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Inventors	Alessandro Falchi, Ottorino De Lucchi, Andrea Castellin
Original Assignee	Phf S.A.

Brinzolamide is a carbonic anhydrase II inhibitor, used to lower intraocular pressure and glaucoma. It is sold by Alcon under the name of Azopt, as 1% ophthalmic suspension.

EP 527801 claims Brinzolamide and describes a process to prepare it in 14 steps starting from 3-acetylthiophene (scheme 1). It is a synthesis typical of medicinal chemistry not applicable at industrial level, for which no specific preparations are described, because Brinzolamide is not among the preferred compounds of the invention.

This synthesis is not very efficient because requires the change of the oxidation status of the functional group in position 4 for three times; indeed this is first reduced with Sodium borohydride (step (5)) to α-bromoalcohol and then oxidized with Sodium dichromate (step (11)), a very toxic reagent. This sequence is necessary to obtain the cyclization (6), which brings only to degradation products on the ketone, and which requires a complex and not much efficient procedure as far as the quality and yield of the isolated product is concerned. The second reduction (12) occurs in the presence of (+)-β-chlorodiisopinocamphenylborane, an expensive enantioselective reducing agent, with a stoichiometric excess of 5:1, which requires reaction conditions not easily achievable at industrial scale (3 days of reaction at −22° C., difficult work up and chromatography) to isolate the product.

It can be inferred from the patent that there is the possibility to fix the stereogenic centre through selective crystallization of the salt of a chiral acid as di-p-toluoyl-D-tartaric acid, expensive resolution agent, with consequent loss of at least half of the substrate.

EP 617038 describes a process for the preparation of Brinzolamide and its analogues starting from 3-acetyl-2,5-dichlorothiophene (scheme 2).

The reduction (6) with (+)-β-chlorodiisopinocamphenylborane and the cyclization (7) bring to the optically active alcohol 2H-thieno[3,2-e]-1,2-thiazin-4-ol, 6-chloro-3,4-dihydro-, 1,1-dioxide, (4S)-. The formation of a product enriched with one of the enantiomer is too early in the synthesis, with a consequent risk of racemisation during the following steps, while the reduction would be more efficient if performed on a more advanced intermediate. The disadvantages of the use of the enantioselective reducing agent (6) and of the cyclization of the alcohol (7) are the same of the method described in Scheme 1. Another disadvantage is the alkylation (8) with 1-bromo-3-methoxypropane, that, in order to avoid the reaction of the oxydrilic group, is performed portionwise, with low temperatures and long reaction times.

The sulfonamide is introduced in position 6 through metallation with n-butyl lithium, an expensive raw material, and then with a reaction with sulphurous anhydride and hydroxylamino-O-sulphonic acid. The base should be used in substantial excess (2,3 eq.), because the oxydrilic group reacts with the first equivalent. In this case the protection of the oxydrilic group as described in Scheme 1 is not possible without running the risk of racemization of the substrate.

Lastly, the conversion of the secondary alcohol to the amine is difficult and requires the protection (10) of the primary sulfonamide with trimethyl orthoacetate, the activation (11) of the oxydrilic group with tosyl chloride and finally the substitution (12) of the tosyl group with ethylamine and at the same time the aminolysis of the protection of sulfonamide with the excess of ethylamine.

This synthesis is described in Org. Process Res. Dev. 3, 1999, 114, written by the R&D laboratories of Alcon. So it is reasonable to believe that this synthesis is used by Alcon at industrial level. Anyway, due to the low purity of the product obtained (97%), several crystallizations are needed to have a product of acceptable pharmaceutical grade.

U.S. Pat. No. 5,470,973 describes a variant of the synthesis in scheme 1, which involves an alternative preparation of the syntone 2H-thieno[3,2-e]-1,2-thiazin-4-ol, 6-chloro-3,4-dihydro-2-(3-methoxypropyl)-, 1,1-dioxide, (4S)- and the other analogues lacking chlorine in position 6 or the 3-methoxypropylic chain (scheme 3).

To introduce the chiral centre, firstly the oxidation (8) with dichromate is performed, and then the stereoselective reduction (9) with (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrol[1,2-c][1,3,2]oxazaborole are performed. The need of oxidizing first and then reducing was already commented in the description of the first synthetic path; the low enantiomeric excess (92%) is another disadvantage.

So it is evident the need of an alternative process for the preparation of Brinzolamide which can resolve the above mentioned technical problems.

OVERVIEW

Brinzolamide, 56, is used to treat glaucoma and can be synthesised by a 14-step route from acetylthiophene. This route is described as inefficient because of several changes of the oxidation state of one of the functional groups. Other routes have fewer steps but are still not very efficient. This patent describes a method for making compounds that are intermediates in the synthesis of56. The route is outlined in Schemes 20 and 21 and starts from the thiophene 49a or its chloro-derivative 49b (X = Cl). The first step is protection of the carbonyl group in 49a by reaction with 50to form 51a that is isolated in 87% yield. In the next step 51a is treated with K₂CO₃ to effect intermolecular cyclisation and formation of 52a. This can be obtained in 90% yield, or the reaction mixture can be treated with 53 without isolation of 52a to form 54a that is isolated 90% yield.

The next stage is the introduction of the second sulphonamide group as shown in Scheme 21. This begins with treatment of 54a with BuⁿLi followed by addition of liquid SO₂. The intermediate reaction product is isolated as a solid and then treated with H₂NOSO₃H to form 54c that is recovered in 76% yield. The protective diol group is then removed by acid hydrolysis to give 55a in 97% yield. The conversion of 55a to 56 is not described in the patent, and reference to alternative syntheses of 56 indicate that this proceeds via asymmetric reduction of 56 to a hydroxy group that is then converted to the amine.

Compound 55a can be prepared by the same sequence of reactions shown in Schemes 20 and21 when starting from 49b. The yields of the corresponding intermediates are similar to or better than those reported for the method starting from 49a. The patent does not indicate the scale of the reactions, and the examples merely state the amounts of reactants used in terms of equivalents. The purity of the intermediates is not given, although ¹H NMR data are provided. The patent does not disclose how to obtain either of the starting materials, 49a or 49b, that are unlikely to be commercially available, and their synthesis will presumably add more steps to the synthesis of 56.