138890-62-7

Basic information

• Product Name: Brinzolamide
• Synonyms: H-Thieno[3,2-e]-1,2-thiazine-6-sulfonamide, 4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-, 1,1-dioxide, (4R)-;Brinzolamide (R)-4-(Ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;(5R)-5-Ethylamino-3-(3-methoxypropyl)-2,2-dioxo-2?6,9-dithia-3-azabicyclo[4.3.0]nona-7,10-diene-8-sulfonamide;ANTI-GAGE7 (C-TERM) antibody produced in rabbit;Cancer/testis antigen 4.7;CT4.7;G antigen 7;GAGE-12I
• CAS NO: 138890-62-7
• Molecular Formula: C₁₂H₂₁N₃O₅S₃
• Molecular Weight: 383.51
• EINECS: 1308068-626-2
• Product Categories: Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals;Brinzolamide;BETOPTIC
• Mol File: 138890-62-7.mol
• Article Data: 11

Chemical Properties

• Melting Point: 130.0 to 134.0 °C
• Boiling Point: 586 °C at 760mmHg
• Flash Point: 308.2 °C
• Appearance: white to beige/
• Density: 1.5 g/cm³
• Vapor Pressure: 1.03E-13mmHg at 25°C
• Refractive Index: 1.625
• Storage Temp.: ?20°C
• Solubility: DMSO: ≥10mg/mL
• PKA: 9.62±0.40(Predicted)
• Merck: 14,1376
• CAS DataBase Reference: Brinzolamide(CAS DataBase Reference)
• NIST Chemistry Reference: Brinzolamide(138890-62-7)
• EPA Substance Registry System: Brinzolamide(138890-62-7)

Safety Data

• WGK Germany: 3
• RTECS: XJ9095055
• Hazardous Substances Data: 138890-62-7(Hazardous Substances Data)

Usage

Description

Brinzolamide is a carbonic anhydrase inhibitor developed by Alcon (now Novartis) as a treatment for primary and open-angle glaucoma and ocular hypertension. It was First approval in the United States in 1998 under the trade name Azopt. It is the second of this class after dorzolamide (1995). Brinzolamide was approved as a generic medication in the United States in November 2020.Brinzolamide is a white powder commercially formulated as a 1% ophthalmic suspension to reduce intraocular pressure (IOP). In patients with primary open-angle glaucoma or ocular hypertension, brinzolamide produced significant reductions in IOP and showed less ocular discomfort than dorzolamide.

Chemical Properties

Brinzolamide has a molecular weight of 383.5 and a melting point of about 131°C. It is a white powder or crystalline Solid, which is insoluble in water, very soluble in methanol and soluble in ethanol.

Originator

Alcon (US)

Uses

Different sources of media describe the Uses of 138890-62-7 differently. You can refer to the following data:
1. 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.
2. Brinzolamide has been used as a melanin binding compound or drug in melanin binding assays. It has also been used as a carbonic anhydrase inhibitor (CAI).

Definition

ChEBI: 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.

Preparation

Brinzolamide synthesis method: using thiophene as raw material, 3-acetyl-2,5-dichlorothiophene (4) is obtained by chlorination and acetylation, and 4 is reacted with sodium benzyl sulfide to obtain 6,6, which is chlorinated and ammoniated. Chemical and oxidation reactions "one-pot" synthesis of 7, Carbon-based α-hydrobromination of 7 with Pyridinium tribromide gives 9,9 is asymmetrically reduced under the action of (+)-Ipc2BCl to obtain 11, which is then subjected to N-alkylation and sulfonamidation to generate (S)-3,4-dihydro-4-hydroxy-2-(3-methoxyl propyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide, the sulfonamide group was protected with trimethyl orthoacetate to give 15 , first introduce p-toluenesulfonyl group and then replace it with ethylamino group, and remove the sulfonamide group protecting group to obtain brinzolamide. The synthesis of intermediate 4 in this route is convenient, and each step of the reaction does not require column chromatography, and the total yield is 13.4%.Graphical Synthetic Routes of Olanzapine

Indications

Brinzolamide, a heterocyclic sulfonamide, is a topical CAI suspension that has a high affinity for the carbonic anhydrase II isoenzyme.Because the ocular hypotensive effect of the drug is equivalent whether dosed twice or three times daily, brinzolamide 1% may be administered twice daily.

