DESC:RELATED PATENT APPLICATION(S):
This application claims the benefit of Indian Patent Application No. 201741012681 filed on April 07, 2017; the disclosure of which are incorporated herein by reference.
FIELD OF INVENTION:
The present invention relates to an improved method of preparation of substantially pure Methazolamide (I) with more than 99.5% purity.

BACKGROUND OF INVENTION:
Methazolamide is a sulfonamide derivate chemically known as (E)-N-(3-methyl-5-sulfamoyl-1,3,4-thiadiazol-2(3H)-ylidene) acetamide. It is indicated in the treatment of increased intraocular pressure in chronic open-angle glaucoma and secondary glaucoma.
The synthesis of Methazolamide was reported in many patents and non-patent literature. The contents of which are hereby incorporated as reference in their entirety.
US5912258 describes the synthesis 5-(benzylthio)-1,3,4-thiadiazol-2-amine (IV), a potential intermediate for the preparation of Methazolamide (I) by treating 2-amino-5-mercapto-1,3,4-thiadiazole with benzyl bromide, potassium hydroxide, methanol, drying over sodium sulphate and recrystallizing from n-hexane/methanol.

US9284287 specifies the preparation of 5-(benzylthio)-1,3,4-thiadiazol-2-amine (IV) by reacting 2-amino-5-mercapto-1,3,4-thiadiazole with potassium hydroxide solution in ethanol, followed by its conversion to N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl) acetamide (III) by reacting with acetic anhydride, acetic acid in water.

US2783241 describes the synthesis of Methazolamide (I) by chlorinating 5-acetylimino-4-methyl-2-benzylmercapto-?2-1,3,4-thiadiazoline (II) with 33% aqueous acetic acid, followed by addition of different liquid ammonia, acidifying using hydrochloric acid and recrystallization from, hot water or ethyl acetate and petroleum ether to give Methazolamide (I).

Journal of the American Chemical Society, 1956, vol. 78, p. 4649, 4652 describes the complete process for the synthesis of Methazolamide (I) by reacting 2-amino-5-mercapto-1,3,4-thiadiazole (V) with benzyl chloride in presence of potassium hydroxide, ethanol and washing with cold water and ether to obtain 5-(benzylthio)-1,3,4-thiadiazol-2-amine (IV), which was then treated with acetic anhydride and acetic acid to form intermediate (III). Intermediate (III) was reacted with sodium dissolved in methanol, methyl bromide and sodium hydroxide to give intermediate (II), which further reacted with glacial acetic acid, and chlorine gas to form sulphonyl chloride intermediate (E)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-sulfonyl chloride (Ia) in situ. The reaction mass in situ was immediately treated with liquid ammonia and concentrated hydrochloric acid to form Methazolamide (I).

Most of the prior art process involves use of acetic anhydride and chlorine gas for the preparation of intermediates of Methazolamide. The present inventors therefore report an improved process for synthesis of Methazolamide (I) thereof using safe, environmental friendly and commercially viable reagents.

SUMMARY OF THE INVENTION:

One object of the present invention is to provide improved process for the preparation of substantially pure Methazolamide (I).
In another object of the invention, a method of preparing a substantially pure Methazolamide having purity greater than or equal to 99.5 % by High performance liquid chromatography (HPLC) is provided.
Another object of the invention is to provide a method of preparing Methazolamide intermediates with purity greater than or equal to 99 % purity by HPLC.
The current invention describes a modified method for the synthesis of pharmaceutical grade Methazolamide which comprises the following steps:
a) Treating 5-amino-1,3,4-thiadiazole-2-thiol (V) with benzyl chloride in the presence of a suitable base to yield 5-(benzylthio)-1,3,4-thiadiazol-2-amine (IV)
b) Acetylating 5-(benzylthio)-1,3,4-thiadiazol-2-amine (IV) with acetyl chloride in the presence of triethylamine, to obtain N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl) acetamide (III)
c) Methylation of 1,3,4-thiadiazol ring of (III) using dimethyl sulfate in the presence of potassium hydroxide to obtain (E)-N-(5-(benzylthio)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene) acetamide (II)
d) Chlorination of (E)-N-(5-(benzylthio)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene) acetamide (II) with N-chlorosuccinimide in presence of acetic acid to obtain (E)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-sulfonyl chloride (Ia)
e) Treating (E)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-sulfonylchloride (Ia) with aqueous ammonia and adjusting the pH to 5.0-7.5 to obtain crude Methazolamide (I) and purifying crude Methazolamide (I) from a suitable protic solvent to yield Methazolamide (I) with purity greater than 99.5 % by HPLC.
The intermediates produced in the above process are having purity greater than 99 % by HPLC.
BRIEF DESCRIPTION OF THE DRAWING

