Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 13]

1. TITLE OF THE INVENTION
An Improved Process for the Preparation of (R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazine-6-sulfonaniide-l,l-dioxide"
2. APPLICANT
(a)NAME: USV LIMITED
(b)NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
(c)ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the nature of this invention and
the manner in which it is to be performed.
1

An Improved Process for the Preparation of (R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyI)-2H-thieno[3,2-e]-l,2-thiazine-6-suIfonamide-l,l-dioxide
Technical Field:
The present invention relates to an improved process for the preparation of (R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazinc-6-sulfonamide-1,1 -dioxide (I) via novel intermediates.

I
Background& Prior Art:
Brinzolamide is a carbonic anhydrase inhibitor indicated for the use of elevated intraoccular pressure in patients with ocular hypertension or open angle gluocoma. US patent 5,240,923 describes preparation of Brinzolamide from 3-acetyl thiophenc as depicted in scheme 1.
US patent 5,240,923 describes preparation of Brinzolamide from 3-acetyl thiophenc (II) as depicted in scheme 1. It involves protection of keto group in 3-acetyl thiophenc (II) with 2,2-dimefhyl-l,3-propanediol in presence of an hydrogen chloride gas and concentrated sulfuric acid to form 3-(2,5,5-trimethyl-l,3-dioxan-2-yl) thiophcnc (III). The product is isolated by vacuum distillation.
2

Further formation of sulfonamide group at C(2) is accomplished in three stages. In the first stage C(2) proton is abstracted using n-butyllithium in hexane followed by reaction of the anion thus formed with sulfur dioxide gas in hexane/tetrahydrofuran solvent mixture to form a lithium sulfinate salt. The salt is then reacted with hydroxylamine-O-sulfonic acid to provide 3-(2,5,5-trimethyl-l,3-dioxan-2-yl)-2-thiophenesulfonamide (IV).
Deprotection of compound (IV) using hydrochloric acid in water and tetrahydrofuran gives 3-Acetyl-2-thiophenesulfonamide (V).
Bromination of (V) with pyridinium bromide perbromide in tetrahydrofuran provides 3-bromoacetyl-2-thiophenesulfonamide (VI).
Reduction and cyclisation of the above compound in ethanol using sodium borohydride forms 3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-1,1 -dioxide (XI).
The compound (XI) is alkylated with 1,3-dibomopropane in anhydrous DMF using sodium hydride as base provides 2-(3-bromopropyl)-3,4-dihydro-4-hydroxy-2II-thiene[3,2-e] 1,2-thiazine-1,1 -dioxide (XII).
Further protection of the hydroxyl group is accomplished using ethyl vinyl ether in presence of p-toluenesulfonic acid.
Bromide displacement is then carried out using sodium methoxide to form 4-(1-
ethoxy)ethoxy-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazine
(XIV).
The formation of sulfonamide group at C-6 position is accomplished essentially as described in step 2. The subsequent removal of protecting ether group forms 3.4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazine-6-
3

sulfonamide-1,1-dioxide (XV).
Scheme 1

Oxidation of hydroxyl group using Jones reagent (chromium trixide /sulfuric acid) provides 3,4-dihydro-4-oxo-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1 -dioxide(XVI).
4

The asymmetric reduction of the keto group using five mole equivalents of (+)-(3-chlorodiisopinocampheylborane in tetrahydrofuran provides (+)-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-l,l-dioxide (IX).
Finally formation of Brinzolamide (I) is accomplished through formation of intermediate tosylate and subsequent displacement with ethylamine.
The process as described has following disadvantages;
(a) It involves number of stages offering low overall yield of 2%.
(b) Two protection-deprotection stages are involved.
(c) The synthetic sequence involves synthesis of racemic intermediate, oxidation and chiral reduction.
(d) The oxidation involves chromic acid, which is an explosive reagent.
(e) Separation of the intermediates involves column chromatography which is not industrially viable and amenable for scale-up.
US patent 5,344,929 describes the improved process for preparation of Brinzolamide starting from 3-acetyl-2,5-dichlorothiophene in 17% overall yield as depicted in scheme 2.
In the first step, C(2) chloro of 3-acetyl-2,5 dichlorothiophene is displaced with mercaptide to form the 3-acetyl-5-chloro-2-(benzylthio)thiophene (XVIII).
In the second step compound (XVIII) is converted to 3-acetyl-5-chloro-2-thiophene sulfonamide in three stages. In the first stage it is converted to sulfenyl chloride by passing chlorine gas followed by ammonia to form sulfenamide. In the third stage intermediate sulfenamide is oxidized with sodium tungstate dihydrate to form 3-acetyl-5-chloro-2-thiophene sulfonamide (XIX).
5

