PL177122B1 - Novel derivative of 3-t-butylo-2-phenyloxazolydine, method of obtaining same and thymolol obtaining method - Google Patents

Abstract

1. A new derivative of 3-t-butyl-2-phenyloxazolidine, which is (5S) - (-) - 5-acetoxymethyl-3-t-butyl-2-phenyloxazolidine about formula 1.

Description

The invention relates to a novel 3-t-butyl-2-phenyl-oxazolidine derivative and a method for its preparation.

The new derivative is an intermediate for the synthesis of timolol ((S) - (-) - 3-morpholine-4 - [(3-t-butylamino-2-hydroxy) propoxy] -1,2,5-thiadiazole). Timolol in the form of hydrogen maleate is used as an active ingredient in anti-glaucoma and antihypertensive drugs.

(5S) - (-) - 5-Acetoxymethyl-3-t-butyl-2-phenyloxazolidine has not yet been described in the literature.

In known processes (e.g. from Polish patent specification No. 85165), timolol is obtained from (S) -3-t-butylamino-1,2-O-isopropylidene-1,2-diol, which is hydrolyzed to (S) -3 -t-butylaminopropane-1,2-diol and this is converted to (5S) -2-phenyl-3-t-butyl-5-hydroxymethyloxazolidine which is reacted with 3-morpholine-4-chloro-1,2,5 -thiadiazole and the product obtained is hydrolyzed in an acid medium.

The known process consists of a number of reaction steps, which makes it difficult to obtain the high purity end product required for an active drug substance. It turned out, however, that the process of obtaining timolol can be simplified and shortened by using a new intermediate for its synthesis.

Thus, the essence of the invention is the novel 3-t-butyl-2-phenyloxazolidine derivative which is (5S) - (-) - 5-acetoxymethyl-3-t-butyl-2-phenyloxazolidine of the formula I.

The (5S) - (-) - 5-acetoxymethyl-3-t-butyl-2-phenyloxazolidine of formula I is obtained by the process according to the invention, which consists in the fact that (S) -3-t-butylamino-1,2- The O-isopropylidenepropane-1,2-diol of formula II is reacted first with an aqueous acetic acid solution and then with benzaldehyde in a water-immiscible organic solvent.

The temperature of the reaction with benzaldehyde should not exceed 120 ° C. As organic solvent, solvents such as aromatic hydrocarbons, for example benzene, toluene, xylene, or chlorinated hydrocarbons, such as dichloromethane, are used.

The (5S) - (-) - 5-acetoxymethyl-3-t-butyl-2-phenyloxazolidine according to the invention can be used to obtain timolol in crude form directly after its preparation without further purification.

However, if desired, it may be purified by conventional procedures, for example by distillation.

To obtain timolol hydrogen maleate, (5S) - (-) - 5-acetoxymethyl-3-t-butyl-2-phenyloxazolidine of formula I is reacted with 3-morpholine-4-chloro-1,2,5-thiadiazole in the presence of a strong base in in an organic solvent, and then the product of this reaction is subjected to hydrolysis. The resulting timolol base is converted to the hydrogen maleate with one equivalent of maleic acid.

177 122

The invention is illustrated by the following embodiment.

Example d. Preparation of (5S) - (-) - 5-acetoxymethyl-3-t-butyl-2-phenyloxazolidine (S) -3-t-Butylamino-1,2-O-isopropylidenepropane-1,2-diol (56, 1 g, 0.3 mol) and 240 ml of 60% acetic acid was refluxed for 4 hours, then water and acetic acid were distilled off under reduced pressure. 200 mL of toluene and benzaldehyde (50 µL, 0.5 mol) were added to the residue and heated to reflux for about 4 hours, collecting water (6 mL total) in a Dean-Stark trap. Toluene was distilled off under reduced pressure and excess benzaldehyde was removed by distillation at 53 Pa. 73 g of crude oil were obtained with the composition determined by gas chromatography (weight percent):

(5S) - (-) - 5-acetoxymethyl-3-t-butyl-2-phenyloxazolidine 80.5%, (5S) - (-) - 2-phenyl-3-t-butyl-2-hydroxymethyloxazolidine 15.5 %, (S) -3-t-butylamino-1,2-O-isopropylidenepropane-1,2-diol 2%, benzaldehyde 6.2%. A sample of this mixture was purified by column chromatography (flash) on silica gel eluting with hexane-ethyl acetate 8: 2. Homogeneous fractions (studied by thin layer chromatography) were combined and evaporated and distilled in an air bath. (S) - (-) - 5-acetoxy-3-t-butyl-2-phenyloxazolidine distilled at 119 ° C / 27 Pa.

[α] 405 = -35 ° (c = 1, toluene)

IR (CHCl) v _m ax: 1736, 1369, 1261 cm ¹ H NMR (CDCl3): δ (ppm) 7.60 - 7.50 (m, 2H, aromatic), 7.40 - 7.23 (m , 3H, aromatic), 5.73 and 5.60 (2s, together 1H), 4.30 - 3.85 (m, 3H), 3.42 - 3.15 (m, 1H), 2.85 - 2.70 (m, 1H), 2.08 and 2.00 (2s, 'total 3H, COCH3), 1.23 and 1.06 (2s, total 9H, C (CH3) 2.

Claims (2)

Patent claims 1. The novel 3-t-butyl-2-phenyloxazolidine derivative which is (5S) - (-) - 5-acetoxymethyl-3-t-butyl-2-phenyloxazolidine of the formula 1. 2. The method of obtaining the new (5S) - (-) - 5-acetoxymethyl-3-t-butyl-2-phenyloxazolidine of formula 1, characterized in that (S) -3-t-butylamino-1,2, O- The isopropylidenepropane-1,2-diol of formula II is first reacted with acetic acid and then with benzaldehyde in a water-immiscible organic solvent.