CLIAMS:An improved process for preparation of brinzolamide in high yield and purity comprising;
a. Heating the solution of 3-(1-hydroxyethyl)-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide (I) with IBX in solvent to obtain 3-acetyl-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide (II);
b. Reacting compound (II) with a brominating agent such as Pyridinium Bromide Perbromide (PBP) under acidic condition at 0-5°C to obtain 3-(2-bromoacetyl)-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide (III) which is used as such in the next step;
c. Reacting cold solution of compound (III) with chiral reducing agent such as DIP chloride at -40 to -30°C under nitrogen atmosphere, stirring at -25°C to obtain(S)-4-hydroxy-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e] [1,2] thiazine-6-sulfonamide 1,1-dioxide (IV) which is used as such in the next step;
d. Reacting the mixture of compound (IV) and methane sulphonic anhydride in solvent and ethylamine to obtain Brinzolamide (V).

2. The process according to claim 1, wherein the temperature of step (a) is in the range of 70-80°C.

3. The process according to claim 1, wherein the solvents are selected from polar or non-polar, protic or aprotic solvents.

Dated this 20th day of March, 2015

Dr. Gopakumar G. Nair
(Regn.No.: IN/PA 509)
Agent for the Applicant
Gopakumar Nair Associates ,TagSPECI:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)

1. TITLE OF THE INVENTION:

“AN IMPROVED PROCESS FOR PREPARING BRINZOLAMIDE”

2. APPLICANT:

(a) NAME: MAITHILI LIFE SCIENCES PVT. LTD.

(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956

(c) ADDRESS: Plot No 16-31-HIG/117, KPHB Phase VI Kukatpalli,
Hyderabad- 500072, Telangana State, India.

3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to an improved process for preparation of brinzolamide with high yield and purity.

BACKGROUND AND PRIOR ART:
Brinzolamide which is chemically (4R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide is a carbonic anhydrase inhibitor used to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

The product and its preparation are described in US 5240923, US 5378703 and US 5461081, EP2825174, US8344136, EP2348026, EP527801, EP617038, WO96/10573, WO2008132114 etc. The industrial processes described are expensive and involves extensive purification and crystallization steps to have a product of acceptable pharmaceutical grade.

US20120095219 in its process variant 2, have disclosed the preparation of brinzolamide starting from 3-acetyl-2,5-dichlorothiophene or a protected acetyl derivative thereof and comprises the steps of (a) sulphonation (b) chlorination followed by reaction with methoxypropylamine to obtain N-Substituted Sulfonamide (c) reduction of keto group with NaBH4 (d)(i) reacting the reduced compound with an organometallic compound followed by treatment with SO2 and subsequently with hydroxylamine-O-sulphonic acid (d)(ii) oxidizing the 1-hydroxy-ethyl group to keto compound (e) brominating the keto alkyl group (f) cyclisation of compound obtained in step (e) using a chiral reducing agent (g) reacting the free hydroxy group with an amine in presence of methane sulfonic anhydride to obtain crude brinzolamide and further crystallisation in IPA to obtain pure compound.

In the process described in US’219 the steps of oxidation (d) (ii), bromination (e), reducing with a chiral reducing agent (f) produces compounds/ intermediates in relatively low yield and involves extensive washings and crystallization to obtain the compound/intermediate in relatively pure form.

The present inventors in their quest for developing a process for synthesis of brinzolamide in high yield and purity accidentally came across US20120095219 and during working of said process observed that the yield and purity of the oxidised compound of step (d)(ii) can be improved by replacing the oxidation reagent used. US’219 employs Dess martin Periodinane (DMP) as the oxidizing agent. Although it is an effective oxidation reagent, the compound is highly soluble in most common organic solvents which may affect the yield and purity of the oxidised intermediate and hence the subsequent compounds and brinzolamide thereof.

In view of the above shortcomings, the need to provide an improved process for the preparation of brinzolamide in high yield and purity under milder conditions is still a matter of great interest in industry.

SUMMARY OF THE INVENTION:
To meet the objective, the present invention provides an improved process for preparation of brinzolamide in high yield and purity using a mild and selective oxidation reagent such as 2-Iodoxybenzoic acid (IBX) for oxidation of 3-(1-hydroxyethyl)-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide used as a starting material.

