AT391696B - METHOD FOR PRODUCING S-3MORPHOLINO-4- (3'-TERT-BUTYLAMINO-2'-HYDROXYPROPOXY) -1,2,5THIADIAZOLE - Google Patents

Description

No. 391 696

The invention relates to a process for the preparation of the pharmacologically valuable β-blocking S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -l, 2,5-thiadiazole of the formula o-ch2- c-ch2-nh-c (ch3) 3

OH

(S-D

The preparation of the compound also known under the name timolol with the formula y

0-CH2-CH-CH2-NH-C (CH3) 3 OH

N N either as a racemic mixture, i.e. H. R, S form or as R or S enantiomer is described in numerous patents. In U.S. Patent Nos. 3,655,663 and 3,729,469, R, S-timolol is prepared by the process according to Scheme 1 below, first by a 3-RQ, 4-OH substituted 1,2,5-thiadiazole of the formula II, in which Rq is chlorine or the morpholino group, or its alkali metal salt is reacted with epichlorohydrin in the presence of a basic catalyst, after which the hydroxyhalide of the formula ΙΠ obtained as an intermediate or the epoxide of the formula IV formed from this under alkaline conditions is reacted with tert-butylamine will, where

Scheme 1

R OH '(Na) R0 0-CH2-tH-CH2Cl \ - / 6h

N H 4 H, C-CH-CH, Ct 2 \ f 2 0 N N

an R, S-alkanolamine of the formula V is obtained which is identical to R, S-timolol if Rq is a -2-

No. 391 696

Morpholino group means. When Rq in the formula V is chlorine, it can be replaced by treating it with an excess of morpholine with the morpholino group.

The alkanolamine of the formula V can also be obtained from the hydroxyhalide m or from the epoxide IV according to Scheme 1 by first treating it with ammonia, giving a primary alkanolamine of the formula VI which contains the alkanolamine of the formula V with tert-butyl chloride forms.

According to JP-PS 7413176, R, S-timolol is obtained by reacting a sulfonyl ester of the formula VII,

N N

O-CHj-CH-Ch ^ -O-SOj-Rj VD

OH

S wherein Rj represents an alkyl or aryl group, with tert-butylamine.

ES-PS 486629 describes a process according to the following scheme for the preparation of R, S-timolol, in which the diethylacetal of glycidaldehyde (formula VIII) has been reacted with an alkali metal salt of 1,2,5-thiadiazole of the formula II (where Rq is the same as above), after which the resulting acetal (formula IX) has been hydrolyzed to the corresponding aldehyde (formula X),

Scheme 2

2 ^ h-chioc2h5j2 OH

N N V II

VIII Η N S '

IX

w N N (CH ^ C-NH ^ o-ch2-ch-ch = h-c (ch3) 3

0H w N N / s

OH

XI

Red. - > R, S-timolol whose Schiff base (formula XI) formed with tert-butylamine has been reduced to R, S-timolol.

In US Pat. No. 3,655,663, the decomposition of the racemic alkanolamine of the formula V (Rq = chlorine) via optically active salts, such as with 0.0-di-toluoyl - (+) - or - (-) - tartaric acid, is 0.0 -Dibenzoyl - (+) - or - (-) - tartaric acid or (+) - or (-) - tartaric acid. The S-enantiomer of formula V (Rq = chlorine) - from the S-timolol through

Treatment with morpholine can be prepared - has been obtained from the mother liquors formed after the separation of the salts mentioned under the specified conditions, which are more easily precipitated R-enantiomers. The yields of the decomposition are low and the R-shape remained unused. The production of an optically pure -3-

No. 391 696 or almost pure or an S-enantiomer corresponding to the drug requirements by such salt crystallization also requires fractional crystallizations which are practically difficult to drive through, which leads to a further decrease in the yield.

The preparation of the enantiomers of the formula I from starting materials with the desired stereochemistry is, for. As described in U.S. Patent Nos. 3,655,663,3,657,237 and 3,729,469. For the preparation of S-timolol (cf. Scheme 3), D-glyceraldehyde (formula ΧΠ) or its 2,3-acetonide (formula ΧΙΠ) was used as the starting material, from which one can be obtained by reducing amination in the presence of tert-butylamine and in Connection with the 2,3-acetonide after acid hydrolysis, Sl, 2-dihydroxy-3-tert-butylamino-propane (formula S-XTV), which as such or in the 1-position, for. B. activated by a benzenesulfonyl or tosyl group (formula S-XIV-A, R3 = H, CHß, NO2, Br) or as the corresponding S-oxazolidine (formula S-XV, R2 = H, (CHß ^ CH- , CgHj- etc.), which can also be activated (formula S-XV-A), with 1,2,5-thiadiazole (Rq = moipholino group) of the formula Π or

Scheme 3

^ HD CHO | HC-0H 1 HC-D. J 1 CH ^ OH D-glyceraldehyde χ \ ι XIII

-4-

No. 391 696 3-chloro-4-morpholino-1,2,5-thiadiazole (formula XVI) is reacted in the presence of alkalis, after which, if oxazolidines are used as intermediates, they are hydrolyzed by acid treatment, the product in all Fall S-Timolol is obtained. Satisfactory or good yields are achieved with some of these processes, but their general use is limited by the high price and the often difficult availability of the starting materials required in the processes with the correct stereochemical configuration. US Pat. No. 3,657,237 describes, in addition to the processes mentioned, some alternative processes for the preparation of S-timolol. Thus, a D-10-camphorsulfonate salt of the S1, 2-epoxide prepared from the tosylate of the formula S-XTV-A (Rg = CHg) with 3-morpholino-4-hydroxy-l, 2,5-thiadiazole (formula II, Na salt) was implemented, the product obtained being S-timolol.

