Brinzolamide

Crystalline SolidBrinzolamide was introduced as Azopt in the US for the treatment of elevated intraocular pressure (IOP) in patients with ocular hypertension or openangle glaucoma. Brinzolamide is a potent inhibitor of human carbonic anhydrase Ⅱ lowering IOP after topical administration . It is the second of this class after dorzolamide (1995). Brinzolamide can be prepared in an eight-step sequence from 3-acetyl-2,5-dichlorothiophene. In patients with primary open-angle glaucoma or ocular

Solid

Brinzolamide is a sulfonamide and a thienothiazine. It has a role as an antiglaucoma drug and an EC 4.2.1.1 (carbonic anhydrase) inhibitor.|Brinzolamide is a highly specific, non-competitive, reversible carbonic anhydrase inhibitor. Carbonic anhydrase (CA) is an enzyme found in many tissues of the body including the eye. It catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. In humans, carbonic anhydrase exists as a number of isoenzymes, the most active being carbonic anhydrase II (CA-II). Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. The result is a reduction in intraocular pressure. Brinzolamide is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.|Brinzolamide is a Carbonic Anhydrase Inhibitor. The mechanism of action of brinzolamide is as a Carbonic Anhydrase Inhibitor.|Brinzolamide is a sulfonamide and carbonic anhydrase inhibitor with specific affinity for carbonic anhydrase II. Following topical ocular administration, brinzolamide inhibits carbonic anhydrase II, an enzyme that is responsible for the movement of sodium and fluid transport in the eye. This inhibition leads to a decrease in aqueous humor secretion, probably by slowing the formation of bicarbonate ions, and results in a reduction in intraocular pressure. Brinzolamide is used to treat increased pressure in the eye caused by open-angle glaucoma.