Figure 1:Fourier-transform infrared spectroscopy (FTIR) spectrum of Methazolamide (I)
Figure 2: X-Ray powder diffraction pattern of Methazolamide (I)
Figure 3: Particle size distribution graph of Methazolamide (I)
Figure 4: Differential scanning calorimetry (DSC) of Methazolamide(I)

DETAILED DESCRIPTION OF THE INVENTION:

The above scheme outlines the steps involved in the synthesis of Methazolamide (I).

In one embodiment, this invention provides an improved method for the synthesis of substantially pure Methazolamide (I) with purity more than 99.5 % by HPLC.

In another embodiment, this invention provides a process for the preparation of Methazolamide intermediates with purity greater than 99 % by HPLC

Step a) comprises of condensation of 5-amino-1,3,4-thiadiazole-2-thiol (V) with benzyl chloride in a suitable protic solvent in the presence of suitable base at 0-5 °C. Suitable base is selected from the group comprising of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate or the like; potassium hydroxide being the most preferred base. The reaction mass was cooled to 0-10 °C , preferably to 0 to 5 °C to obtain the solid. The solid so obtained was purified by preparing a slurry in a suitable protic solvent and filtering under vacuum to yield of 5-(benzylthio)-1,3,4-thiadiazol-2-amine (IV) with 99.94 % purity by HPLC.

Step b) relates to the formation of N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl) acetamide (III) following the Schotten-Baumann reaction which proceeds by reacting 5-(benzylthio)-1,3,4-thiadiazol-2-amine (IV) with acetyl chloride in the presence of base triethylamine in a suitable aprotic solvent at 10-15 °C. The reaction temperature ranges from 10 to 35 °C, preferably 10 to 25 °C. The product was purified by preparing a slurry in a suitable protic solvent to yield N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl) acetamide (III) with 99.83 % purity by HPLC.

Prior art process requires hazardous reagent like acetic anhydride for the preparation of N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl) acetamide (III), which is not commercially viable on large scale. Thus, acetylation using acetyl chloride in the presence of base, preferably triethyl amine makes the process simple and economical.

It was found surprisingly that, reaction steps a & b, does not require further purification by way of recrystallization in any organic solvent after preparing slurry in water. None of the prior art procedures describe processes for obtaining these intermediates in greater than or equal to 99.5 % purity without purifying from an organic solvent, thus rendering the water-slurry- purification process novel. Due to the simplicity of the work up and low costs, it has high industrial applicability.

Step c) describes methylation of N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl) acetamide (III) by reacting with a suitable alkylating agent preferably dimethyl sulfate in presence of a base, preferably potassium hydroxide. On completion of the reaction, the reaction mass was washed and dissolved in suitable protic solvents at 25-30 °C, then cooled to 10-15 °C to give (E)-N-(5-(benzylthio)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene) acetamide (II) with purity 99.58 % by HPLC.

Step d) comprises of the formation of (E)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-sulfonyl chloride (Ia) in situ by chlorinating (E)-N-(5-(benzylthio)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene) acetamide (II) with N-chlorosuccinimide in the presence of acetic acid in an aprotic solvents at 25-30 °C. N-chlorosuccinimide is less toxic and a safe reagent. Hence, chlorination using N-chlorosuccinimide is industrially more viable than use of chlorine gas as reported in prior art methods because chlorine gas is highly toxic and dangerous when used on large scale.

After chlorination, the reaction mass is quenched with a suitable protic solvent and the product was extracted with a suitable aprotic solvent to obtain (E)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-sulfonyl chloride (Ia).

Step e) describes treatment of E)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-sulfonyl chloride (Ia) with aqueous ammonia. Intermediate (Ia) was treated with aqueous ammonia and pH was adjusted to 5.0 to 7.5, preferably 6.5 to 7.0 with 10% aqueous hydrochloric acid at 10-15 °C. The precipitated solid was filtered under vacuum and washed with suitable protic solvent to obtain crystalline Methazolamide (I) which was further purified.