According to a variant, the morpholino ring of the formula I is formed in two stages so that the S-form alkanolamine of the formula V (Rq = chlorine) is first reacted with diethanoiamine, after which the 3- (β, β-dihydroxy) diethylamino group thus formed is cyclized to a morpholino group

S-timolol is also obtained by treating with sulfur monochloride of the S-dinitrile of the formula XVII below obtained by reacting 1-morpholinocyanogen and oxazolidine of the formula S-XV

NH NH ÖH has been manufactured.

US Pat. No. 3,619,370 describes a process for the preparation of timolol by reducing a ketone corresponding to it according to Scheme 4, either chemically with sodium borohydride or aluminum alkoxides, with racemic

Scheme 4

Timolol or, microbiologically with reductase, receives products in S-form.

As a result of the very unstable character of both the ketone and some of the intermediates used in the implementation, we have not been able to repeat the processes mentioned in the said patent for the preparation of the ketone of the formula XVIII, so that the production process of the ketone (XVIH) mentioned is repeated. at least not suitable for the scale of industrial production.

The invention relates to a process for the preparation of S-3-morpholino-4- (3'-tert-butyiamino-2'-hydroxypropoxy) -l, 2,5-thiadiazole (formula I) d. H. of S-timolol, from its racemate by performing a decomposition on its dialkanoyl-, diaroyl- or alkanoyl-aroyl-L-tartaric acid-O-monoesters according to the formula R, SIL-XIX, Scheme 5, in which formula R4 and R5 independently of one another a straight or -5-

No. 391 696 branched alkanoyl group with 1 to 5 carbon atoms in the alkyl group, mean a benzoyl or p-methylbenzoyl group. Accordingly, R4 and R5 mean an alkanoyl group, the acetyl, propionyl, butyryl, pentanoyl or hexanoyl group, which can be a straight or branched group, and preferably mean the acetyl group.

The monoesters of the formula R, SIL-XIX, the preparation of which is the subject of the invention, can easily by reacting the R, S-timolol base (R, SI) with a dialkanoyl, diaroyl or alkanoyl-aroyl-L-tartaric anhydride Formula L-XIX, wherein R4 and R5 are as above, in an inert, anhydrous, organic solvent, such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, benzene, toluene etc., preferably at room temperature or at a temperature range from 0 * 70 ° C with a reaction time of 10 minutes to 3 hours. Evaporation of the solvent gives the dialkanoyl, diaroyl or alkanoylaroyl-L-tartaric acid-O-monoester of R, S-timolol in pure form and with a quantitative yield. It has already been found that the substitution takes place only as an O substitution under the specified conditions, which is also confirmed by the mass spectra measured in the products, in which no fragments characteristic of the N-substituted molecules occur, whereas the fragment m / z 86 (CH2 = + NH-C (CH2) 3, also the motpholino group) occurs strongly. If the product is N-substituted, i.e. H. an amide, this would not be worth mentioning among the O-substituted product d. H. hydrolize typical hydrolysis conditions.

It was surprisingly found that the decomposition of an R, S-timolol-dialkanoyl-, -diaroyl- or -alkanoyl-aroyl-L-tartaric acid-O-monoester (formula RS-IL-XIX) with a very good, both chemical and optical yield can also be carried out by the racemate from Cj-Cj alcohols, such as methanol,

Ϊ 0-CHj-C-tHj-NH -C (CH3) 3? S-I-L-XIX .0 "- j -0% RjO-r - H C00H R-l-l-XIX

H h * / h2o h * / h2o r- timolol base -6-

No. 391 696

Η

I O-CH, -C-CH, -NH-C (CH,), * | 2 3 3

OH S-Tirolol base ethanol, N-propanol or isopropanol or from their mixtures or water-containing solutions is crystallized in a pH range from 7 to 2 and in a temperature range from 0 to 30 ° C, the S-enantiomer of timolole dialkanoyl , -diaroyl- or -alkanoyl-aroyl-L-tartaric acid-O-monoesters (formula SIL-XIX) due to its lower solubility in the above solutions or solution mixtures, crystallized and separated from the mother liquor by known methods.

Crystallization of the R, S-timolol-diacetyl-L-tartaric acid-O-monoester (formula R, SIL-XIX; R ^ = R ^ = CH3-CO-) has proven to be a particularly advantageous way of carrying out the decomposition Mixture of water and methanol in a pH range of approx. 4 to 5 at room temperature or in a temperature range of 0 to 30 ° C, the S-enantiomer with a yield of approx. 75% and with an optical purity of the product of> 91% crystallized. Recrystallization gives optically pure S-timolol-diacetyl-L-tartaric acid-O-monoester. This very advantageous optical yield is primarily due to the strong tendency of the S-form of the timolol-L-tartaric acid derivative - due to the stereochemical structure - to form an inner salt under the existing crystallization conditions and the poor solubility of this salt in the crystallizing solution mixture.