Scheme 2

In the third step bromination of (XIX) with pyridinium bromide perbromide in presence of concentrated sulfuric acid and ethyl acetate gives 3-bromoacetyl-5-chloro-2-thiophene sulfonamide (XX).
The fourth step involves chiral reduction of 3-bromoacetyl-5-chloro-2-thiophcne sulfonamide with (+)-p-chlorodiisopinocampheylborane to form intermediate (S)-bromohydrin which in situ cyclized with aqueous sodium hydroxide to form (S)-3,4-
6

dihydro-6-chloro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-1,1 -dioxide (XXI).
In the fifth step of process, alkylation of (XXI) with l-bromo-3-methoxypropanc in presence of potassium carbnate and dimethyl sulfoxide forms (S)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl) -2H-thieno[3,2-e]-l,2-thiazine-1,1-dioxide (XXII).
The sixth step of the process comprises the conversion of C(6)-chloro atom of (XXII) to a sulfonamide group in three stages. In the first stage C(6) anion is formed by halogen-metal exchange. In the second stage the C(6) anion is reacted with sulfur dioxide gas in tetrahydrofuran to form a lithium sulfonate salt. In the third stage salt is reacted with hydroxylamine-O-sulfonic acid to form (S)-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-l,l-dioxide (IX).
The last step of the process is conversion of (IX) to Brizolamide in three stages. In the first stage sulfonamide group is protected with trimethyl orthoacetate to prevent formation of sulfonimide during activation of the C(4) hydroxyl group with p-toluenesulfonyl chloride. In the second stage C(4) hydroxyl group is converted to tosylate in presence of triethylamine. Stage three is accomplished by converting the tosylate to ethylamino group by reacting with aqueous ethylamine solution. In the subsequent acid-base workup preotecting group is removed to form brinzolamide.
The process described has following disadvantages:
(a) The process involves pyridinium bromide perbromide as a brominating agent. which is not viable for large scale preparation.
(b) It also involves protection of sulfonamide in the last stage using trimethyl orthoacetate.
US Patent 5470973 is directed to the enantioselective synthesis of (S)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]thiazine-4-ol and related compounds as depicted
7

3-bromoacetyl-2-thiophenesulfonmide (VI) is reduced to racemic 3-(2-bromo-l-hydroxyethyl)-2-thiophenesulfonamide (XXIII), which is cyclised to (XI) with sodium hydroxide. Alkylation in the subsequent step with l-bromo-3-methoxypropane gives (XXIV), which is further oxidized with chromic acid to form ketone (XXV). In the next step ketone (XXV) is reduced with oxazaborole catalyst to give compound (VIII).
Objective of the invention:
An object of the present invention is to provide an improved process for commercial manufacture of (R)-4-(emylamino)-3,4-dmydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-1,1-dioxide commonly known as Brinzolamide.
8

Another object of the invention is to provide a process for brinzolamide, which avoids use of hazardous and explosive reagents.
A further object of the invention is to provide a process for brinzolamide, which avoids column chromatography and hence industrially feasible.
Summary of the Invention
The present invention provides a process for preparing (R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l ,2-thiazine-6-sulfonamide-l ,1 -dioxide of formula (I)

I the process comprising
(II)
9
(a) Protection of keto group in 3-acetyl thiophene (II) with diol in presence of sulfonic acid acid catalyst in non-polar aprotic solvent, preferably toluene to form 3-(2,5,5-trimethyl-l,3-dioxan-2-yl)thiophene (III).