In another embodiment the process of final purification of Methazolamide (I) comprises of the following steps:
I. Dissolving Methazolamide (I) in a suitable protic solvent
II. Heating the reaction mixture to 60-65 °C
III. Filtering the reaction mixture at 60-65 °C
IV. Cooling the filtrate to 0-5 °C
V. Isolating pure methazolamide (I)

The protic solvents used in the above steps are selected from group comprising of methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, DM water or the like, preferably DM water, methanol and isopropyl alcohol (IPA) were used in the present invention.
The aprotic solvents used in the above steps were selected from a group comprising of acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, xylene, toulene, tetrahydrofuran or the like, preferably dichloromethane and methyl tertiary butyl ether were used in the present invention.

The alkylating agents used for the formation of intermediate (IV) is selected from the group comprising dimethyl sulphate, dimethyl carbonate, dimethyl decarbonate, diazomethane dimethoxypropane or the like. Preferably dimethyl sulphate was used in the present invention.

The crystalline Methazolamide (I) so obtained in the above process is having total impurities less than 0.5 %(w/w), preferably less than 0.10 % (w/w), which forms another embodiment of the invention.

Impurity A
Impurity B

Impurity C

Impurity D

Impurity E

Impurity F

Impurity G
Impurity H

Impurity I

In yet another embodiment, Methazolamide (I) produced in the above method is crystalline, which is characterized by Fourier-transform infrared spectroscopy (FTIR) spectrum as illustrated in figure1 and the X-Ray powder diffraction as shown in figure 2, Table I. In the differential scanning calorimetry, an endothermic peak was observed at 213.6 °C as illustrated in figure 4.
In another aspect, the particle size distribution of Methazolamide (I) produced in the above method is having D (0.1) between 30-45 µm; D (0.5) between 100-120 µm; D (0.9) between 200-250 µm and D (1.0) between 300-380 µm as shown in figure 3.

Table I
S.no. 2(?) deg. Relative Intensity
1. 11.74 8
2. 13.28 10
3. 13.59 23
4. 13.82 100
5. 15.08 15
6. 16.17 8
7. 16.56 8
8. 16.77 43
9. 18.52 14
10. 18.69 38
11. 20.34 4
12. 20.47 16
13. 20.69 23
14. 21.01 25
15. 21.61 7
16. 21.83 78
17. 22.10 14
18. 22.36 12
19. 23.11 6
20. 23.66 41
21. 24.57 8
22. 25.26 32
23. 26.41 3
24. 26.67 28
25. 27.43 4
26. 28.06 4
27. 28.32 21
28. 30.28 3
29. 30.43 18
30. 31.23 9
31. 31.61 7
32. 32.44 12
33. 32.76 7
34. 34.31 6
35. 35.13 18
36. 36.09 17
37. 36.70 3
38. 37.25 8
39. 37.91 6
40. 38.13 17
41. 40.61 5
42. 42.14 5
43. 44.74 5
44. 45.66 10
45. 47.34 9
46. 48.12 3

The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.

EXAMPLES

EXAMPLE-1:
Preparation of 5-(benzylthio)-1,3,4-thiadiazol-2-amine (IV)
50.5 g (0.90 mole) of potassium hydroxide was added to 100 mL of DM water in a clean and dry flask and cooled to 0-5 °C. A mixture of 100 g (0.75 mole) of 5-amino-1,3,4-thiadiazole-2-thiol (V) and 114 g (0.90 moles) of benzyl chloride dissolved in 200 mL of methanol was added to the above alkali solution over a period of 1 -2 hrs. at 0-5 °C and stirred. On completion of reaction, 500 mL chilled DM water was added to the above reaction mixture, stirred for 1 hr at 0-5 °C. The reaction mass was filtered under vacuum. The obtained solid was washed with chilled water. The solid was taken in 250 mL of water at 25-30 °C, stirred for 20-30 min and filtered. The solid was then washed with water, methanol and dried under vacuum below 55 °C to obtain 160-165 g of 5-(benzylthio)-1,3,4-thiadiazol-2-amine (IV).
Yield %: 90-95
Purity % : 99.94