The peaks found in the IR spectra of such salts, in the ranges from 1575 to 1600 cm '* and 2250 to 2700 cm "* (1 to 5 peaks), as well as the perception made in the * ^ C NMR spectra that the signal of carbon atom 2 (cf. the structural formula and the values in Table 1) has shifted by 5-7 ppm into the lower field, which is characteristic if an acid group has a salt structure (- + NH2 *) (cf.Acta Chem. Scand. B 38 (1984) 67) are an indication that the S-timolol-L-tartaric acid derivative occurs as an inner salt. These observations found in the IR and * ^ C NMR spectra, which substantiate the salt structure, also show that the reaction of the R, S-timolol with the dialkanoyl, diaroyl or alkanoyl-aroyl-L-tartaric anhydride as one O substitution and not as an N substitution, since in the latter case there would be no formation of an inner salt. Table 1 13 lists the chemical shifts in the C-NMR spectra of the S- and R, S-timololdiacetyl-L-tartaric acid 0-monoester and the corresponding dibenzoyl esters and the S-timolol base. The S-timolol Base can from the above-mentioned esters by acid hydrolysis in aqueous solution for 1 to 24 hours in a pH range from 0 to 5 and in a temperature range from 25 to 100 ° C using z. B. of mineral acid, such as sulfuric acid or phosphoric acid.

It has proven advantageous to boil an aqueous solution, adjusted to pH 2 with sulfuric acid, under reflux for 10 hours. The recovery of the S-timolol base is carried out by this from a, for. B. with alkali hydroxide or ammonia, alkaline (pH 10 to 13) reaction mixture in an organic solvent such as methylene chloride, 1,2-dichloroethane, benzene, toluene, ethyl acetate etc. is extracted, from which the S-timolol base after distillation of the solvent in almost quantitative yield with an optical purity of > 97% can be won. The S-timolol base can optionally be further purified by crystallization from an organic solvent, or it can be converted into the corresponding acid addition salt, such as the hydrochloride or hydrogen maleate, in a manner known per se. -7-

No. 391 696 c Oß o II u CS Cs SO CO SO so

c ao M GO σ {oö so 1—1 I SO SO SO C «SP * So VI TT Ö p- Io SO so e. £? CO in oo K SO i cs3 o Ό c < co \ CH CM hIh u

PC fn ci q co q O) c \ -M- «j m cm« η < N co

ε i I CJ

x I

Table 1

οι. X LT \ t_)

σ \ co cd cn U o u

ooq '*; in p * · / —s > nv P ** cn in in 1 C 1 p- p * r- P * so Cs SO OS U 65.8 65.7 66.8 65.5 66.3 00 ü > n \ oqq $ 5 ? 3 5 S P- U r- ο- 'TT q q r-; q §jq Cs Cs OS O * 3 Cs Os m, ^ tt H t — 4 i— * {N iH i- ^ »w» so U f ^ S CS 00 cs c 00 Tp cn cn cn, 2P c4 cn m in in co m «n ^ iH i“ H i -4 m ü qq Jd qq CO CO 'co cm " r ~ o t " r »tj * < J q q £ £ oo CS cs *» P- Ό Ό g g Ό cn CJ ^ q ^ q i — 1 1–4 i — 4 ^ rp CM U A A 00 g, 00 ^ § > q q Ό Ό Ό · £ Μ · O m n un in in in CN CN 'W' M— ^

εco aoc 3 COOεo > 3 2 2 / -s < N ü

CN i-H CN Γ- cs in CN in CN SO CN in <N 00 CN CO 00 C T! 3 2 CO 3O · -i-i ε

+ O O cn η co Ίη Q Q U. O

O U CM / —N cn Q CJ + o o cn n CS CM co'co Q Q Ü o

CJQU o c o cn tn V2 cn Ό c oo Ξ Pi Qi 3 06 cn

CO K U

COsU

ΌSSΌU »nSSu3 3’SΞ §P« O * 3 Is co bOC 3 coO nJε§ -O • • 4 • o cnü m

o CN

in CN o cn in cn -8

No. 391 696

The decomposition of the R, S-timolol by crystallizing the corresponding dialkanoyl, diaroyl or alkanoylaroyl-L-tartaric acid-O-monoester (formula RS-IL-XIX) preferably the diacetyl ester from an alcohol or an alcohol-water mixture in a pH range &lt; 7 and in a temperature range of 0 to 30 ° C, the L-tartaric acid-O-monoester (formula SIL-XIX) of S-timolol can be separated with a good yield and optically almost pure, and by its hydrolysis in a pH Range from 0 to 5 for S-timolol, has proven to be a very advantageous process for the preparation of the substance in question, and no such decomposition has been described in the literature for alkanolamines of this type, in which one of the Would have received enantiomers with a good yield or even optically pure.

The versatility of the process is also shown by the fact that if the decomposition is carried out with corresponding D-tartaric acid derivatives, R-timolol can be prepared in an analogous manner with a good yield and optically pure (cf. Example 7).