(b) Abstracting the C(2) proton from compound of formula III using alkyllithium in hexane, tetrahydrofuran(THF) or mixtures thereof and reacting the anion thus formed with sulfur dioxide gas in presence of THF to form a lithium sulfinate. further reacting the lithium sulfinate with hydroxylamine-O-sulfonic acid to provide 3-(2,5,5-trimethyl-1,3-dioxan-2-yl)-2-thiophenesulfonamide of formula (IV).

(IV)
(c) Deprotecting compound of formula (IV) using acid catalyst in water and polar aprotic solvent, preferably THF to form 3-Acetyl-2-thiophenesulfonamide of formula (V).
10

(d) Brominating compound of formula (V) with n-bromosuccinimide in presence of acid catalyst such as p-toluenesulphonic acid and polar aprotic solvent, preferably acetonitrile to obtain 3-bromoacetyl-2-thiophenesulfonamide of formula (VI).

(VI)
(e) Reducing compound of formula VI with (+)-(3-chlorodiisopinocampheylborane in polar aprotic solvent such as THF to obtain intermediate chiral bromohydrin, and subsequently without isolating, cyclizing to a compound (S)-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-l,2-thiazine-1,1 -dioxide of formula (VII) using an aqueous alkali selected from sodium or potassium hydroxide.
11
OH


(VII)

(f) N-Alkylating compound of formula (VII)) with l-bromo-3-methoxy propane in presence of sodium or potassium carbonate and phase transfer catalyst such as tetrabutyl ammonium bromide to form (S)-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazine-1,1-dioxide of formula (VIII) in acetone.

(g) Abstracting the C(6) proton from the compound of formula (VIII) using alkyl lithium in THF and reacting the anion thus formed with sulfur dioxide gas to form lithium sulfinate, reacting the lithium sulfinate with hydroxylamine-O-sulfonic acid to obtain compound (S)-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-1,1-dioxide of formula (IX).

(h) Esterifying the hydroxyl group of compound (IX) using activated sulfonic acid
12

derivatives and displacing the ester group THF with ethylamine to provide compound of formula (I).
(i) Alternatively esterifying the hydroxyl group of compound (VIII) using activated sulfonic acid derivatives such as p-toluenesulfonyl chloride or methanesulfonyl chloride in polar aprotic solvent and displacing the ester group with ethylamine to provide compound of formula (X).

(X)
(j) Abstracting the C(6) proton from the compound of formula (X) using alkyl lithium in THF and reacting the anion thus formed with sulfur dioxide gas to form lithium sulfinate, reacting the lithium sulfinate with hydroxylamine-O-sulfonic acid to obtain compound of formula (I).
(k) Alternatively sequential treatment of X with fuming sulfuric acid, thionyl chloride and ammonia to form compound I.
Detailed Description
The present invention provides a process for preparing (R)-3,4-dihydro-4-
ethylamino-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-1,1 -dioxide of
formula (I), comprising steps, as depicted in Scheme 4.
13

Scheme 4


o_ ,o

m

GO
II JJ\ , Nil-,
O G
IV

VI

OH
Nil
o o

OH

0H

vm


OCH3 JJ 11 N
H2NO,S S S"
o o
IX

OCH3

0CH3
H2N02S
GCH3

Step I:
The first step of the process involves protection of 3-acetyl thiophene (II) with diol to form ketal. It is accomplished by reacting compound II with 2,2-dimethyl-l,3-popanediol in presence of a sulfonic acid preferably p-toluene sulfonic acid and toluene as a reaction medium. Water formed is azeotropically distilled during the reaction. The product 3-(2,5,5-trimethyl-l,3-dioxan-2-yl)thiophene (III) is isolated by basic workup.
Step II:
14