EXAMPLE-2:
Preparation of N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl) acetamide (III)
100 g (0.44 mole) of 5-(benzylthio)-1,3,4-thiadiazol-2-amine (IV) was added to 500 mL of dichloromethane, followed by addition of 45.6 g (0.45 mole) of triethylamine at 25-30 °C. The reaction mass was cooled to 10-15 °C with addition of 53 g (0.67 mole) of acetyl chloride added and stirred for 20-30 min. Temperature of the reaction mass was raised to 25-30 °C and stirred for 1-2 hrs. After completion of reaction, the reaction mass was cooled to 10-15 °C, stirred for 1-2 hrs and filtered. The solid obtained was washed with 100 mL of chilled dichloromethane at 10-15 °C and treated with 500 mL of water. The reaction mass was stirred for 10-20 minutes at 25-30 °C and filtered under vacuum. The obtained solid was washed with a mixture of water and methanol at 25-30 °C and dried under vacuum below 50 °C to get 85-90 g of N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl) acetamide (III).
Yield %: 80-85
Purity %: 99.83

EXAMPLE-3:
Preparation of (E)-N-(5-(benzylthio)-3-methyl-1,3,4-thiadiazol-2(3h)-ylidene)acet amide (II)
100 g (0.37 mole) of N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl) acetamide (III) was dissolved in 500 mL of methanol at 25-30 °C and cooled to 10-15 °C. 327 g (2.96 mole) of dimethyl sulfate and 500 mL of potassium hydroxide solution was added and stirred to the reaction mixture and stirred. On completion of the reaction, the reaction mass was dissolved in 200 mL of water, stirred and filtered. The solid so obtained was washed with water at 10-15 °C and dried. The dried solid was dissolved in 400 mL of isopropyl alcohol and stirred at 25-30 °C for 30-60 minutes to form a clear solution. The clear solution was cooled to 10-15 °C, stirred for 1 hr and filtered under vacuum. The solid was washed with isopropyl alcohol at 10-15 °C and dried under vacuum below 55 °C to obtain (E)-N-(5-(benzylthio)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene) acetamide (II).
Yield%: 55-60
Purity%: 99.58

EXAMPLE-4:
Preparation of (E)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-sulfonyl chloride (Ia)
100 g (0.35 mole) of (E)-N-(5-(benzylthio)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene) acetamide (II) was taken in 800 mL of acetic acid and 400 mL of dichloromethane and stirred for 20-30 min at 25-30 °C. 120 g (0.89 mole) of N-chlorosuccinimide was added slowly to the reaction mass and stirred for 3-4 hrs at 25-30 °C. After completion of the reaction, the reaction mass was quenched with water and stirred for 5-10 min at 25-30 °C. The aqueous layer was extracted with dichloromethane. The total organic layer was washed with water and distilled off under vacuum. The residue was taken in methyl t-butyl ether at 25-30 °C, then cooled at 0-5 °C and stirred for 20-30 minutes. The obtained solid was filtered and washed with chilled methyl t-butyl ether to obtain crude intermediate (Ia). This compound is immediately converted into amide in the next step.
EXAMPLE-5:
Preparation of Methazolamide or (E)-N-(3-methyl-5-sulfamoyl-1,3,4-thiadiazol-2(3H)-ylidene) acetamide (I)
250 mL of aqueous ammonia was added to the intermediate (Ia) obtained in example-4 at 25-30 °C, stirred for 2-3 hrs and heated at 35-40 °C. On completion of the reaction, the reaction mass was cooled to 10-15 °C and adjusted pH to 5.0-6.0 using 10 % aqueous hydrochloric acid. The reaction mass was stirred for 1 hr at 10-15 °C and filtered. The solid so obtained was washed with chilled water to yieldMethazolamide (I).
Yield %: 50-55
Purity %: 99.91

EXAMPLE-6: Alternative Process for the preparation of (E)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-sulfonyl chloride (Ia)
To 100 g (0.35 mole) of (E)-N-(5-(benzylthio)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene) acetamide (II), 500 mL of concentrated hydrochloric acid was added at 25-30 °C. 166.8 g (1.25 mole) of N-chlorosuccinimide in 400mL of dichloromethane was added dropwise to the reaction mixture at 10-15 °C for 20 min. The reaction mass was then quenched with DM water for 15-20 min at 10-15 °C. The aqueous layer was extracted with dichloromethane and 10 % of methanol in dichloromethane. The total organic layer was washed with DM Water and distilled off completely under vacuum at 35-40 °C. The crude was washed with cyclohexane and cooled to 0-5 °C to obtain crude intermediate (E)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-sulfonyl chloride (Ia). This compound is immediately converted into amide in the next step (Example-7).