Since the S-esters can also be easily hydrolyzed to S-timolol with a very good yield without racemization, the decomposition is also suitable for production on an industrial scale. This process for the preparation of S-timolol is also advantageous in that the dialkoyl, diaroyl or alkanoyl-aroyl-L-tartaric acid-O-monoesters of R, S-timolol to be used as the starting materials for the decomposition using racemic timolol and L-tartaric anhydrides, which are known from the literature and can be prepared easily, and that, as starting materials, those substances are not required, as in most processes known from the literature, in which the chiral center is already present in the correct stereochemical configuration and which are usually difficult to heat and are expensive.

Another fact which makes the process according to the invention very advantageous is that from the mother liquor obtained on the separation of the S-timolol-L-tartaric acid-O-monoester, which mainly contains the above R-enantiomer, the &quot; valuable &quot; Part d. H. the 3-morpholino-4-hydroxy-1,2,5-thiadiazole, can easily be regenerated by hydrolyzing the ether bond of timolol (cf. Example 5).

In the R enantiomer of timolol, an inversion can also be carried out in the manner known in principle from the literature (cf., for example, JP-PS 7475545, J. Org. Chem. 46 (1981) 4321 and Tetrahedron Lett. (1973) 1619). The R-timolol can also be exploited by racemizing it in the ways known from the literature (cf., for example, BJ Chem. Soc., Chem. Commun. (1974) 309) and using the racemate as a starting material for the above Disassembly.

In addition to the processes described in the literature, the R, S-timolol can also be prepared by the process known per se, which is set out in Scheme 6 (cf., for example, JP-PS 72 19259 or ES-PS 459.725) using 3-hydroxy-4-morpholino-l, 2,5-thiadiazole or preferably its alkali metal salt (formula XX, Rg = H, Na, K) and l-tert-butyl-3-azetidinol or its hydrochloride (formula XXI) or one other acid addition salt as starting materials. & hemaji

&gt; R, S-timolol

The reaction is preferably carried out in an inert organic solvent, such as benzene, toluene, xylene, in a chlorinated, aliphatic or aromatic hydrocarbon, dimethylformamide or dioxane, in a temperature range from 40 to 160 ° C. with a reaction time of 1 to 24 hours. It is advantageous to use the equivalent amounts of starting materials or an excess of 5 to 10% of azetidinol (formula XXI) in the reaction. The reaction can be accelerated and the yield improved by adding 2 to 20% of a phase transfer catalyst, such as tetrabutylammonium bromide or hydrogen sulfate, to the reaction mixture. The product is extracted by extracting its -9-

No. 391 696 acid addition salt into water and the base released therefrom with alkali into an organic solvent and by evaporation of the solvent. The R, S-timolol base obtained with a yield of about 70% can be purified by crystallization or by conversion into the desired acid addition salt, such as the hydrochloride or hydrogen maleate. It should be noted that although the tautomerism occurring in the 3-hydroxy-1,2,5-thiadiazoles in the reaction according to Scheme 6 enables N substitution even under the above reaction conditions, the O substitution proves to be the The small amount of by-products resulting from the N-substitution can easily be hydrolyzed for 1 to 3 hours by adding water at the end of the reaction and continuing to boil under reflux, the hydrolysis of the N-substituted by-product being quantitative and has no influence on the extraction or purification of the desired product under the conditions used.

The 3-hydroxy-4-morpholino-1,2,5-thiadiazole (formula XX) used as the one starting material in the process for the preparation of the R, S-timolol according to scheme 6 can be prepared by processes known from the literature ( see, e.g., BJ Org, Chem. 41 (1976) 3121 and J. Org. Chem. 32 (1967) 2823 and DE-PS 1,914,496), some of which are set out in Scheme 7. .OR, c

N NH 2

SCI

CI

Scheme 7 c - c U il H'l * C III «XXNNN cyan \ o-aminoacetonitrile SCI2 \ SCI2 s s2ci2 \ II NC1 CI CI IT N Π1 N ALkylcyanoformimidate alkylcyanochloro-3,4-dichloro-1,2,5-thiadiazole formimidat

* / 'W * N N \ / S XXII hydrolysis

'mf N N

OH

Morpholine i

CI

N S ^ 3-chloro-4-norpholino-1,2,5-thiadazole

N OH

S 3-chloro-4-hydroxy-1,2,5-thiadiazole w

H II N. / 3-hydroxy-4-morpholino-1,2,5-thiadiazole (XX) -10-

No. 391 696

An alternative process (see Example 1) for the preparation of 3-hydroxy-4-morpholino-1,2,5-thiadiazole, shown in Scheme 8, is carried out by reacting 3-chloro-4-alkoxy-l, 2,5- thiadiazole (formula ΧΧΠ, Ry = Cj-C ^ alkyl) with morpholine and by subsequent hydrolysis by known methods of the intermediate obtained

Scheme 8

XXII XXIII XX 3-morpholino-4-alkoxy-l, 2,5-thiadiazole (formula ΧΧΙΠ, Ry as above) to 3-morpholino-4-hydroxy-l, 2,5-thiadiazole.

The l-tert-butyl-3-azetidinol used as the other starting material for the process for the production of R, S-timolol according to scheme 6 and its hydrochloride (formula XXI) or another acid addition salt can advantageously be obtained from epichlorohydrin and tert-butylamine according to one processes known in principle in the literature (cf. J. Org. Chem. 32 (1976) 2972), which was improved, as a result of which pure 1-tert-butyl-3-azetidinol hydrochloride with a yield of 60% (cf. Example 1) could be produced.