The second step of the process comprises the introduction of sulfonamide functionality at C(2) of 3-(2,5,5-trimethyl-l,3-dioxan-2-yl)thiophene (III) to produce 3-(2,5,5-trimethyl-l,3-dioxan-2-yl)-2-thiophenesulfonamide (IV). It involves three stages. In the first stage formation of C(2) anion is accomplished using 1 to 2 equivalents of butyl lithium. Preferably hexane, tetrahydrofuran and mixture thereof is selected as aprotic organic solvent. Preferably reaction is carried out at a temperature of-70 to 30°C. In the second stage, the C(2) anion is reacted with sulfur dioxide to form an intermediate lithium sulfinate. This is accomplished by passing sulfur dioxide into solution of the anion at -78 to -20°C until the pH of the solution is acidic. In the third stage solvent is removed, the solid lithium sulfinate is dissolved in water and treated with hydroxylamine-O-sulfonic acid in presence of sodium acetate trihydrate at temperature -5 to 30°C. After a reaction time of 10-20 hours, the product is isolated by extraction with ethyl acetate and evaporation of solvent.
Step III:
In the third step deprotection of 3-(2,5,5-trimethyl-l,3-dioxan-2-yl)-2-thiophenesulfonamide(IV) to produce 3-acetyl-2-thiophenesulfonamide (V) is accomplished using hydrochloric acid in polar aprotic solvent preferably tetrahydrofuran as a solvent and refluxing the reaction mixture for 1 to 4 hours. The product is precipitated by removing the solvent and basifying the reaction mass with saturated sodium bicarbonate solution. The product is isolated by filtration.
Step IV:
The fourth step of the process is bromination of 3-acetyl-2-thiophenesulfonamide (V) to provide 3-bromoacetyl-2-thiophenesulfonamide (VI). The preferred brominating agent is N-bromosuccinimide in non-polar aprotic solvent preferably acetonitrile and p-toluenesulfonic acid as a catalyst. After the reaction is complete, solvent is evaporated and water added to free the solids, which are isolated by filtration. The
15

crude is crstallised from mixture of ethyl acetate and hexane to reduce the content of dibromo compound. This crystallised product is typically contaminated with less than 10% dibromo compound.
Step V:
In the fifth step of the process, 3-bromoacetyl-2-thiophenesulfonamide (VI) is
reduced with chiral reducing agent in polar aprotic solventto provide initially an (S)-
bromohydrin, which upon subsequent treatment with aqueous alkali cyclizes to (S)-
3,4-dihydro-4-hydroxy-2H-thieno [3,2-e] -1,2-thiazine-1,1 -dioxide (VII). The
preferred reducing agent is (+)-P-chlorodiisopinocampheylborane in tetrahydrofuran as a solvent. The reduction is typically carried out using 2 to 4 equivalents of (+)-(3-chlorodiisopinocampheylborane at a temperature of -40 to -20°C for 4-8 hours. Alter the reduction is complete, aqueous sodium or potassium hydroxide is added and the mixture is stirred at ambient temperature for 5-15 hours. The product is separated by phase separation, acidification of the aqueous phase, extraction and solvent removal. Acidification is accomplished with hydrochloric acid, acetic acid, formic acid. The use of acetic acid and formic acid gives higher enantiomeric excess. The enantiomeric excess of the VII is typically greater than 96%.
Step VI:
The sixth step of the process is N-alkylation of (VII) with l-bromo-3-methoxypropane to form (S)-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2II-thieno[3,2-e]-l,2-thiazine-1,1 -dioxide (VIII). This can be accomplished by refluxing VII with l-bromo-3-methoxypropane in polar aprotic solvent preferably acetone in presence of sodium or potassium carbonate. The use of phase transfer catalyst preferably tetrabutyl ammonium bromide accelerates the reaction.
Step VII:
16