In an aspect, the improved process for preparation of brinzolamide comprises the steps of;
i. Heating the solution of 3-(1-hydroxyethyl)-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide (I) with IBX in a solvent to obtain 3-acetyl-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide (II);
ii. Reacting compound (II) with a brominating agent such as Pyridinium Bromide Perbromide (PBP) under acidic condition at 0-5°C to obtain 3-(2-bromoacetyl)-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide (III) which is used as such in the next step;
iii. Reacting cold solution of compound (III) with chiral reducing agent such as DIP chloride at -40 to -30°C under nitrogen atmosphere, stirring at -25°C adjusting the pH to obtain (S)-4-hydroxy-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide 1,1-dioxide (IV) which is used as such in the next step;
iv. Reacting the mixture of compound (IV) and methane sulphonic anhydride in solvent, with ethylamine at 0-5°C, stirring at 25-30°C to obtain Brinzolamide (V).

The solvents used in the process are selected from polar or non-polar, protic or aprotic solvents such as lower alcohols, ethers, halogenated hydrocarbons, DMSO and the like.

In another aspect, the compound 3-(1-hydroxyethyl)-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide of formula (I) is obtained by a process disclosed in US20120095219.

Abbreviations:
IBX is 2-Iodoxybenzoic acid
DIP chloride is (+)-B-Chlorodiisopinocampheylborane

DETAILED DESCRIPTION OF THE INVENTION:
In an embodiment, the present invention relates to an improved process for preparation of brinzolamide of pharmaceutical grade in high yield under mild reaction conditions. The process employed in the present invention eliminates the need to purify the compounds/intermediates formed resulting in more economical and industrially feasible route of synthesis.

In a preferred embodiment, the process steps are described in detail herein below:
Step (i): The solution of 3-(1-hydroxyethyl)-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide I and IBX in ethylene dichloride (EDC) was heated at 70±5°C for about 5-7 hrs. After completion of the starting material by TLC, reaction mixture was cooled to 25-30°C and filtered through hyflo bed. Filtrate was removed under reduced pressure to give 3-acetyl-N2-(3-methoxypropyl) thiophene-2,5-disulfonamide (II) as off white solid.

Step (ii): To the solution of 3-acetyl-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide (II) and Pyridinium Bromide Perbromide in ethyl acetate was added H2SO4 at 0-5oC, and the reaction mixture was stirred at 0oC for about 2 hrs. After completion of the starting material, as indicated by TLC, the reaction mass was poured into cold water. The organic layer was separated, dried on Na2SO4 and concentrated under reduced pressure to give 3-(2-bromoacetyl)-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide(III). The product so obtained was used for the next reaction without any further purification.

Step (iii): To a cold solution of 3-(2-bromoacetyl)-N2-(3-methoxypropyl) thiophene-2,5-disulfonamide (III) in THF was added (+) DIP chloride dissolved in hexane at -40 to -30 oC under nitrogen atmosphere. Reaction mixture was stirred at -25oC for 4-5 hours. After completion of the starting material by TLC, aqueous layer was separated and washed with MTBE (1L). Aqueous layer was adjusted to pH 1-2 with HCl (50% in water) at 0 -10 oC and extracted with ethyl acetate. The organic layer was dried on Na2SO4 and concentrated under reduced pressure to give (S)-4-hydroxy-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide 1,1-dioxide (IV). This material was used for the next reaction without any further purification.

Step (iv): To the solution of (S)-4-hydroxy-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide 1,1-dioxide (IV), methane sulphonic anhydride in THF was added pyridine at 0-5oC. The reaction mixture was stirred at 0-5oC for 1-2 h. After completion of starting material as indicated by TLC, ethyl amine ( 70% solution in water, 15 vol) was added at 0oC. The reaction mixture was stirred at 25-30oC for 15 hrs. After completion of the methane sulphonyl intermediate as indicated by TLC, solvent was removed below 80oC under reduced pressure. Reaction mixture was adjusted to pH 1 with HCl (50% in water) and washed with MTBE (2× 250 mL). Aqueous layer was adjusted to pH 8 with NaHCO3, extracted with ethyl acetate and concentrated under reduces pressure to give (R)-4-(ethylamino)-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide 1,1-dioxide (Brinzolamide) (V).