Brand name

Azopt (Alcon).

Therapeutic Function

Antiglaucoma

General Description

Brinzolamide is a small molecular weight compound that has an ability to bind melanin. This drug is used in ocular therapy.

Biochem/physiol Actions

Brinzolamide is a carbonic anhydrase II inhibitor used to lower intraocular pressure.

Clinical Use

Brinzolamide is indicated for the treatment of elevated IOP in patients with ocular hypertension or open-angle glaucoma.The drug is commercially available as a sterile 1.0% aqueous suspension with a pH of approximately 7.5. BAC 0.01% is added as a preservative. The efficacy and safety of brinzolamide 1%, either two or three times daily, were evaluated in 572 patients with open-angle glaucoma or ocular hypertension against timolol 0.5% twice daily and dorzolamide 2.0% three times daily. Mean IOP changes were -3.8 to -5.7 mm Hg, -4.2 to -5.6 mm Hg, and-4.3 to-5.9 mm Hg for two- and three-times-daily brinzolamide and dorzolamide dosing, respectively. The mean IOP changes for timolol 0.5% ranged from -5.6 to -6.3 mm Hg (Figure 10-15). Brinzolamide was well tolerated, with 1.8% (twice daily) and 3% (three times daily) of patients reporting ocular discomfort versus 16.4% with dorzolamide. Complaints of blurred vision were higher with brinzolamide (5–6%) than dorzolamide (1%) or timolol (0%). A meta-analysis of randomized clinical trials reported peak ocular hypotensive effect on IOP of 17% (19% to 15%) and trough effect of 17% (19% to 15%).

Side effects

Both brinzolamide and dorzolamide exhibit similar taste abnormalities. A single case report of the development of metabolic acidosis from topical brinzolamide has been described after twice-daily dosing. Other adverse events are negligible for brinzolamide except for some blurring of vision, attributable to its suspension vehicle.

Veterinary Drugs and Treatments

Brinzolamide is chemically similar to dorzolamide and reduces aqueous humor production by altering H+/Na+ active transport mechanisms associated with aqueous humor production in the ciliary epithelial cells. It can be used as a substitute for dorzolamide and some patients that exhibit excessive topical irritation following application of dorzolamide drops, tolerate brinzolamide better or vice versa. Cats seem to be particularly sensitive to irritation from topical dorzolamide and often brinzolamide can be used in these patients. Comparative data is available suggesting that brinzolamide and dorzolamide are equally effective in animal patients.

Precautions

Brinzolamide has the same contraindications and precautions as dorzolamide.

references

[1] desantis l. preclinical overview of brinzolamide. surv ophthalmol. 2000 jan;44 suppl 2:s119-29.

InChI:InChI=1/C12H21N3O5S3/c1-3-14-10-8-15(5-4-6-20-2)23(18,19)12-9(10)7-11(21-12)22(13,16)17/h7,10,14H,3-6,8H2,1-2H3,(H2,13,16,17)/t10-/m0/s1

Synthetic route

C21H29N3O8S4 → brinzolamide (138890-62-7)

Conditions	Yield
With sodium thiomethoxide In methanol at 0 - 25℃; for 12h; Reagent/catalyst;	83%

C21H29N5O9S4 → brinzolamide (138890-62-7)

Conditions	Yield
With sodium tetradecyl mercaptan In methanol at 0 - 25℃; Reagent/catalyst;	81%

C11H18N2O8S4 + ethylamine (75-04-7) → brinzolamide (138890-62-7)

Conditions	Yield
In tetrahydrofuran; water at 0 - 30℃;	66.3%

(R)-3,4-dihydro-4-ethylamino-6-chloro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide hydrochloride → brinzolamide (138890-62-7)

Conditions	Yield
Stage #1: (R)-3,4-dihydro-4-ethylamino-6-chloro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide hydrochloride With sodium hydrogencarbonate Stage #2: With n-butyllithium In tetrahydrofuran; hexane at -40℃; for 1h;	63%

C20H26N2O9S4 + ethylamine (75-04-7) → brinzolamide (138890-62-7)

Conditions	Yield
In water at 11 - 20℃; for 15h; enantioselective reaction;	61%
Stage #1: C20H26N2O9S4; ethylamine In water at 10 - 12℃; for 15h; Stage #2: With hydrogenchloride In water at 20℃; for 1h; Temperature;	2.4 g