The seventh step of the process comprises the introduction of sulfonamide functionality at C(6) of (S)-3,4-dihydro-4-hydroxy-2-(3-mefhoxypropyl)-2H-thieno[3,2-e]-l,2-thiazine-l,l-dioxide (VIII) to produce (S)-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1 -dioxide (IX). Formation of C(6) anion is accomplished using 2-10 equivalents of an alkyllithium in polar aprotic solvent preferably tetrahydrofuran at a temperature of -70 to 0°C. In the second stage, the C(6) anion is reacted with sulfur dioxide to form an intermediate lithium sulfinate. This is accomplished by passing sulfur dioxide into -78 to -20°C solution of the anion until the pH of the solution is acidic. In the third stage solvent is removed, the solid lithium sulfinate is dissolved in water and treated with hydroxylamine-O-sulfonic acid in presence of sodium acetate trihydrate at temperature -5 to 30°C. After a reaction time of 10-20 hours, the product is isolated by extracting with ethyl acetate and evaporation of solvent.
Step VIII:
The eighth step of the process is conversion of the (S)-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-1,1-dioxide (IX) to a (R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-1,1-dioxide of structure I. This is accomplished in two stages consisting of (a) esterification of the C(4) hydroxyl group and (b) displacement of the activated hydroxyl group in SN2 fashion using ethylamine with inversion of stereochemistry at C(4). The reaction is carried out by reacting (IX) with p-toluenesulfonyl or methanesulfonyl chloride in the presence of an organic base preferably triethylamine and polar aprotic solvent preferably tetrahydrofuran. Use of 2 to 2.5 equivalents of p-toluenesulfonyl chloride and triethylamine at a tempertature of -10 to 30°C for a period 1 to 4 hours are preferred. After tosylation is complete stage two is accomplished by adding 10 to 40 equivalents of ethylamine at a temperature of-10 to 30°C. After a period of 10 to 40 hours, the product is isolated
17

by an acid-base workup.
Alternative route:
In an alternative route, formation of Brinzolamide from compound VIII can be accomplished in two steps as depicted in scheme 3. The first step comprises of conversion of the (S)-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno|3,2-c]-1,2-thiazine-1,1 -dioxide (VIII) to (R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazine-l,l-dioxide of formula (X) . This is accomplished in two stages consisting of (a) activation of the C(4) hydroxyl group and (b) displacement of the activated hydroxyl group in SN2 fashion using ethylamine with inversion of stereochemistry at C(4). The reaction is carried out by reacting VIII with p-toluenesulfonyl or methanesulfonyl chloride in the presence of a base such as triethylamine. 2 to 2.5 equivalents of p-toluenesulfonyl chloride and triethylamine at a tempertature of -10 to 30°C for a period 10 to 24 hours are preferred. The reaction is carried out in a polar aprotic solvent preferably Tetrahydro furan. After tosylation is complete, stage two is accomplished by adding 10 to 40 equivalents of ethylamine at a temperature of-10 to 30°C. After a period of 10 to 40 hours, the product (X) is isolated by an acid-base workup.
In the second step introduction of sulfonamide functionality at C(6) of (S)-3,4-dihydro-4-ethylamino-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (X) produces compound of formula (I). The formation of C(6) anion is accomplished using 2-10 equivalents of an alkyllithium in a solvent such as tetrahydrofuran at a temperature of -70 to 0°C. In the second stage, the C(6) anion is reacted with sulfur dioxide to form an intermediate lithium sulfinate. This is accomplished by passing sulfur dioxide into -78 to -20°C solution of the anion until the pH of the solution is acidic. In the third stage the solvent is removed and the solid lithium sulfinate is dissolved in water and treated with hydroxylamine-O-sulfonic
18

acid in presence of sodium acetate trihydrate at temperature -5 to 30°C. After a reaction time of 10-20 hours, the product is isolated by extracting with ethyl acetate and evaporation of solvent.
Alternatively the sulfonamide group may be introduced at C(6) of X by sulfonation of (X) with fuming sulfuric acid followed by reaction reaction with thionyl chloride to form sulfonyl chloride and finally reaction of sulfonyl chloride with ammonium carbonate to form compound of formula I
The synthesis of the present invention is further illustrated by the following examples, wherein specific embodiments of the invention are described in detail.
19