The spectra given in this document were obtained with the following apparatus:

Mass spectra: Jeol JMS D 300 / JMA 2000 H

^ H NMR spectra: Varian EM 360 L ^ C NMR spectra: Jeol JNM PFT-100 IR spectra: Perkin-Elmer 1420

The specific rotations were measured with a &quot; ATAGO &quot; polarimeter equipped with a Na lamp and the melting points were measured with a &quot; Gallenkamp &quot; melting point meter. The melting points have been corrected. Liquid chromatography (high performance column chromatography HPLC) is performed as follows

Pumps - Waters M-45 G and 510 as well as automatic gradient control detector - Waters model 481 LC spectrophotometer columns - e.g. B. Waters Bondapak Cjg The following examples illustrate the invention:

Example 1: RS-3-Moroholino ^ -G'-tert-butvlamino-2, -hvdroxyproDoxvV1.2.5-thiadiazole (= RS-Timolon 93.6 g (0.5 mol) 3-hydroxy-4-morpholino-1,2,5- thiadiazole are mixed with 750 ml of toluene, and 90 g of a 30% sodium methylate solution are added dropwise to the mixture over the course of about 10 minutes, after which the mixture is stirred for a further 10 minutes and 91 g (= 0.55 mol) of 1-tert -butyI-3-azetidinol hydrochloride and 8.5 g (= 0.025 mol) of tetrabutylammonium hydrogen sulfate are added, the mixture is heated to boiling and distilled to 90 ° C., after which the mixture is stirred under reflux for 10 hours, after which 100 ml of water are added added and stirring is continued for 2 hours under reflux, the mixture is cooled and 800 ml of 3N hydrochloric acid are added at <20 ° C. The mixture is filtered and the water phase of the filtrate becomes alkaline with a concentrated sodium hydroxide solution at <20 ° C. The mixture is mixed with -11-

No. 391 696, 500 ml of methylene chloride are extracted, and the extract is dried and evaporated in vacuo. The oily R, S-timolol base obtained as the evaporation residue is purified by crystallization from a mixture of toluene and hexane, giving approximately 100 g (= 63% of theory) of colorless R, S-timolol base. Salary &gt; 96% (HPLC). S. p. 71 to 72 ° C. 1H-NMR (CDC13: δ 1.1 (s, 9H), 2.4 - 3.0 (m. 3H), 3.3 - 4.0 (m, 9H), 4.3 - 4.5 (d. 2H), 13C-NMR (CDC13): cf. Table 1. IR (KRr tablet): 3280, 3120, 3015, 2950, 2910, 2850, 1525, 1490, 1445, 1415, 1375, 1360, 1325, 1310, 1290, 1255, 1220, 1170, 1120, 1110, 1060,1022, 990,940, 920, 900, 850 cm * 1.

The starting materials used in Example 1 can be prepared as follows: 1-tert-butyl-3-azetidinol hydrochloride: 92.5 g (= 1 mol) of epichlorohydrin are dissolved in 200 ml of ethanol, and the solution is stirred with the mixture within approx 1 hour 73.1 g (= 1 mol) of tert-butylamine are added dropwise. After the exothermic reaction has ended, the solution is boiled under reflux for 1 hour, after which about 90% of the ethanol is distilled off. 200 ml of acetone are added to the residue and the mixture is stirred for 3 hours. The crystalline product is filtered, washed with acetone and recrystallized from isopropanol. The yield obtained is approximately 83 g (= 50% of theory) of colorless 1-tert-butyl-3-azetidinol hydrochloride. Content (HPLC) &gt; 96%. S. p. 157 to 158 ° C. ^ -NMRiCDC ^): δ 1.4 (s, 9H), 4.1 (quintet, 4H), 4.4 - 5.0 (m, 1H), 5.9 (br, s, 1H) 3-Hvdroxv-4-morpholino-1 -2.5- thiadiazole: a. 3-isopropoxy-4-morpholino-l, 2,5-thiadiazole: 17.9 g (0.1 mol) of 3-isopropoxy-4-chloro-l, 2,5-thiadiazole are dissolved in 65 ml of morpholine and the mixture is added to 100 to 110 ° C stirred for 16 hours, and the excess morpholine distilled off in vacuo. 100 ml of methylene chloride are added to the residue, after which the insoluble part is separated off by filtration. The filtrate is washed with 1N hydrochloric acid and water, dried over magnesium sulfate and then filtered. The filtrate is evaporated to dryness in vacuo to give 3-isopropoxy-4-morpholino-l, 2,5-thiadiazole as a yellow, gradually crystallizing oil. The yield is 90 to 95% of the theoretical value. 1H-NMR (CDC13): δ 1.4 -1.5 (d, 6H), 3.4 - 3.9 (m. 8H), 4.9 - 5.4 (Μ, 1H). b. 3-Hydroxy-4-morpholino-l, 2,5-thiadiazole: 22.9 g (= 0.1 mol) of 3-isopropoxy-4-morpholino-l, 2,5-thiadiazole are dissolved in 400 ml of 1,2-dichloroethane and the 75 g (= 0.4 mol) of titanium tetrachloride are added to the mixture with stirring and cooling. The mixture is stirred under reflux for 20 hours, then cooled and, with cooling, 80 ml of water are added

The water phase is made basic with a 20% sodium hydroxide solution, water is added, the mixture is stirred and filtered. The filtrate is acidified with hydrochloric acid, the 3-hydroxy-morpholino-1,2,5-thiadiazole precipitating. The product is separated by filtration, washed with water and dried. The yield obtained is about 12.5 g (= 67% of theory) of a light brown product, which is purified by recrystallization from absolute ethanol. S. p. 197 to 199 ° C. 1H NMR (CD3) 2SO): δ 3.2 - 4.0 (m, 8H).

Example 2

The preparation and decomposition of diacetvl-L-tartaric acid-O-monoester of RS-3-morpholino-4- (3'-tert-butvlamino-2'-hvdroxvDropoxvV1.2.5-thiadiazole 108 g (= 0.5 mol) diacetyl-L- tartaric anhydride (preparation: "Organic Syntheses", Coli. Vol. IV, 2nd edition, 1967, p. 242, in which D-tartaric acid is replaced with L-tartaric acid) are dissolved in 750 ml of methylene chloride and the solution is dissolved within 10 to 158 g (= 0.5 mol) of R, S-timolol base in 350 ml of methylene chloride were added dropwise at room temperature with stirring and the mixture was evaporated to the dry state in a vacuum, yielding 266 g (= 100% of theory) of pure diacetyl-L -tartaric acid-O-monoester of R, S-3-morpholino4- (3'-tert-butylamino-2'-hydroxypropoxy) -l, 2,5-thiadiazole.1H-NMR (CDC13): δ 1.5 (s, 9H ), 2.1 - 2.2 (d, 6H), 3.0 - 4.0 (m, 10H), 4.3 - 5.8 (m, 5H). 13C-NMR ((CD3) 2SO + (CD3) 2CO): see Table 1.IR (KBr tablet): 3420.2970.2840.1745.1635.1530.1495.1445.1370.1310.1290.1255.1220.1115, 1060.970.950.925 cm * 1 MS (CI, i-butane): M + 57 589, Μ + 1 533, 317, 86 -12-

No. 391 696 MS (EI, 70 EV): 517, 386, 130, 86 decomposition 266 g (= 0.5 mol) diacetyl-L-tartaric acid-O-monoester of the R, S-3-morpholino-4- (3'-tert -butylamino-2'-hydroxypropoxy) -l, 2,5-thiadiazole are dissolved in 430 ml of water, which is 2% based on acetic acid and has a pH of 4 to 5 (NH4OH). 290 ml of methanol are added to the mixture, after which the mixture is allowed to crystallize at room temperature for 15 to 20 hours. The product is separated by filtration and washed with cold, 50% ethanol and dried. The optical yield is approx. 93 g (= 70% of theory) of diacetyl-L-tartaric acid-O-monoester of S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -l, 2,5-thiadiazole with an optical purity of &gt; 97% (HPLC). Repeated crystallization gives the optically pure product. S. p. 191 ° C.

[a] D20 ° C = + 20.5 ° (c = 1 g / 10 ml, HOAc). ^ -NMR (CDCI3: CD3OD; 3: 1): 6 1.5 (s, 9H), 2.2 (s, 6H), 2.8 - 4.1 (m, 10H), 4.5 - 5.5 (m, 5H), 13C-NMR ( (CD3) 2SO + (CD3) 2CO): cf. Table 1.IR (KBr tablet): 3450,2970,2890, 2840, 2660, 2610,2400,1750,1735,1590,1530,1495,1445,1390, 1370, 1305,1290, 1255, 1230, 1215, 1195, 1140, 1115, 1090, 1055, 1020, 960, 930, 890, 870, 840 cm * 1.

Example 3 S-3-morpholino-4- (3'-tert-butvlamino2'-hvdroxvpropoxv) -1.2.5-thiadiazole base (= S-timolol base) 106.5 g (= 0.2 mol) diacetyl-L-tartaric acid O-monoesters of S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -l, 2,5-thiadiazole (optical purity> 97%) are mixed with 1.1 liters of water and the pH is adjusted to about 2 with 5% strength sulfuric acid. The mixture is stirred under reflux for 15 hours and cooled to room temperature, and the pH is adjusted to about 12 with a sodium hydroxide solution. The mixture is extracted with 300 ml of methylene chloride, and the extract is washed with 200 ml of water, dried and evaporated in vacuo. About 63 g (= 100% of theory) of oily, gradually crystallizing S-timolol base are obtained as a yield. Product content &gt; 99% (HPLC) and optical purity> 97% (HPLC). ^ -NMR (CDCI3): δ 1.1 (s, 9H), 2.4 - 3.0 (m, 3H), 3.3 - 4.0 (m, 9H), 4.3 - 4.5 (d, 2H). 13C-NMR (CDCI3): cf. Table 1.IR (KBr film): 3400, 2950, 2900, 2840, 1525, 1490, 1440, 1360, 1305, 1290, 1255, 1220, 1110, 1065, 1050,1020,995,945,920,850 cm * 1,

Example 4

Hydrogen maleate of S-3-morpholino-4-ß'-tert-butvlamino-2'-hvdroxypropoxvVlJ2.5-thiadiazole (= hydrogen maleate from S-timolol) 63.3 g (= 0.2 mol) S-timolol base (optical purity > 97%) are dissolved in 100 ml of tetrahydrofuran and a solution of 23.2 g (= 0.2 mol) of maleic acid in 70 ml of tetrahydrofuran is added to the mixture. The mixture is left to stand in ice water for 1 hour, and the precipitated product is filtered off and washed with tetrahydrofuran and air-dried. About 82 g (= 95% of theory) of S-timolol hydrogen maleate are obtained as a yield. Salary &gt; 99% (HPLC) and optical purity &gt; 97% (HPLC). The product can be recrystallized from absolute ethanol in> 95% yield.

