138890-50-3

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.

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.

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.

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

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.

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.

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

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

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.

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.

A process for synthesizing carbonic anhydrase inhibitors is disclosed.

Sulfonamides and pharmaceutical compositions containing the compounds useful in controlling intraocular pressure are disclosed. Methods for controlling intraocular pressure through administration of the compositions are also disclosed.