Examples
Example 1: 3-(2,5,5-trimethyl-l,3-dioxan-2-yl)thiophene (III)
To mechanical stirred solution of 3-acetyl thiophene (100 gm, 0.794 moles) in toluene (2000ml) added 2,2-dimethyl 1,3-propanediol (247.6 gm, 2.381 moles) and para toluene sulfonic acid (0.1 gm). The mixture was heated to reflux for 48 hours with water removal using Dean stark trap. The mixture was allowed to cool to room temperature and anhydrous potassium carbonate (10 gm) was added followed by saturated solution of sodium bicarbonate (500 ml). The organic phase was separated and aqueous phase extracted by toluene (500 ml). The combined organic phase was washed with saturated sodium chloride solution (500 ml). The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was distilled through 12 inch Vigreus column to provide the compound of the formula III (150 gm, 89 %) as a colorless liquid (bp- 88°C/ 0.1 mm of Hg).
Example 2: 3-(2,5,5-trimethyl-l,3-dioxane-2-yl)-2-thiophenesulfonamide (IV)
A solution of the compound from Example 1 (150 gm, 0.71 moles) in hexane (1500ml) was cooled to -60°C under nitrogen atmosphere. n-Butyl lithium (522.5 ml of 1.6 M hexane solution) was added over 15 min while the temperature was maintained below -60°C. The mixture was stirred 1 hour at the same temperature and then stirred for 2 hours at ambient temperature. Again cooled the reaction mixture to -65 °C and added tetrahydrofuran (750 ml). Sulfur dioxide gas was bubbled through reaction mass at -65°C till the reaction mixture is acidic. The reaction mixture is stirred overnight while warming it to ambient temperature. The reaction mass then concentrated to dryness on the rotary evaporator under reduced pressure to get the lithium sulfinate salt which further dissolved in cold water (2250 ml) and washed
20

with hexane (300 ml). Cooled the solution to -5 to 0°C and added sodium acetate trihydrate (577.4 gm, 4.25 moles). Hydroxyl amine-O- sulfonic acid was slowly added to reaction mass below 0°C. The reaction mass was stirred at ambient temperature overnight. Extracted the reaction mixture with ethyl acetate (2 X 1500 ml)) and the combined extracts were washed with sodium bicarbonate solution, brine and dried over sodium sulfate. Evaporation to dryness gave a viscous oily Compound of the formula IV (165 gm, 80%) that was used as such for further step.
Example 3: 3-Acetyl-2-thiophenesulfonamide (V)
A mixture of the compound from Example 2(165 gm, 0.57 moles) and IN HO (907 ml) in tetrahydrofuran (907 ml) was heated to reflux for 1 hour. Evaporated tetrahydrofuran was and made the aqueous solution basic by the addition of saturated solution of sodium bicarbonate. Cooled the mixture to 5°C and the precipitate was filtered, washed with cold water followed by hexane and dried to give the compound of the formula V (91 gm, 78%)
Example 4: 3-Bromoacetyl-2-thiophenesulfonamide (VI)
The product from Example 3 (91 gm, 0.44 moles) was suspended in acetonitrile (2000 ml) and cooled to 20°C. Added p-toluenesulfonic acid (114.5 gm, 0.66moles) to the reaction mass at 20°C. Allowed the reaction mixture to stir at ambient temperature for 0.5 hours. Added N-bromosuccinimide (78 gm, 0.44 moles) slowly to reaction mixture, Refluxed the reaction mass for 2 hours. The volatiles were evaporated and the residue was mixed with cold water. Filtered the precipitate, washed with the cold water and hexane, dried in air to get the compound of the formula VI (91 gm, 72%)
21