(R)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide (165117-54-4) + ethylamine (75-04-7) → brinzolamide (138890-62-7)

Conditions	Yield
Stage #1: (R)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide With zinc(II) tosylate; triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20 - 80℃; for 8h; Stage #2: ethylamine In tetrahydrofuran at 0 - 20℃; for 36h; Product distribution / selectivity;	49%
Stage #1: (R)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide With zinc(II) tosylate; triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20 - 80℃; Stage #2: ethylamine In tetrahydrofuran at 0 - 20℃;

(S)-3,4-dihydro-4-hydroxy-2(3-methoxypropyl)-4H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide (154127-42-1) + ethylamine (75-04-7) → brinzolamide (138890-62-7)

Conditions	Yield
Stage #1: (S)-3,4-dihydro-4-hydroxy-2(3-methoxypropyl)-4H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide With toluene-4-sulfonic acid; triethylamine In tetrahydrofuran at 0 - 20℃; for 18h; Stage #2: ethylamine In tetrahydrofuran at 0 - 20℃; for 36h;
Stage #1: (S)-3,4-dihydro-4-hydroxy-2(3-methoxypropyl)-4H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide With triethylamine; p-toluenesulfonyl chloride In tetrahydrofuran at 0 - 20℃; for 18h; Stage #2: ethylamine In tetrahydrofuran at 0 - 20℃;

C12H19N2O5S3(1-)*Li(1+) → brinzolamide (138890-62-7)

Conditions	Yield
With sodium acetate; hydroxylamine-O-sulfonic acid In hexane at 0 - 20℃; Product distribution / selectivity;

(R)-3,4-dihydro-4-(N-ethylamino)-2-(3-methoxy)propyl-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (1029324-92-2) → brinzolamide (138890-62-7)

Conditions	Yield
Stage #1: (R)-3,4-dihydro-4-(N-ethylamino)-2-(3-methoxy)propyl-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide With n-butyllithium In tetrahydrofuran; hexane at -60℃; for 8.75h; Inert atmosphere; Stage #2: With sulfur dioxide In tetrahydrofuran; hexane at -65 - 20℃; Stage #3: With sodium acetate trihydrate; hydroxylamine-O-sulfonic acid In ethyl acetate at 0 - 20℃;

brinzolamide → brinzolamide (138890-62-7)

Conditions	Yield
With chiral-prep-HPLC (Chiralpak IA0.46x15 cm, 5 umChiral-A (IA)002IA00CD-LF007) Resolution of racemate;

(S)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-4H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (160982-13-8) → brinzolamide (138890-62-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / tetrahydrofuran / 0 - 20 °C 2.1: water; tetrahydrofuran / 0 - 20 °C 2.2: pH 1 - 3 3.1: sodium hydrogencarbonate 3.2: 1 h / -40 °C View Scheme
Multi-step reaction with 4 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 3.5 h / -70 - -66 °C / Inert atmosphere 1.2: 20 °C / pH 4 1.3: 15 h / 0 - 25 °C 2.1: acetonitrile / 19 h / 30 - 85 °C / Reflux 3.1: triethylamine / tetrahydrofuran / 2 h / -10 - -2 °C / Inert atmosphere 4.1: water / 15 h / 11 - 20 °C View Scheme

C17H20ClNO6S3 → brinzolamide (138890-62-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: water; tetrahydrofuran / 0 - 20 °C 1.2: pH 1 - 3 2.1: sodium hydrogencarbonate 2.2: 1 h / -40 °C View Scheme

(R)-(+)-4-ethylamino-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide maleate (1448780-04-8) → brinzolamide (138890-62-7)

Conditions	Yield
With triethylamine In water at 25 - 30℃; for 2h; pH=7 - 8.5;	45 g

Brinzolamide hydrochloride (150937-43-2) → brinzolamide (138890-62-7)

Conditions	Yield
With triethylamine In water at 25 - 30℃; for 2h; pH=7 - 8.5;	500 g

