# US 5,344,929 A · Preparation of carbonic anhydrase inhibitors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 5,344,929 A
- Document ID: US5344929A
- Status: Granted
- Kind: A
- Application number: 08/019,012
- Filed: 1993-02-18
- Granted: 1994-09-06
- Earliest claimed: 1993-02-18
- Assignees: Alcon Laboratories, Inc.
- Inventors: William D. Dean; Paul W. Zinke; Steven J. Sproull; Michael E. Deason; Raymond E. Conrow; Anura P. Dantanarayana
- Web page: https://patentgrep.com/patent/US5344929A

## CPC

- C07D 513/04: Ortho-condensed systems
- A61P 27/02: Ophthalmic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 333/34: Sulfur atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A process for synthesizing carbonic anhydrase inhibitors is disclosed.

## Claims

### Claim 1

A process for synthesis of compounds of formula ##STR7## wherein: R.sub.1 and R.sub.2 are both chosen from H or C.sub.1-4 alkyl; R.sub.3 =C.sub.1-6 alkyl or CH.sub.2 (CH.sub.2).sub.n OR.sub.4 where R.sub.4 =CH.sub.3 or (CH.sub.2).sub.n CH.sub.3 and n=1-4; or (CH.sub.2).sub.n Ar where Ar=unsubstituted phenyl, 3-methoxyphenyl, or 4methoxyphenyl and n=1 or 2 which comprises:
a. displacing the C(2)-chloro of 3-acetyl-2,5-dichlorothiophene with benzyl mercaptide to form 3-acetyl-5-chloro-2-(benzylthio)thiophene.
b. converting the compound formed in Step a to 3-acetyl-5-chloro-2-thiophenesulfonamide by first reacting the compound formed in Step a with chlorine to form 3-acetyl-5-chloro-2-thiophenesulfenyl chloride, followed by reaction with ammonia to form 3-acetyl-5-chloro-2-thiophenesulfenyl and oxidation to 3-acetyl-5-chloro-2-thiophenesulfonamide;
c. brominating the compound from Step b to provide 3-bromoacetyl-5-chloro-2-thiophenesulfonamide;
d. reducing the compound of Step c with an asymetric reducing agent and then treating it with aqueous base to form (S)-3,4-dihydro-6-chloro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxi de;
e. selectively alkylating the compound of Step d using a metal carbonate in dimethyl sulfoxide to provide (S)-3,4-dihydro-6-chloro-4-hydroxy-2-substituted-2H-thieno[3,2-e]-1,2-thia zine-1,1-dioxide;
f. forming (S)-3,4-dihydro-4-hydroxy-2-substituted-2H-thieno[3,2-e]-1,2-thiazine-6-su lfonamide-1,1-dioxide from the compound of Step e by first reacting with an alkyl lithium, then reacting the resulting anion with sulfur dioxide to form a lithium sulfinate, and then reacting the lithium sulfinate with hydroxylamine-O-sulfonic acid;
g. protecting the C(6)-sulfonamide of Step f, with trimethyl orthoacetate, activating the C(4)-hydroxyl and displacing it with an amine.

### Claim 2 (depends on 1)

The process of claim 1 wherein the extraction solvent used in step e is t-butyl methyl ether.

### Claim 3 (depends on 1)

The process of claim 1 wherein the halogen-metal exchange in step f is accomplished using n-butyllithium in tetrahydrofuran.

### Claim 4 (depends on 1)

The process of claim 1 wherein protection of the C(6)-sulfonamide in step g is accomplished using a lower alkyl orthoacetate in refluxing acetonitrile.

### Claim 5 (depends on 4)

The process of claim 4 wherein the lower alkyl orthoacetate is trimethyl orthoacetate.

### Claim 6 (depends on 1)

The process of claim 1 wherein activation of the C(4)-hydroxyl in step g is accomplished using p-toluenesulfonyl chloride and triethylamine in tetrahydrofuran.

### Claim 7 (depends on 1)

The process of claim 1 wherein benzyl mercaptide in step a is generated by reaction of thiourea with benzyl chloride followed by treatment with aqueous sodium hydroxide.

### Claim 8 (depends on 1)

The process of claim 1 wherein the displacement reaction in step a is carried out in a mixture of ethanol and aqueous sodium hydroxide.

### Claim 9 (depends on 1)

The process of claim 1 wherein conversion of 3-acetyl-2,5-dichlorothiophene to the intermediate 3-acetyl-5-chloro-2-thiophenesulfenyl chloride in step b is accomplished using chlorine in ethyl acetate.

### Claim 10 (depends on 1)

The process of claim 1 wherein conversion of the intermediate 3-acetyl-5-chloro-2-thiophenesulfenyl chloride to the intermediate 3-acetyl-5-chloro-2-thiophenesulfenamide in step b is accomplished using ammonia in ethyl acetate.

### Claim 11 (depends on 1)

The process of claim 1 wherein conversion of the intermediate 3-acetyl-5-chloro-2-thiophenesulfenamide to 3-acetyl-5-chloro-2-thiophenesulfonamide in step b is accomplished using sodium tungstate dihydrate in a mixture of aqueous hydrogen peroxide and ethyl acetate.

### Claim 12 (depends on 1)

The process of claim 1 wherein conversion of 3-acetyl-5-chloro-2-thiophenesulfonamide to 3-bromoacetyl-5-chloro-2-thiophenesulfonamide in step c is accomplished using pyridinium bromide perbromide.

### Claim 13 (depends on 12)

The process of claim 12 wherein the reaction solvent is ethyl acetate.

### Claim 14 (depends on 12)

The process of claim 12 wherein sulfuric acid is used as an acid catalyst.

### Claim 15 (depends on 1)

The process of claim 1 wherein the reducing agent in Step d is (+)-.delta.-chlorodisopinocampheylborane.

### Claim 16 (depends on 15)

The process of claim 15 wherein the reaction solvent is t-butyl methyl ether.

### Claim 17 (depends on 1)

The process of claim 1 wherein cyclization of the intermediate bromohydrin obtained by reduction of 3-bromoacetyl-5-chloro-2-thiophenesulfonamide in step d is accomplished by addition of aqueous sodium hydroxide directly to the reaction mixture.

### Claim 18 (depends on 1)

The process of claim 1 wherein the alkylation in step e is accomplished using an appropriate alkylating agent and potassium carbonate in dimethylsulfoxide.

### Claim 19 (depends on 1)

The process of claim 1 wherein the alkylating agent in step e is 1-bromo-2-methoxyethane.

### Claim 20 (depends on 1)

The process of claim 1 wherein alkylating agent in step e is 1-bromo-3-methoxyethane.

### Claim 21 (depends on 1)

The process of claim 1 wherein the alkylating agent in step e is 1-bromo-4-methoxybutane.