.
3. A process for the preparation of 4-methoxy-4-oxobut-2-enoic acid of formula
(I) according to claim 1, wherein reaction of halo compound is carried out in step a) at temperature not exceeding 50°C and not less than 40°C.
4. A process for the preparation of 4-methoxy-4-oxobut-2-enoic acid of formula
(I) according to claim 1, wherein the molar ratio of the maleic anhydride to halo compound is in a range of 1: 0.05-0.15.

5. A process for the preparation of 4-methoxy-4-oxobut-2-enoic acid of formula
(I) according to claim 1, wherein the molar ratio of the maleic anhydride to methyl alcohol is in a range of 1: 0.85-1.1.
6. A process for the preparation of 4-methoxy-4-oxobut-2-enoic acid of formula
(I) according to claim 1, wherein a non-polar organic solvent used in step b) is selected from toluene or xylene.
7. A process for the preparation of 4-methoxy-4-oxobut-2-enoic acid of formula
(I) according to claim 1, wherein isolating the highly pure 4-methoxy-4-oxobut- 2-enoic acid in step b) comprising the further steps of filtering, washing with a non-polar organic solvent and drying the material under vacuum at temperature not exceeding 60°C.
8. A highly pure 4-methoxy-4-oxobut-2-enoic acid compound of formula (I) according to the process of claim-1 having purity exceeding 99.5 % by HPLC.
9. The highly pure thermodynamically stable crystalline form designated as Form SMF characterized by
a). X-ray powder diffraction peaks at about 6.4, 12.8, 19.3, 23.0, 25.8, 27.9, 42.5 and 45.9 ±0.2º 2?;
b). Differential Scanning Calorimetric thermogram having peak ranging between 144-152ºC;
c). IR spectra peaks at 3082, 2963, 2549, 1721, 1689, 1634, 1428, 1321, 1287, 1179, 998, 898, 778 ±5 cm-1.