Example 5: 3,4-Dihydro-4(S)-hydroxy-2H-theino [3,2-e] 1,2-thiazinel, 1 dioxide (VII)
To the solution of product from Example 4 (91 gm, 0.32 moles) in tetrahydrofuran (2725 ml) at -40°C added a solution of (+)-β-chlorodiisopinocampheyborane (306.8 gm, 0.96 moles) in hexane. Allowed the reaction mixture to warm to -20°C and maintained for 4 hours. 1 M NaOH solution (3200 ml) was added to reaction mass at 0°C and the solution was stirred for 10 hours at ambient temperature. Separated the two layers and aqueous layer back washed with toluene (910 ml). Acidified aqueous layer with acetic acid at 5°C and extracted by ethyl acetate (2X 910 ml). Washed the combined ethyl acetate layer with brine (500 ml), dried over sodium sulfate and concentrated to dryness under reduced pressure. Added hexane (200ml) and filtered the product, washed with hexane, dried in air to get the compound of the formula VII (50 gm, 75%).
Example 6: 3,4-Dihydro-4(S)-hydroxy-2-(3-methoxypropyl)-2H-theino[3,2-e] 1,2-thiazine-l,l-dioxide (VIII)
To the solution of product from Example 5 (50 gm, 0.24 moles) in acetone (1500 ml) was added anhydrous potassium carbonate (67gm, 0.48 moles), l-bromo-3-methoxy propane (44.8 g, 0.29 moles) and tetra butyl ammonium bromide (5 gm). The reaction mixture was refluxed for 24 hour. Cooled the reaction mixture to ambient temperature and filtered, washed with acetone (200 ml). Concentrated the filtrate to get oily residue, which further dissolved, in ethyl acetate (1000 ml). Washed the organic layer with cold 1M NaOH solution followed by water (500ml), dried over sodium sulfate and evaporated under reduced pressure to get compound of the formula VIII (58 gm. 87%) as oily syrup.
Example 7: 3,4-Dihydro-4(S)-hydroxy-2-(3-methoxypropyI)-2H-theino[3,2-e]-
22