C13H20N2O7S3 → brinzolamide (138890-62-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 2 h / -10 - -2 °C / Inert atmosphere 2: water / 15 h / 11 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: triphenylphosphine; di-isopropyl azodicarboxylate / dichloromethane / 15 h / 0 - 20 °C / Inert atmosphere 2: sodium thiomethoxide / methanol / 12 h / 0 - 25 °C View Scheme

3-acetyl-5-chloro-2-thiophenesulfenamide → brinzolamide (138890-62-7)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: sodium tungstate (VI) dihydrate; dihydrogen peroxide / water / 19 h / 15 - 35 °C 2.1: pyridinium hydrobromide perbromide; sulfuric acid / ethyl acetate / 1.5 h / 1 - 5 °C / Large scale 3.1: B-chlorodiisopinocampheylborane / tert-butyl methyl ether / 3.5 h / -40 - -32 °C / Inert atmosphere 3.2: 2 h / 0 - 22 °C 4.1: potassium carbonate / dimethyl sulfoxide 5.1: n-butyllithium / hexane; tetrahydrofuran / 3.5 h / -70 - -66 °C / Inert atmosphere 5.2: 20 °C / pH 4 5.3: 15 h / 0 - 25 °C 6.1: acetonitrile / 19 h / 30 - 85 °C / Reflux 7.1: triethylamine / tetrahydrofuran / 2 h / -10 - -2 °C / Inert atmosphere 8.1: water / 15 h / 11 - 20 °C View Scheme

3-acetyl-5-chloro-2-thiophenesulfonamide → brinzolamide (138890-62-7)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: pyridinium hydrobromide perbromide; sulfuric acid / ethyl acetate / 1.5 h / 1 - 5 °C / Large scale 2.1: B-chlorodiisopinocampheylborane / tert-butyl methyl ether / 3.5 h / -40 - -32 °C / Inert atmosphere 2.2: 2 h / 0 - 22 °C 3.1: potassium carbonate / dimethyl sulfoxide 4.1: n-butyllithium / hexane; tetrahydrofuran / 3.5 h / -70 - -66 °C / Inert atmosphere 4.2: 20 °C / pH 4 4.3: 15 h / 0 - 25 °C 5.1: acetonitrile / 19 h / 30 - 85 °C / Reflux 6.1: triethylamine / tetrahydrofuran / 2 h / -10 - -2 °C / Inert atmosphere 7.1: water / 15 h / 11 - 20 °C View Scheme

3-(2-Bromoacetyl)-5-chloro-thiophene-2-sulfonamide → brinzolamide (138890-62-7)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: B-chlorodiisopinocampheylborane / tert-butyl methyl ether / 3.5 h / -40 - -32 °C / Inert atmosphere 1.2: 2 h / 0 - 22 °C 2.1: potassium carbonate / dimethyl sulfoxide 3.1: n-butyllithium / hexane; tetrahydrofuran / 3.5 h / -70 - -66 °C / Inert atmosphere 3.2: 20 °C / pH 4 3.3: 15 h / 0 - 25 °C 4.1: acetonitrile / 19 h / 30 - 85 °C / Reflux 5.1: triethylamine / tetrahydrofuran / 2 h / -10 - -2 °C / Inert atmosphere 6.1: water / 15 h / 11 - 20 °C View Scheme

3-acetyl-2,5-dichlorothiophene (36157-40-1) → brinzolamide (138890-62-7)

Conditions

Yield

Multi-step reaction with 11 steps 1.1: thiourea / ethanol; water / 2 h / Reflux; Large scale 1.2: 3 h / Reflux; Large scale 2.1: chlorine / toluene / 0.42 h / 8 °C / Cooling with ice 3.1: ammonia / 1 h / 5 - 15 °C 4.1: sodium tungstate (VI) dihydrate; dihydrogen peroxide / water / 19 h / 15 - 35 °C 5.1: pyridinium hydrobromide perbromide; sulfuric acid / ethyl acetate / 1.5 h / 1 - 5 °C / Large scale 6.1: B-chlorodiisopinocampheylborane / tert-butyl methyl ether / 3.5 h / -40 - -32 °C / Inert atmosphere 6.2: 2 h / 0 - 22 °C 7.1: potassium carbonate / dimethyl sulfoxide 8.1: n-butyllithium / hexane; tetrahydrofuran / 3.5 h / -70 - -66 °C / Inert atmosphere 8.2: 20 °C / pH 4 8.3: 15 h / 0 - 25 °C 9.1: acetonitrile / 19 h / 30 - 85 °C / Reflux 10.1: triethylamine / tetrahydrofuran / 2 h / -10 - -2 °C / Inert atmosphere 11.1: water / 15 h / 11 - 20 °C View Scheme