EXAMPLE-7: Alternative process for the preparation of crude Methazolamide (I)
To (E)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-sulfonyl chloride (Ia) obtained in example-6 aqueous ammonia was added at 25-30 °C and cooled to 10-15 °C. The reaction mixture was maintained at 35-40 °C for 1-2 hrs and then cooled to 0-5 °C. The pH was adjusted to 6.5-7.0 with concentrated hydrochloric acid, stirred for 45-60 min. The obtained solid was taken in methanol at 25-30 °C and stirred for 1 hr to form a clear solution, then distilled out 80 % of the solvent at 50-55°C. The reaction mixture was cooled for 10 hr at 25-30 °C. The reaction mass was then gradually cooled to 0-5 °C and the precipitated solid was filtered and washed with chilled methanol at 0-5 °C. The obtained solid was dried under vacuum below 50 °C to obtain crystalline Methazolamide (I) with 99.97 % purity by HPLC.
Yield %: 65-70
Purity %: 99.97

EXAMPLE-8
Purification of crude Methazolamide (I)
100 g of crude Methazolamide (I) was taken in 800 ml of methanol and heated to 60-65 °C. The reaction mixture was stirred for 30-40 minutes at 60-65 °C and filtered through Hyflo bed. The filtrate so obtained was cooled to 0-5 °C and the precipitated solid was filtered under vacuum. The solid so obtained was washed with chilled methanol at 0-5 °C and dried under vacuum at below 50 °C to yield pure crystalline Methazolamide (I).
Yield %: 50-55
Purity %: 99.9
,CLAIMS:
1. A process for the preparation of Methazolamide (I), said process comprising the following steps:

a) Treating 5-amino-1,3,4-thiadiazole-2-thiol (V)

with benzyl chloride in the presence of a suitable base to obtain 5-(benzylthio)-1,3,4-thiadiazol-2-amine (IV)

b) Acetylating 5-(benzylthio)-1,3,4-thiadiazol-2-amine (IV) with acetyl chloride in the presence of base, to obtain N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl) acetamide (III)

c) Methylation of N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl) acetamide (III) using dimethyl sulfate in the presence of potassium hydroxide to obtain (E)-N-(5-(benzylthio)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene) acetamide (II)

d) Chlorination of (E)-N-(5-(benzylthio)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene) acetamide (II) with N-chlorosuccinimide in presence of acetic acid to obtain (E)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-sulfonyl chloride (Ia)

e) Treating (E)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-sulfonyl chloride (Ia) with a suitable base and purifying Methazolamide (I) from a suitable protic solvent to yield Methazolamide (I) with purity greater than 99.5% by HPLC.
2. The process as claimed in claim 1, wherein the base employed in step a) is selected from the group comprising of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate or the like.
3. The process as claimed in claim 1, wherein the base employed in step b) is triethyl amine.
4. The process as claimed in claim 1, wherein the alkylating agent employed in step c) is selected from the group comprising dimethyl sulphate, dimethyl carbonate, dimethyl dicarbonate, diazomethane 2,2-dimethoxypropane or the like.
5. The process as claimed in claim 1, wherein the base employed in step e) is aqueous ammonia.
6. A process for the purification of 5-(benzylthio)-1,3,4-thiadiazol-2-amine (IV) and N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl) acetamide (III) by preparing slurry in water and filtering the solid.

7. A process for the purification of Methazolamide (I), comprising:
I. Dissolving Methazolamide (I) in a suitable protic solvent
II. heating the reaction mixture at 60-65 °C
III. filtering the reaction mixture at 60-65 °C
IV. cooling the filtrate to 0-5 °C
V. isolating pure Methazolamide (I).
8. The process as claimed in claim 7, wherein the protic solvent is selected from the group comprising of methanol, ethanol, isopropyl alcohol (IPA) or the like.
9. The crystalline Methazolamide (I) as claimed in claim 1, is characterized by X-Ray powder diffraction pattern having principal peaks at 13.59, 13.82, 16.77, 18.69, 20.69, 21.01, 21.83, 23.66, 25.26, 26.67, 28.32, 30.43 and 35.13± 2 theta degrees.
10. The process as claimed in claim 1, wherein the obtained Methazolamide (I) is crystalline Methazolamide having impurities less than 0.5 % (w/w) as illustrated below

Impurity A
Impurity B

Impurity C

Impurity D

Impurity E

Impurity F

Impurity G
Impurity H

Impurity I