The process steps are indicted in Scheme 1 below:

In an embodiment, the compound (I) used in the present invention for preparation of brinzolamide is obtained by a process described in US20120095219.

In another embodiment, brinzolamide prepared by the improved process of the instant invention is useful in ophthalmic preparations to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

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 included within the scope of the invention. The examples included herein are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention.

Examples:
Example 1: Preparation of 3-acetyl-N2-(3-methoxypropyl) thiophene-2,5-disulfonamide (II)
The solution of 3-(1-hydroxyethyl)-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide I (50 g, 0.1396 mol) and IBX (78.2 g, 0.279 mol ) in EDC (500 ml) was heated at 70±5°C for 6 hrs until TLC indicated completion of the starting material. The reaction mixture was then cooled to 25-30°C, and filtered through hyflo bed. Filtrate was removed under reduced pressure to give 3-acetyl-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide (II) (45 g, 90.5%) as off white solid.

Example 2: Preparation of 3-(2-bromoacetyl)-N2-(3-methoxypropyl) thiophene-2,5-disulfonamide (III)
To the solution of 3-acetyl-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide (II) (45 g, 0.126 mol) and Pyridinium Bromide Perbromide (53 g, 0.126 mol) in ethyl acetate (900 mL) was added H2SO4 (23 mL) at 0-5°C. Reaction mixture was stirred at 0°C for 2 hrs. After completion of the starting material by TLC, the reaction mass was poured into cold water. The organic layer was separated, dried on Na2SO4 and concentrated under reduced pressure to give 3-(2-bromoacetyl)-N2-(3-methoxypropyl) thiophene-2,5-disulfonamide (III) (52 g, 94.8%). This material was used for the next reaction without any further purification.

Example 3: Preparation of (S)-4-hydroxy-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide 1,1-dioxide (IV)
To a cold solution of 3-(2-bromoacetyl)-N2-(3-methoxypropyl)thiophene-2,5-disulfonamide (III) (70 g, 0.1612 mol) in THF (700 mL) was added (+) DIP chloride (238 mL, 65% in hexane) at -40 to -30 oC under nitrogen atmosphere. Reaction mixture was stirred at -25 oC for 4-5 hours. After completion of the starting material by TLC, aqueous layer was separated and washed with MTBE (1 L). Aqueous layer was adjusted to pH 1-2 with HCl (50% in water) at 0 -10 oC and extracted with ethyl acetate (1.2 L). Organic layer was dried on Na2SO4 and concentrated under reduced pressure to give (S)-4-hydroxy-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide 1,1-dioxide (IV) (50 g, 87%). The material was used for the next reaction without any further purification.

Example 4: Preparation of (R)-4-(ethylamino)-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide 1,1-dioxide (Brinzolamide) V
To the solution of (S)-4-hydroxy-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide 1,1-dioxide IV (53 g, 0.148 mol), methane sulphonic anhydride (31.08 g, 0.178 mol) in THF (530 mL) was added pyridine (133 mL) at 0-5°C. The reaction mixture was stirred at 0-5°C for 1-2 hrs. After completion of starting material by TLC, ethyl amine (795 mL, 70% solution in water, 15 vol) was added at 0°C. The reaction mixture was stirred at 25-30°C for 15 hrs. After completion of the methane sulphonyl intermediate by TLC, solvent was removed below 80°C under reduced pressure. Reaction mixture was adjusted to pH 1 with HCl (50% in water) and washed with MTBE (2× 250 mL). Aqueous layer was adjusted to pH 8 with NaHCO3, extracted with ethyl acetate (1 L) and concentrated under reduced pressure to give (R)-4-(ethylamino)-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide 1,1-dioxide (Brinzolamide) V (40g, 70%)

Industrial Advantages:
1. The present process uses mild, selective and environment friendly oxidation agent such as IBX.
2. The intermediate compounds are obtained in high yield and purity.
3. The present process eliminates the need to purify the compounds/intermediates in each step thus making it industrially feasible.