(S)-3,4-dihydro-6-chloro-4-hydroxy-4H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide → brinzolamide (138890-62-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium carbonate / dimethyl sulfoxide 2.1: n-butyllithium / hexane; tetrahydrofuran / 3.5 h / -70 - -66 °C / Inert atmosphere 2.2: 20 °C / pH 4 2.3: 15 h / 0 - 25 °C 3.1: acetonitrile / 19 h / 30 - 85 °C / Reflux 4.1: triethylamine / tetrahydrofuran / 2 h / -10 - -2 °C / Inert atmosphere 5.1: water / 15 h / 11 - 20 °C View Scheme

3-Acetyl-2-(phenylmethyl)thio-5-chlorothiophene (160982-09-2) → brinzolamide (138890-62-7)

Conditions

Yield

Multi-step reaction with 10 steps 1.1: chlorine / toluene / 0.42 h / 8 °C / Cooling with ice 2.1: ammonia / 1 h / 5 - 15 °C 3.1: sodium tungstate (VI) dihydrate; dihydrogen peroxide / water / 19 h / 15 - 35 °C 4.1: pyridinium hydrobromide perbromide; sulfuric acid / ethyl acetate / 1.5 h / 1 - 5 °C / Large scale 5.1: B-chlorodiisopinocampheylborane / tert-butyl methyl ether / 3.5 h / -40 - -32 °C / Inert atmosphere 5.2: 2 h / 0 - 22 °C 6.1: potassium carbonate / dimethyl sulfoxide 7.1: n-butyllithium / hexane; tetrahydrofuran / 3.5 h / -70 - -66 °C / Inert atmosphere 7.2: 20 °C / pH 4 7.3: 15 h / 0 - 25 °C 8.1: acetonitrile / 19 h / 30 - 85 °C / Reflux 9.1: triethylamine / tetrahydrofuran / 2 h / -10 - -2 °C / Inert atmosphere 10.1: water / 15 h / 11 - 20 °C View Scheme

(S)-3,4-dihydro-4-hydroxy-2(3-methoxypropyl)-4H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide (154127-42-1) → brinzolamide (138890-62-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetonitrile / 19 h / 30 - 85 °C / Reflux 2: triethylamine / tetrahydrofuran / 2 h / -10 - -2 °C / Inert atmosphere 3: water / 15 h / 11 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / acetonitrile / 5 h / 78 °C 2.1: triethylamine / tetrahydrofuran / 3 h / -10 - -4 °C 3.1: water / 15 h / 10 - 12 °C 3.2: 1 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: acetonitrile / 1 h / 5 - 15 °C / Inert atmosphere 2: triphenylphosphine; di-isopropyl azodicarboxylate / ethyl acetate / 15 h / 0 - 20 °C / Inert atmosphere 3: sodium tetradecyl mercaptan / methanol / 0 - 25 °C View Scheme
Multi-step reaction with 3 steps 1: acetonitrile / 1 h / 5 - 15 °C / Inert atmosphere 2: triphenylphosphine; di-isopropyl azodicarboxylate / dichloromethane / 15 h / 0 - 20 °C / Inert atmosphere 3: sodium thiomethoxide / methanol / 12 h / 0 - 25 °C View Scheme

3-acetyl-5-chloro-2-thiophenesulfenyl chloride → brinzolamide (138890-62-7)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: ammonia / 1 h / 5 - 15 °C 2.1: sodium tungstate (VI) dihydrate; dihydrogen peroxide / water / 19 h / 15 - 35 °C 3.1: pyridinium hydrobromide perbromide; sulfuric acid / ethyl acetate / 1.5 h / 1 - 5 °C / Large scale 4.1: B-chlorodiisopinocampheylborane / tert-butyl methyl ether / 3.5 h / -40 - -32 °C / Inert atmosphere 4.2: 2 h / 0 - 22 °C 5.1: potassium carbonate / dimethyl sulfoxide 6.1: n-butyllithium / hexane; tetrahydrofuran / 3.5 h / -70 - -66 °C / Inert atmosphere 6.2: 20 °C / pH 4 6.3: 15 h / 0 - 25 °C 7.1: acetonitrile / 19 h / 30 - 85 °C / Reflux 8.1: triethylamine / tetrahydrofuran / 2 h / -10 - -2 °C / Inert atmosphere 9.1: water / 15 h / 11 - 20 °C View Scheme

brinzolamide → (S)-brinzolamide + brinzolamide (138890-62-7)