Thiourea (1.287kg, 16.93mol), benzyl chloride (1.858L, 2.044kg, 16.14mol), 13.5L of ethanol and 4.5L of water were refluxed together for 2h. In 20min, cool to 74°C. 3-Acetyl-2, 5-dichlorothiophene (3.0 kg, 15.38mol) and 10 L of 4 mol/L sodium hydroxide aqueous solution were sequentially added. Reflux for 3h until the reaction is complete and cool to room temperature overnight. Then add 10L of water and stir for 30min, then add 3L of 5.25% sodium hypochlorite solution and stir for 30min. The solid was collected by filtration, washed with 4×2.5L of water and 3×2L of isopropanol, and dried to constant weight in the air at room temperature to obtain 4.224kg of compound (I) with a yield of 97% and a melting point of 86-88°C. Compound (I) (1kg, 3.53mol) was dissolved in 20L of ethyl acetate, and at a temperature of 2-10°C under stirring, chlorine gas was introduced until no compound (I) was detected. Blow with a large air flow for 1 h, and then introduce ammonia gas to maintain the temperature of 5 ~ 15 ℃, the reaction until the intermediate product sulfinyl chloride is completely converted. Blow with air for another 1h, add 5L of water and cool to 15°C. Add sodium tungstate trihydrate (583g, 1.77mol), then add 8L of 30% hydrogen peroxide in 5min. The mixture was stirred at 35°C for 2h and then at room temperature for 16h. Add 5L of water, separate the organic layer, and then add 5L of water. Sodium bisulfite was added until no peroxide was detected, and the organic layer was separated, washed first with saturated sodium bicarbonate to Ph value 8, and then washed with saturated brine. Dry, filter, concentrate, add tert-butyl methyl ether to the residue, collect the solid by filtration, wash with tert-butyl methyl ether, and dry to constant weight in the air to obtain 597g of compound (II), yield 71%, melting point 178 ~179°C. Compound (II) (1.087kg, 4.55mol) was dissolved in 22L of ethyl acetate, and 90% hydrobromopyridine bromide anchor (1.305kg, 3.67mol) was added under ice bath cooling. 544ml of sulfuric acid was added in 10min to raise the temperature to 5°C. After stirring for 1 h until the reaction was complete, it was stirred for another 30 min. Add 5L of water and stir for 5min. The organic layer was separated and washed with 4×5 L of saturated saline until the Ph value of the washing solution was 3. Dry, filter, and concentrate. Add 2 L of dichloromethane to the residue and freeze for 15 min. The solid was collected by filtration and dried to constant weight in air at room temperature to obtain 1.041 kg of compound (III), with a yield of 72% and a melting point of 147-148°C. Under the protection of nitrogen, compound (III) (4855g, 2.68mol) and 12.5L of tert-butyl methyl ether were added to the reaction flask, and the mixture was cooled to -40°C with stirring. In 30min, add 4.5L of 1.2mol/L, (+)-β-chlorodiisobornanyl boron tert-butyl methyl ether solution. Stir for 3.5 h at -25 to -20°C until the reaction is complete, and rise to 0°C. Add 11 L of 1 mol/L sodium hydroxide aqueous solution in 10 min to raise the temperature to 22°C. Stir vigorously at room temperature for 2h, and separate the organic layer. The aqueous layer was extracted with 3L tert-butyl methyl ether, and the remaining aqueous layer was acidified with concentrated hydrochloric acid to Ph value 1, and then extracted with 2×4L ethyl acetate. The ethyl acetate extract was washed with 3L saturated brine, dried, filtered and concentrated. Add 2L of toluene, collect the crystals by filtration, wash with 2L of toluene, and then wash with 2L of dichloromethane, and dry to constant weight in air at room temperature to obtain 498g of compound (IV), yield. 77%, melting point 126～127℃. Compound (IV) (5350g, 1.46mo1), 1.75L of dimethyl sulfoxide and potassium carbonate (605g, 4.38mo1) were mixed, and 1-bromo-3-methoxypropane (268g, 1.75mo1) was added in 8-part intervals of 1h . After completion of the reaction, the reaction is complete, about 1.5h. With stirring, the reaction solution was poured into 18 L of saturated brine, and the original reactor was washed with water and tert-butyl methyl ether. The reaction liquid and the washing liquid were combined and extracted with 2×4 L of tert-butyl methyl ether. The extract was washed with 2L 1mol/L sodium hydroxide aqueous solution, 2L 1:1 sodium hypochlorite/water, and 2L saturated saline. After filtering and distilling out most of the solvent, it was concentrated under reduced pressure at 50°C. 427g of compound (V) was obtained in 94% yield as a light yellow oil. Under the protection of nitrogen, compound (V) (1.065kg, 3.42mol) was added to 27L of dry tetrahydrofuran, cooled to -70℃, and in 2.5h, 3.08L of 2.5mol/L n-butyl lithium in hexane was added dropwise , Maintain the temperature of the reaction liquid below -66 ℃. After reacting for 1h, sulfur dioxide was passed to Ph value 4. Let the temperature rise to room temperature and leave overnight. It was concentrated and the residue was dissolved in 5L of water. This was added to a solution of sodium acetate trihydrate (2.796kg, 20.5mol) at 0°C and hydroxylamine-O-sulfonic acid (1.549kg, 13.7mol) dissolved in 6L of water to raise the temperature to 25°C. After stirring at room temperature for 15 h, it was extracted with 3×4 L of ethyl acetate. The extract was first washed with saturated sodium bicarbonate solution until the washing liquid became alkaline, and then washed with saturated brine. Dry, filter, and concentrate. 6L of dichloromethane was added to the residue, and 5g of seed crystals were added to crystallize. The crystals were collected by filtration, washed with methylene chloride, and dried to constant weight in air at room temperature. 748 g of compound (VI) was obtained with a yield of 61% and 111-113°C. Compound (VI) (28.5g, 0.08mol), 285ml of acetonitrile and 23.4ml of trimethyl orthoacetate were mixed and refluxed for 16h. After cooling for 1 hour, the solvent was distilled off, and the residue was dissolved in 150 ml of dry tetrahydrofuran. Under the protection of nitrogen, 24.5ml of triethylamine and 30.5g of p-toluenesulfonyl chloride were added at 4°C, and stirred at 4-7°C for 2h. 70% ethylamine (260ml, 2.80mol) was added dropwise in 30min, maintaining the temperature below 15°C. After the addition is complete, stir at room temperature for 18.5 h. Cool to 5℃, add 280ml of concentrated hydrochloric acid dropwise in 1h to maintain the temperature below 30℃. Extract with 2 x 250 ml of ether, and extract with 200 ml of 1 mol/L hydrochloric acid. The hydrochloric acid extract was adjusted to Ph value 8 with solid sodium bicarbonate and frozen for 2h. The crystals were collected by filtration and washed with water. The filtrate also contained product, which was extracted with ethyl acetate. The crystals obtained above are dissolved in the extract, and ethyl acetate may be added. Dry, filter, and concentrate. 24.0 g of product was obtained with a yield of 78%. Can be recrystallized with isopropyl alcohol, melting point 125 ~ 127 ℃.

For the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Molecular Weight:383.5
XLogP3:-0.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:9
Rotatable Bond Count:7
Exact Mass:383.06433430
Monoisotopic Mass:383.06433430
Topological Polar Surface Area:164
Heavy Atom Count:23
Complexity:598
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes