PL171803B1 - Method of obtaining /5s/-2-phenyl-3-/tert-butylo-5-hydroxymethyl oxazolidine - Google Patents

Abstract

1. The method produces 5SS1-2 Ienyl T-tert-butyl - 5-hydroxymethyloxavolidine in the reaction of (2S) -1,2-dihydroxy-3-tert-butylaminopropane with benzaldehyde, characterized by this. that the reaction is carried out in the presence of an acid catalyst.

Description

The present invention relates to a process for the preparation of (5S) -2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine, which is used as an intermediate in the synthesis of timolol hydrogen maleate, a drug used in the treatment of glaucoma.

The Polish patent specification No. 103,683 describes a method of producing (5S) -2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine by reacting (2S) -1,2-dihydroxy-3-tertbutylaminopropane with benzaldehyde in benzene. This reaction is very slow, and the long reaction time causes the formation of many by-products that contaminate the final product and have an adverse effect on the course and efficiency of the subsequent steps in the synthesis of timolol hydrogen maleate and its quality.

It has surprisingly been found that the above-described disadvantages can be avoided by carrying out the reaction in the presence of an acid catalyst.

The process for producing (5S) -2-phenyl-3-tcrt-butyl-5-hydroxymethyloxazolidine according to the invention consists in reacting (2S) -1,2-dihydroxy-3-tert-butylaminopropane with benzaldehyde in the presence of an acid catalyst .

Both mineral acids and organic acids can be used as the acid catalyst. Among the inorganic acids, acids such as hydrochloric acid, sulfuric acid and phosphoric acid can be used.

The inorganic acid is used in an amount of 1-5 mol% with respect to (2S) -1,2-dihydroxy-3-tert-butylaminopropane.

For example, organic acids are preferably carboxylic acids of the formula R'COOH, where R1 is hydrogen, an alkyl group having one to three carbon atoms, optionally substituted with halogen atoms, or phenyl, optionally substituted with substituents such as NO2, lower alkyl, halogen . Acids such as, for example, formic, acetic, propanoic, butanoic, chloroacetic, bromoacetic, dichloroacetic, tnfluoroacetic, benzoic acids can be used. Acetic acid is particularly preferably used.

Also more preferably, organic sulfonic acids of formula R2SO3H are used as the acid catalyst, where R2 is an alkyl group having 1 to 3 carbon atoms or the group

Aryl, optionally substituted with NO2, lower alkyl, halogen. P-toluenesulfonic acid is particularly preferably used

The organic acid is used in an amount of 5-20 mol% with respect to (2S) -1,2-dihydroxy-3-tert-butylaminopropane.

The (5S) -2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine obtained by the process of the invention can be used directly for the further steps in the synthesis of timolol hydrogen maleate without further purification. However, if desired, it may be purified by conventional procedures, for example by distillation under reduced pressure.

The process according to the invention enables the reaction time for the preparation of (5S) -2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine in the final product to be shortened.

Example I

A) Preparation of (2S) -1,2-dihydroxy-3-tert-butylammopropane

3-t-Butylamino-1,2-isopropyhdenopropanediol (28.05 g, 0.15 mol), concentrated hydrochloric acid (13.5 ml, 0.158 mol) in 15 ml of methanol was heated for 1.5 hours in a water bath at 70 ° C. The mixture was then cooled and a solution of 8.5 g KOH in 75 ml of methanol was added. The precipitate KC11 was filtered off, the methanol and water were evaporated under reduced pressure.

B) Preparation of (5S) -2-phenyl-3-tert-butyl-5-hydroxymethyloxazoldine

To the (2S) -1,3-tert-butylaminopropane obtained in (A) (approx. 100% hydrolysis yield) was added 100 ml of toluene, benzaldehyde (28 ml, 0.28 mol) and glacial acetic acid (1.5 ml, 0.025 mol) (15 mole% with respect to (2S) -1,2-dihydroxy-3-tert-butylaminopropane) and refluxed for about 4 hours, water collecting in a Dean-Stark trap. After cooling, washed with 5% NaHCO.3 and water, distilled toluene under reduced pressure, excess benzaldehyde was removed by distillation under pressure (53.33 Pa). 28.8 g of residue were obtained. Gas chromatographic analysis showed the residue to be composed as follows (weight percent): 91.6% (5S) -2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine, 0.5% 3-t-butylamino-- 1,2-benzylidenepropanediol, 6.9% benzaldehyde. The (5S) -2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine can be purified by distillation under reduced pressure (120 ° C 39.99 Pa).

C) Preparation of timolol hydrogen maleate

To the residue obtained in (B), (28 g), containing 0.1 mole of (5S) -2-phenyl-3-tci'l-butyl-5-hydroxymethyloxazolidip, y was added sodium t-butoxide prepared from 4.6 g 80% NaH (0.15 mol) and 200 ml of t-butanol. Stirred for 1 hour at room temperature. Then 32.9 g (0.16 mol) of 4-chlorc-3-morphine-1,2,5-thiadiazole was added and left overnight with the magnetic stirrer on. Then t-butanol was distilled off under reduced pressure, then the residue was treated with 200 ml of 1N HCl and stirred for 1 hour at a temperature of about 60 ° C. The organic layer was separated and extracted 3 times with 60 ml of 1N HCl. The combined aqueous layers were washed 3 times with 100 ml of methylene chloride and basified with anhydrous K2CO3 to a pH of about 10. The oil that separated out was extracted three times with 200 ml of CH2Cl4, washed with 100 ml of water and dried with anhydrous MgSO4. The solvent was completely evaporated and 22.4 g of timolol base was obtained, which was converted to the hydrogen maleate in the usual manner. 25.9 g of the product was obtained (60% yield) with a purity of 99.5% and [α] ² ° 405 = -12 (c = 5.1NHCl). '

Example II.

29.4 g (0.2 mol) of (2S) -1,2-dihydroxy-3-tert-butylaminopropane prepared as described in Example 1A, 90 ml of toluene, 30 ml (0.15 mol) of benzaldehyde and

3.4 g (0.02 mol) of p-toluenesulfonic acid was refluxed for 5 hours, with water collection in a Dean-Stark trap. After cooling, 7.4 g of a residue, mainly 3-tert-butylamino-1,2-benzylidene propanediol, was filtered off. Toluene was distilled off the filtrate under reduced pressure, the excess benzaldehyde was removed by distillation under pressure (53.33 Pa). 39 g of residue were obtained with the composition of 92.0% (5S) -2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine, 2.3% 3-tert-butylamino-1,2-benzylidenepropanediol, 5.7% benzaldehyde.

171 803

Publishing Department of the UP RP. Circulation of 90 copies Price PLN 2.00

Claims (6)

Patent claims 1. A method for the preparation of (5S) -2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine by the reaction of (2S) -1.2-dihydroxy-3-tert-butylaminopropane with benzaldehyde, characterized in that the reaction is carried out in the presence of an acid catalyst . 2. The method according to claim 1, characterized in that an inorganic acid is used as the acid catalyst. 3. The method according to p. The process of claim 1, wherein the acid catalyst is a carboxylic acid R ^and COOH, wherein R1 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, optionally substituted with halogen atoms, or phenyl, optionally substituted with substituents such as NO2, a lower alkyl group , halogen. 4. The method according to p. A process as claimed in any one of the preceding claims wherein the acid catalyst is acetic acid. 5. The method according to p. The process of claim 1, wherein the acid catalyst is an organic sulfonic acid of formula R ² SO 3 H, wherein R ² is an alkyl group having 1 to 3 carbon atoms, or an aryl group optionally substituted with substituents such as NO ', lower alkyl, halogen. 6. The method according to p. A process as claimed in any one of the preceding claims wherein the acid catalyst is p-toluenesulfonic acid.