Conditions	Yield
With AmyCoat [tris(3,5-dimethylphenylcarbamate)amylose] (150 x 46 mm id) chiral column In hexane; isopropyl alcohol at 25℃; Reagent/catalyst; Resolution of racemate;

(S)-2-[(1,1-dimethylethyl)diphenylsilyl]oxypropanoic acid (125941-75-5) + brinzolamide (138890-62-7) → (2S)-2-[(tert-butyldiphenylsilyl)oxy]-N-{[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ6-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}propanamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	76%

(S)-2-(tert-butyldiphenylsilanyloxy)propionic acid (S)-1-((S)-1-carboxyethoxycarbonyl)ethyl ester + brinzolamide (138890-62-7) → (2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ6-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl (2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	76%

(2S)-2-{[(2S)-2-{[(2S)-2-(acetyloxy)propanoyl]oxy}propanoyl]oxy}propanoic acid + brinzolamide (138890-62-7) → (2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ6-thieno[3,2-c][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl (2S)-2-(acetyloxy)propanoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	75%

(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-[(tert butyldiphenylsilyl)oxy]propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoic acid + brinzolamide (138890-62-7) → C64H87N3O29S3Si

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	74%

(S)-2-(tert-butyldiphenylsilanyloxy)propionic acid (S)-1-{(S)-1-[(S)-1-((S)-1-carboxyethoxycarbonyl)ethoxycarbonyl]ethoxycarbonyl}ethyl ester + brinzolamide (138890-62-7) → C43H59N3O15S3Si

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	68.6%

brinzolamide (138890-62-7) → (R)-4-(ethylamino)-2-(3-hydroxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide1,1-dioxide (186377-56-0)

Conditions	Yield
With boron tribromide In dichloromethane at -78 - 25℃; for 24.1667h; Inert atmosphere;	66%
Stage #1: brinzolamide With boron tribromide In dichloromethane at -78 - 20℃; for 24.16h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide	66%

(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid (S)-1-carboxy-ethyl ester + brinzolamide (138890-62-7) → (1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ6-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethyl (2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	65%

(S)-2-(tert-butyl-diphenyl-silanyloxy)-propionic acid (S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)-ethoxycarbonyl]-ethyl ester + brinzolamide (138890-62-7) → (2S)-1-{[(2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ6-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl (2S)-2-[(tert-butyldiphenylsilyl)oxy]propanoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	65%

succinic acid (S)-1-{(S)-1-[(S)-1-((S)-1-carboxyethoxycarbonyl)ethoxycarbonyl]ethoxycarbonyl}ethyl ester 3-[1-[4-(2-diethylaminoethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl ester + brinzolamide (138890-62-7) → (3Z)-3-[(4-{[2-(diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl (2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ6-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl butanedioate

Conditions	Yield
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 2h; Inert atmosphere;	46%

(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-[(tert butyldiphenylsilyl)oxy]propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoic acid + brinzolamide (138890-62-7) → C58H79N3O25S3Si

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	44.3%

(2S)‐2‐{[(2S)‐2‐(acetyloxy)propanoyl]oxy}propanoic acid + brinzolamide (138890-62-7) → (S)-2-acetoxypropionic acid (S)-2-[4-ethylamino-2-(3-methoxypropyl)-1,1-dioxo-1,2,3,4-tetrahydro-1λ*6*-thieno[3,2-e][1,2]thiazine-6-sulfonylamino]-1-methyl-2-oxoethyl ester

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	37%

octadecanoic acid (S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxy-ethoxycarbonyl)ethoxycarbonyl]ethoxycarbonyl}ethoxycarbonyl)ethoxycarbonyl]ethyl ester + brinzolamide (138890-62-7) → (2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1{[(2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ6-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl octadecanoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	35%