l,2-thiazine-6-sulfonamide-l,l-dioxide (IX)
A solution of the compound from Example 6 (58 gm, 0.20 moles) in tetrahydrofuran (1500ml) was cooled to -60°C under nitrogen atmosphere. n-Butyl lithium (1160 ml of 1.6 M hexane solution) was added over 45 min while maintaining the temperature below -60°C. Stirred the mixture for 4 hours at the same temperature and then stirred for 1 hour at 0°C. Again cooled the reaction mixture to -65 °C and sulfur dioxide gas was bubbled through reaction mass at -65°C till the reaction mixture is acidic. The reaction mixture is stirred overnight while warming it to ambient temperature. Concentrated the reaction mixture to dryness on the rotary evaporator under reduced pressure to get the lithium sulfinate salt, which further dissolved in cold water (900 ml) and washed with ethyl acetate (116 ml). Cooled the solution to -5°C and added sodium acetate trihydrate (285 gm, 2.1 moles). Added hydroxyl amine-O- sulfonic acid (189 g, 1.67mol) slowly to reaction mass below 0°C. Stirred the reaction mass at ambient temperature overnight. Extracted the reaction mixture with ethyl acetate (2 X 1500 ml)) and washed the combined extracts with sodium bicarbonate solution, brine and dried over sodium sulfate. Evaporation to dryness gives a viscous oily compound of the formula IX (63 gm, 85%)
Example 8: 4(R)-Ethylamino-3,4-dmydro-2-(3-methoxypropyl)-2H-theino[3,2~ e]l,2-thiazine-6-sulfonamide-l,ldioxide(I)
To solution of the product from Example 7 (63 gm, 0.18 moles) and triethylamine (54 ml. 0.39 moles) in anhydrous tetrahydrofuran (630 ml) cooled to -20°C added tosyl chloride (68.5 gm, 0.36 moles). Allowed this mixture to warm to room temperature and stirred for 18 hours. Cooled the reaction mixture to -60°C and ethylamine 70% aqueous solution (242 ml) was added and the mixture was again allowed to warm to room to ambient temperature. After 18 hours cooled the reaction mixture to 5°C and
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concentrated hydrochloric acid solution (600 ml) was added drop wise over 1.5hours while temperature was kept below 10°C. The solution was extracted with diethyl ether (2 X 500 ml) and the combined extracts were back extracted with 1 M aqueous hydrochloride acid (4000 ml). The pH of the aqueous phase was adjusted to 8 using solid sodium bicarbonate causing a white solid to precipitate. After chilling for 2 hours, the solid was collected by filtration, washed with water and dried to constant weight of compound of the formula I (35 gm, 51.6%) Material recrystalised from 2-propanol had the following characteristics; mp 125-127T; NMR (DMSO-d()) 8 8.01 (s, 2H), 7.65 (s, 1H), 4.10-4.03 (m,lH), 3.87-3.76 (m, 2H), 3.47-3.33 ( m, 4H), 3.22 (s, 3H) , 3.20-3.09 (m, 1H), 2.59-2.49 (m, 2H), 1.86-1.74 (m, 2H), 1.10 (t, 311, J 7 Hz).
Example 9: 4(R)-Ethylamino-3,4-dihydro-2-(3-methoxypropyl)-2H-theino[3,2-e)-l,2-thiazine-l,ldioxide (X)
To solution of the product from Example 6 (58 gm, 0.21 moles) and triethylamine (58.1 ml. 0.42 moles) in anhydrous tetrahydrofuran (870 ml) cooled to -5 to 0°C was added solution of tosyl chloride (79.6 gm, 0.42 moles) in 80ml. Allowed this mixture to warm to room temperature and stirred for 18 hours. Cooled the reaction mixture to -5 to 0°C and added ethylamine 70% aqueous solution (502 ml). The mixture was again allowed to warm to ambient temperature. After 18 hours concentrated the reaction mixture and added ethyl acetate (200 ml). Washed organic layer with water 200 ml. Added 4M hydrochloric acid solution (700 ml) drop wise over 1.5hours while temperature was kept below 10°C. Washed the aqueous layer with ethyl acetate 200 ml). Adjusted pH of the aqueous phase to 8 using solid sodium bicarbonate to separate brown coloured oil. Added ethyl acetate 400 ml, separated the organic layer and washed with water. Dried organic layer with sodium sulphate and concentrated to constant weight of compound of the formula I (45 gm, 70%).
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Example 10: 3,4-dihydro-4(R)-ethylamino-2-(3-methoxypropyl)-2H-theino[3,2-e]l,2-thiazine-6-sulfonamide l, l dioxide (I)
A solution of the compound from step 9 (45 gm, 0.15 moles) in tetrahydrofuran (1350ml) was cooled to -60°C under nitrogen atmosphere. n-Butyl lithium (471ml of 1.6 M hexane solution) was added over 45 min while the temperature was maintained below -60°C. The mixture was stirred 1 hour at the same temperature and then stirred for 1 hour at 0°C. Again the reaction mixture was cooled to -65 °C and sulfur dioxide gas was bubbled through reaction mass at -65°C till the reaction mixture is acidic. The reaction mixture is stirred overnight while warming it to ambient temperature. Concentrated the reaction mixture to dryness on rotary evaporator under reduced pressure to get the lithium sulfinate salt, which further dissolved in cold water (900 ml) and washed with ethyl acetate (225 ml). Added sodium acetate trihydrate (122.4 gm, 0.9 moles) and cooled the solution to -5 to 0°C. Added hydroxyl amine-O-sulfonic acid (67.8 g, 0.6 mol) slowly to reaction mass below 0°C. Stirred the reaction mixture at ambient temperature overnight. Extracted the reaction mixture with ethyl acetate (2 X 1500 ml)) and washed the combined extracts with sodium bicarbonate solution, brine and dried over sodium sulfate. Evaporation to dryness gives a viscous compound of the formula I (23 gm, 42%). Material recrystalised from 2-propanol had the following characteristics NMR (DMSO-d6) d 8.01 (s, 2H), 7.65 (s, 1H), 4.10-4.03 (m,lH), 3.87-3.76 (m, 2H), 3.47-3.33 ( m, 4H), 3.22 (s, 3H) , 3.20-3.09 (m, 1H), 2.59-2.49 (m, 2H), 1.86-1.74 (m, 2H), 1.10 (t, 3H, J= 7 Hz).
Dated this the 13th day of October, 2006
Dr K G Rajendran
Head-Knowledge Cell
USV Limited
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Abstract:
The present invention relates to an improved process for the preparation of (R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-1,1 -dioxide commonly known as Brinzolamide. The present invention also relates to novel intermediates and process of preparation thereof.
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