[a] D20 ° C = -7.5 ° (c = 2 g / 10 ml, in HCl). S. p. 198 to 199 ° C ^ -NMR ((CD3) 2SO): δ 1.3 (s, 9H), 2.5 (s, 1H), 2.7 - 4.0 (m, 9H), 4.1 - 4.7 (m, 3H). 6.1 (s, 2H). IR (KBr tablet): 3380.3290, 3010, 2965, 2880, 2840, 2560, 250, 1690, 1615, 1570, 1530, 1490, 1445, 1380, 1350, 1310, 1290, 1255, 1225, 1200, 1115 , 1065,1050, 985,950, 860 cm * 1.

Example,?

Regeneration of 3-Hvdroxv-4-morDholino-1.2.5-thiadiazole

Hydrolysis of the L-tartaric acid-O-monoester

From the decomposition of the diacetyl-L-tartaric acid-O-monoester of R, S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -l, 2,5-thiadiazole (cf. Example 2) mother liquor obtained, the methanol and ethanol are evaporated in vacuo, and the residue is hydrolyzed according to Example 3. The released timolol is extracted from an alkaline solution with methylene chloride, and the extract is washed with water, dried and evaporated. About 100 g (= 95% of theory) of oily timolol -13- is obtained as a yield.

No. 391 696

Base containing R and S enantiomers in a ratio of approx. 4: 1

Hydrolysis of the timolol base

The evaporation residue obtained above (100 g = 0.32 mol) is dissolved in 270 ml of isopropyl alcohol and 100 g of a 30% sodium methylate solution (= 0.55 mol) are added to the mixture and the mixture is boiled under reflux for 1 hour. The methanol is distilled off, after which the mixture is still 3 Is refluxed for hours. 135 ml of water are added to the mixture and the pH is adjusted to about 2 using concentrated hydrochloric acid, after which the mixture is stirred in ice water for 2 to 3 hours. The product is filtered, washed with water and air dried. About 54 g (= 90% of theory) of colorless 3-hydroxy-4-morpholino-1,2,5-thiadiazole with a content of about 92 to 94% (HPLC. Contains inorganic salts) are obtained from the yield. After recrystallization from ethanol, the content &gt; 98%. S.p. 192 to 194 ° C. 1H NMR ((CD3) 2SO): 8 3.2 - 4.0 (m, 8H).

Example 6

Preparation and decomposition of the dibenzovl-L-tartaric acid Q-monoester of the R.S-3-morpholino-4- (3'-tert-butvlamino-2'-hvdroxvpropoxv ') - 1.2.5-thiadiazole

The dibenzoyl-L-tartaric acid-O-monoester of R, S-3-morpholino-4- (3, -tert-butylamino-2, -hydroxypropoxy) -1,2,5-thiadiazole is obtained by the method described in Example 2 , but using dibenzoyl-L-tartaric anhydride in place of diacetyl-L-tartaric anhydride (manufactured by: J. Am. Chem. Soc. 55 (1933) 2605), wherein the D-tartaric acid replaces the L-tartaric acid becomes). The yield obtained is 312 g (= 100% of theory) of pure product 13C-NMR ((CD3) 2SO + (CD3) 2CO): cf. Table 1.IR (KBr tablet): 3410, 3050, 3025, 2960, 2840, 1760, 1720, 1640, 1600, 1560, 1530, 1500, 1445, 1380, 1370, 1310, 1290, 1255, 1170, 1110, 1065,1020,1000,950 cm-1.

Disassembly 10 g of the above-prepared dibenzoyl-L-tartaric acid-O-monoester of R, S-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -l, 2,5-thiadiazole are heated with 200 ml of methanol are mixed and the mixture is filtered hot. The precipitate is dried, giving about 4 g (= 80% of theory) of dibenzoyl-L-tartaric acid-O-monoester of S-morpholino-4- (3'-tert-butylamino -2, -hydroxypropoxy) -l, 2,5-thiadiazole, whose optical purity &gt; 97% (HPLC). S. p. 92 to 93 ° C.

[a] D20 ° c = 44.0 ° (c = 1 g / 10 ml HOAc). ^ -NMR (CDC13): 5 1.4 (s, 9H), 2.8 - 3.9 (m, 9H), 4.7 (m, 2H), 5.2 (s, 1H), 5.5 (q, 2H), 7.2 - 8.2 (m , 10H), 9.0 (s, 1H) 13C-NMR ((CD3) 2SO + (CD3) 2CO): cf. Table 1. IR (KBr tablets): identical compared to the corresponding racemic compound (see above).

