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

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

Uses

Used in Ophthalmology:
Brinzolamide is used as an antiglaucoma drug for the treatment of increased pressure in the eye caused by open-angle glaucoma. It acts as a carbonic anhydrase inhibitor with specific affinity for carbonic anhydrase II, which is responsible for the movement of sodium and fluid transport in the eye. By inhibiting this enzyme, brinzolamide leads to a decrease in aqueous humor secretion, likely by slowing the formation of bicarbonate ions, and results in a reduction in intraocular pressure.
Used in Ocular Therapy:
Brinzolamide is used as a carbonic anhydrase inhibitor (CAI) in ocular therapy. It has been shown to produce significant reductions in IOP and demonstrated less ocular discomfort than other CAIs, such as dorzolamide.
Used in Melanin Binding Assays:
Brinzolamide has been used as a melanin binding compound or drug in melanin binding assays, which are used to study the interaction between melanin and various compounds.

Originator

Alcon (US)

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.

Therapeutic Function

Antiglaucoma

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 

Relevant articles and documents

Method for preparing chiral amino compound and intermediate thereof

The invention discloses a method for preparing a chiral amino compound and intermediate thereof. The method comprises the step of performing a deprotection reaction as shown in the specification on acompound in a formula D and mercaptide in a solvent, wherein in the compound in the formula D, X is selected from O or NMe; Y is Me when X is O, and Y is H when X is NMe; n is selected from 0, 1, 2, 3, 4 or 5; each R is independently NO2 or CN; the mercaptide is salt formed by thiol and metal, and is shown as RS-M; M is an alkali metal ion, and is especially selected from one or more of Li, Na, K, Ru and Cs; and R is C14-24 alkyl. The preparation method is simple and convenient to operate, has mild reaction conditions, high yield and high product quality, and is applicableto industrial production.

Preparation methods of brinzolamide and an intermediate thereof

The invention discloses preparation methods of brinzolamide and an intermediate thereof. The preparation method of the brinzolamide intermediate represented by a compound C comprises: carrying out a condensation reaction on a compound B and an orthoester-based compound at a temperature of 70-80 DEG C in an organic solvent in the presence of tertiary amine under an anhydrous condition, wherein theorthoester-based compound is one or a plurality of materials selected from trimethyl orthoacetate, triethyl orthoacetate and trimethyl orthobenzoate. According to the present invention, the condensation reaction is performed by using the tertiary amine as the catalyst, such that the reaction time for the amino protection is substantially shortened, the consumption of the protection reagent is reduced, the reaction temperature is reduced, the yield and the purity of the product are improved, the acid consumption and the alkali consumption during the post-treatment are reduced, the residue on ignition of the product is reduced, the operation is simplified, and the method is suitable for industrial production. The formulas B and C are defined in the specification.

Enantiomeric separation and simulation studies of pheniramine, oxybutynin, cetirizine, and brinzolamide chiral drugs on amylose-based columns

Solid phase extraction (SPE)-chiral separation of the important drugs pheniramine, oxybutynin, cetirizine, and brinzolamide was achieved on the C 18 cartridge and AmyCoat (150 x 46 mm) and Chiralpak AD (25 cm x 0.46 cm id) chiral columns in hum

PHARMACEUTICALLY ACCEPTABLE SALT OF BRINZOLAMIDE AND COMPOSITION THEREOF

The present invention discloses the pharmaceutically acceptable salt of Brinzolamide as Brinzolamide maleate, process for the preparation of the Brinzolamide maleate, its polymorph and composition thereof.

Process for the preparation of brinzolamide and intermediates thereof

Preparation process of brinzolamide comprising the reaction of an halosubstituted precursor, wherein the ethylamine group is optionally protected, first with an halogen-metal exchange reaction, then with sulfur dioxide to form a sulfinate salt, and then reacting the sulfinate salt with an ammonia source. The process allows obtaining brinzolamide at an industrial scale with a high yield and high purity at reduced costs. Some new intermediates are used in this process.

SULFONAMIDE INHIBITORS OF CARBONIC ANHYDRASE

The present invention relates to new sulfonamide inhibitors of carbonic anhydrase activity, pharmaceutical compositions thereof, and methods of use thereof.

PROCESS FOR PREPARING BRINZOLAMIDE

The present invention refers to the preparation and purification of brinzolamide as well as to novel compounds useful in such processes.

Process for the preparation of (R)-(+)-4-(Ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide.

Disclosed herein is an improved process for the preparation of (R)-(+)-4-(Ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide (Brinzolamide) and novel intermediates thereof.

IMPROVED PROCESS FOR THE PREPARATION OF (R)-(+)-4-(ETHYIAMINO)-3,4-DIHYDRO-2-(3- METHOXYPROPYL)-2H-THIENO[3,2-E]-L,2-THIAZINE-6-SULFONAMIDE-L,L-DIOXIDE

Disclosed herein is an improved process for the preparation of (R)-(+)-4- (Ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6- sulfonamide- 1,1 -dioxide (Brinzolamide) and novel intermediates thereof.

Enantioselective synthesis of brinzolamide (AL-4862), a new topical carbonic anhydrase inhibitor. The "DCAT Route" to thiophenesulfonamides

A large scale synthesis of the topical carbonic anhydrase inhibitors AL-4623A (13a-HCl) and AL-4862 (13b) from 3-acetyl-2,5-dichlorothiophene ("DCAT", 1) is described. Reaction of 1 with NaSBn gave thioether 2, which was converted via sulfenyl chloride 3 and sulfenamide 5 to sulfonamide 6. Bromination of 6 gave bromo ketone 7, which upon reduction with (+)-B-chlorodiisopinocampheylborane and cyclization of the resulting bromohydrin produced S thieno[3,2-e]-1,2-thiazine 8a (96% ee) after chromatography. Treatment of 8a in THF with -BuLi at -70 °C resulted in Li-Cl exchange. Reaction of the thienyllithium with SO2 and hydroxylamine O-sulfonic acid afforded bis-sulfonamide 11a. Protection of lia as the acetimidate 12a, followed by tosylation and animation, gave R amine 13a. The synthesis of 13b proceeded via primary sulfonamide 16, which was brominated, reduced, and cyclized to give S thieno[3,2-e]-1,2-thiazine 18 (>98% ee). By virtue of the ionizable NH, 18 was separable from reduction byproducts by base extraction. Alkylation of 18 with 3-bromopropyl methyl ether afforded 8b, which was converted as above, via lib, to AL-4862 (13b). These procedures provided multihundred gram lots of 13a and 13b.