(S)-2-[(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-acetoxypropionyloxy)propionyloxy]propionyloxy}propionyloxy)propionyloxy]-propionic acid + brinzolamide (138890-62-7) → (2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ6-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl (2S)-2-(acetyloxy)propanoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	32%

octadecanoic acid (S)-1-{(S)-1-[(S)-1-((S)-1-carboxyethoxycarbonyl)ethoxy carbonyl]ethoxycarbonyl}ethyl ester + brinzolamide (138890-62-7) → octadecanoic acid (S)-1-[(S)-1-((S)-1-{(S)-2-[4-ethylamino-2-(3-methoxypropyl)-1,1-dioxo-1,2,3,4-tetrahydro-1λ*6*-thieno[3,2-e][1,2]thiazine-6-sulfonylamino]-1-methyl-2-oxo-ethoxycarbonyl}ethoxycarbonyl)ethoxycarbonyl]ethyl ester

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	27.3%

(S)-2-{(S)-2-[(S)-2-((S)-2-acetoxypropionyloxy)propionyloxy]propionyloxy}propionic acid + brinzolamide (138890-62-7) → (2S)-1-{[(2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ6-thieno[3,2-c][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl (2S)-2-(acetyloxy)propanoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	27%

(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-acetoxypropionyloxy)propionyloxy]propionyloxy}propionyloxy)propionic acid + brinzolamide (138890-62-7) → (2S)-1-{[(2S)-1-{[(2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ6-thieno[3,2-c][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl(acetyloxy) propanoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	26%

(2S)-2-{[(2S)-2-{[(2S)-2-[(4-{[(3Z)-3-[(4-{[2-(diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl]oxy}-4-oxobutanoyl)oxy]propanoyl]oxy}propanoyl]oxy}propanoic acid + brinzolamide (138890-62-7) → (3Z)-3-[(4-{[2-(diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl (2S)-1-{[(2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ6-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl butanedioate

Conditions	Yield
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 2h; Inert atmosphere;	26%

octadecanoic acid (S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-{(S)-1-[(S)-1-((S)-1-carboxyethoxycarbonyl)ethoxycarbonyl]ethoxycarbonyl}ethoxycarbonyl)ethoxycarbonyl]ethoxycarbonyl}ethoxycarbonyl)ethyl ester + brinzolamide (138890-62-7) → (2S)-1-{[(2S)-1-{[(2S)-1-{[(2S)-1{[(2S)-1-{[(2S)-1{[(2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ6-thieno[3,2-c][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl]oxy}-1-oxopropan-2-yl octadecanoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	25%

(S)-2-tert-butoxypropionic acid (S)-1-((S)-1-carboxyethoxycarbonyl)ethyl ester + brinzolamide (138890-62-7) → (2S)-1-[(1S)-1-({[(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ6-thieno[3,2-e][1,2]thiazin-6-yl]sulfonyl}carbamoyl)ethoxy]-1-oxopropan-2-yl (2S)-2-(tert-butoxy)propanoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	24%

C54H84O26 + brinzolamide (138890-62-7) → C66H103N3O30S3

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h;	19.4%

C60H92O30 + brinzolamide (138890-62-7) → C72H111N3O34S3

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	8%

Upstream product

• 165117-54-4 (R)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide 
• 75-04-7 ethylamine 
• 154127-42-1 (S)-3,4-dihydro-4-hydroxy-2(3-methoxypropyl)-4H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide 
• 1029324-92-2 (R)-3,4-dihydro-4-(N-ethylamino)-2-(3-methoxy)propyl-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide 
• 138890-50-3 brinzolamide 
• 160982-13-8 (S)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-4H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide 
• 1448780-04-8 (R)-(+)-4-ethylamino-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide maleate 
• 150937-43-2 Brinzolamide hydrochloride 
• 160982-10-5 3-acetyl-5-chloro-2-thiophenesulfonamide 
• 160982-11-6 3-(2-Bromoacetyl)-5-chloro-thiophene-2-sulfonamide 
• 36157-40-1 3-acetyl-2,5-dichlorothiophene 
• 160982-16-1 (S)-3,4-dihydro-6-chloro-4-hydroxy-4H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide 
• 160982-09-2 3-Acetyl-2-(phenylmethyl)thio-5-chlorothiophene 

Downstream Products

• 186377-56-0 (R)-4-(ethylamino)-2-(3-hydroxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide1,1-dioxide 

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