The residue formed on cooling the filtrate after filtering above is filtered and dried, about 3.5 g (= 70% of theory) of dibenzoyl-L-tartaric acid-O-monoester of R-morpholino-4- (3'- tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole with an optical purity of &gt; 97% (HPLC) obtained. Repeating the treatment with methanol gives both the S and R enantiomers with an optical purity &gt; 99.5%. The S and R esters can be hydrolyzed by the procedure outlined in Example 3 to give S and R timolol

Example 7

Production of the hydrogen maleate from R-Timolol

Substance 1: Preparation and decomposition of the diacetyl-D-tartaric acid-O-monoester of R, S-3-morpholino-4- (3-tert-butylamino-2'-hydroxypropoxy) -l, 2,5-thiadiazole: 108 g (0.5 mol) of diacetyl-D-tartaric anhydride (preparation: Organic Syntheses, Coli. Vol. IV, 2nd edition 1967, p. 242) are dissolved in 750 ml of methylene chloride and 158 g are added to the solution within 10 to 15 minutes at room temperature (= 0.5 mol) R, S-timolol base added dropwise in 350 ml methylene chloride and evaporated to dryness in vacuo. The yield obtained is 266 g (= 100% of theory) of pure diacetyl-D-tartaric acid O-monoester desR, S-3-morpholino-4- (3'-tert-butylammo-2, -hydroxypropoxy) -l, 2.5 thiadiazole.

Decomposition 266 g (= 0.5 mol) diacetyl-D-tartaric acid-O-monoester of R, S-3-morpholino-4- (3, -tert-butylamino-2'- -14-

Claims (1)

No. 391 696 hydroxypropoxy) -1, 2,5-thiadiazole are dissolved in 430 ml of water, which is 2% with respect to acetic acid, 290 ml of methanol are added to the solution, after which the solution is stirred for 15 to 20 hours can crystallize at room temperature. The product is separated by filtration and washed with cold, 50% ethanol and dried. About 100 g (= 75% of theory) of diacetyl-D-tartaric acid-O-monoester of R-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -l is obtained as the optical yield, 2,5-thiadiazole with an optical purity of> 97% (HPLC). When the crystallization is repeated, optically pure substance is obtained. [a] D20 ° C = -20.5 ° (c = 1 g / 10 ml, HOAc). Step 2. R-3-morpholino-4- (3, -tert-butylamino-2, -hydroxypropoxy) -l, 2,5-thiadiazole base (= R-timolol base): 106.5 g (= 0.2 mol) Diacetyl-D-tartaric acid O-monoester of R-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole (optical purity> 97%) are mixed with 1.1 Liters of water are mixed and the pH is adjusted to 2 with 5% sulfuric acid. The solution is stirred under reflux for 15 hours and cooled to room temperature, and the pH is adjusted to about 12 using a sodium hydroxide solution. The mixture is extracted with 300 ml of methylene chloride, and the extract is washed with 200 ml of water, dried and evaporated in vacuo. About 63 g (= 100% of theory) of oily R-timolol base are obtained as a yield. Content> 99% optical purity> 97% (HPLC). Stage 3. Hydrogen maleate of R-3-moipholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -l, 2,5-thiadiazole (= hydrogen maleate of R-timolol): 63.3 g (= 0.2 mol) R-timolol base (optical purity> 97%) is dissolved in 100 ml of tetrahydrofuran and a solution of 23.2 g (= 0.2 mol) of maleic acid in 70 ml of tetrahydrofuran is added to the mixture. The solution is left to stand in ice water for 1 hour and the precipitated product is separated off by filtration, washed with tetrahydrofuran and dried in the air. Approx. 84 g (= 97% of theory) of R-timolol hydrogen maleaL content &gt; 99% (HPLC) and optical purity &gt; 97% (HPLC). The product can be extracted from absolute ethanol with a yield of &gt; 95% are recrystallized. [a] D20 ° C = + 7.5 ° (c = 2 g / 10 ml, in HCl). S. p. 193 to 194 ° C. PATENT CLAIM Process for the preparation of S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -l, 2,5-thiadiazole of the formula ff \ H OH (S-I) N i N -15- No. 391 696, characterized in that R, S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -l, 2,5-thiadiazole of the formula rr \ / 0-CH7 -CH-CH_-NH-C (CH0) _ '2 | 2 3 3 OH r N N with a dialkanoyl, diaroyl or alkanoyl aroyl-L-tartaric anhydride of the formula (L-XIX) wherein and R ^ are the same or different and are a straight-chain or branched alkanoyl group having 1 to 5 carbon atoms in the alkyl group, a benzoyl or a p-methylbenzoyl group, is reacted in an inert anhydrous organic solvent, and the resulting Compound of formula 0-CH, -CH-CH5-NH-C (CHo) o \ _ / A I -i C = 0 R, S-I-L-XIX \ / I H - C - &lt; OR4 R, 0 "- C -" H 5 I COOH in which R4 and R ^ have the same meaning as above, is subjected to a decomposition by the compound from an alcohol having 1 to 5 carbon atoms, or from an aqueous solution of such an alcohol, is crystallized in a pH range from 7 to 2 and in a temperature range from 0 to 30 ° C., and the compound of the formula -16- 5 No. 391 696 obtained in crystallized form HT \ _ / 0-CH? -C-CH - NH-C (CHa) - / ά \ ά 3 3 10 Π H 15 RcO 5 0I C = 0I C - OR, I 1 C - HI COOH SIL-XIX subjected to acid hydrolysis from an aqueous solution to form the desired product. -17-