DD234011A5 - METHOD FOR PRODUCING NEW TIMALD INTERMEDIATE PRODUCTS - Google Patents

Abstract

The invention relates to novel dialkanoyl, diaroyl or alkanoyl-aroyl-L-tartaric acid O-monoesters of 3-morpholino-4- (3-tert-butylamino-2-hydroxypropoxy) -1,2,5-thiadiazole of the formula (Rdie Alkyl or aryl group) which are intermediates in the preparation of the valuable b-blocking acting S-3-morpholino-4- (3-tert-butylamino-2-hydroxypropoxy) -1,2,5-thiadiazole d. H. of S-timolol and its acid addition salts. The said L-tartaric acid O-monoesters are prepared from the corresponding L-tartaric anhydride and R, S-timolol, and their decomposition by crystallization of the racemic ester from an alcohol or from a mixture of alcohol and water in a p H- Range of 7 to 2, wherein the L-tartaric acid O-monoester of S-timolol is obtained in the optically pure form, from which the S-timolol is released by Saeurehydrolyse and can be converted to the desired Saeuresalz. formula

Description

New timolol intermediates, their use and manufacture

Field of application of the invention

The invention relates to novel intermediates for the preparation of the pharmacologically valuable β-blocking acting S-3-morpholinop-4- (3'-tert-butylamino-2'-hydroxy-W propoxy) -1, 2,5-thiadiazole and its acid addition salts , as well as their use and manufacture. ,

Characteristic of the known technical solutions

The preparation of this compound - which is also known as timolol and whose formula is as follows:

v-c

HN

-CH ₂ -NH-CCCH ₃ ). OH

either as a racemic mixture, i. R, S-form or as R or S-enantiomer is described in numerous patents. In U.S. Patents 3,655,663 and 3,729,469, R, S-timolol is prepared by the process of Scheme 1 by first preparing a 3-Ro ~ / 4-OH-substituted 1,2,5-thiadiazole of Formula II, wherein Ro is chloro or the morpholino group, or its alkali metal salt is reacted with epichlorohydrin in the presence of a basic catalyst, after which the intermediate

λ 1

968134

hydroxyacetide of the formula III or the epoxide of the formula IV formed therefrom under alkaline conditions is reacted with tert-butylamine, where

Scheme 1

DH

I ί ⁺ H ₂ C _n -CH-CH ₂ Cl

O-CH, -CH-CH, C1

in the

N N Il

epichlorohydrin

H NS

0-CH ₂ -CH-CH ₂

O-CH-CH-CH, -NH-C (CHJ

an R / S-alkanolamine of the formula V is obtained which

is identical to R, S-timolol when Rq is a morpholino group. When Rq in the formula V is chlorine, it can be replaced by treating with an excess of morpholine with the morpholino group.

From the hydroxy halide III or from the epoxide IV according to Scheme 1, the alkanolamine of the formula V is also obtained by first treating it with ammonia to give a primary alkanolamine of the formula VI which reacts with tert-butyl chloride to give the alkanolamine of the formula V forms.

According to Japanese Patent 7413176 R, S-timolol is by reaction of a sulfonyl ester of the formula VII,

0-CH ₂ -CH-CH ₂ -O-SO ₂ -R VII OH

N N S '

wherein R ^ represents an alkyl or aryl group, prepared with tert-butylamine.

Spanish patent specification 486629 describes a process according to Scheme 2 for the preparation of R, S-timolol in which the diethyl acetal of glycidaldehyde (formula VIII) is reacted with an alkali metal salt of the 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),

SchenH 2

ON. ₀ "θO _CM-2 - _i .M tH (Ot _J l _{5). 2}

Il VIII IX

-> R _n O-CH.-CH-CHD

NNN

'- > R, S-Tiitolol

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

In US Patent 3, 655.663 the separation of the racemic alkanolamine of the formula V (Rg = chloro) through optically active salts, such as with 0,0-di-toluoyl - (+) - or - (-) - tartaric acid, 0 , O-dibenzoyl - (+) - or - (-) - tartaric acid or (+) - or (- ^ - tartaric acid described The S-enantiomer of the formula V (Ro = chlorine) - from the S-timolol by treatment with Morpholine can be prepared - has been obtained from the, after the separation of said salts, under given conditions of easier precipitating R-enantiomers, mother liquors

low and the R-form remained unused. The preparation of an optically pure or almost pure, or an appropriate according to drug requirements S-enantiomer by such salt crystallization also requires practically difficult to carry out fractionated crystallizations, resulting in a further decrease in the yield.

The preparation of the enantiomers of the formula I from starting materials with desired stereochemistry is described, for example, in US Pat. Nos. 3,655,663, 3,657,237 and 3,729,469. For the preparation of S-timolol (see Scheme 3), the starting material used was D-glyceraldehyde (formula XII) or its 2,3-acetonide (formula XIII), which are obtained by reducing amination in the presence of tert-butylamine, and in the formula Related to the 2,3-acetonide after acid hydrolysis, SI, 2-dihydroxy-3-tert-butylamino-propane (formula S-XIV) obtained as such or in the 1-position, for example by a benzenesulfonyl or tosyl group , activated (formula S-XIV-A, R ₃ = H, CH ₃ , NO ₂ , Br) or as the corresponding S-oxazolidine (formula S-XV, R ₂ = H, (CH ₃ J ₂ CH-, C ₆ H ₅ - etc.), which may also be activated (formula S-XV-A), with 1,2,5-thiadiazole (Rq = morpholino group) of formula II or

Schena 3

CHO HC-DH CHOHCHO HD

D-glyceraldehyde

XMI

Red. CH ₂ -CH-CH ₂ -NH-C (CH OH OH

SO ₂ ClS-XIV

R CHO

CH-CH-CH_-NH-C (CHj,

I ² I ^{2 3}

OH

S-XIV-AHO-CH ₂ -CH-CH ₂

S-XV-A-SO ₂ -O-CH ₂ -CH-CH ₂

O _x U (CH ₃ ) j CH

Il

S-timolol

3-chloro-4-morpholino-l, 2,5-thiadiazole (Formula XVI) is reacted in the presence of alkalis, after which, when oxazolidines are used as intermediates, these are hydrolyzed by acid treatment, the product being in all cases S-timolol is obtained. Some of these methods produce satisfactory or good yields, but their general use is limited by the high price and 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 abovementioned processes, some alternative processes for the preparation of S-timolol. Thus, a D ^ -10-camphorsulfonate salt of the S-1,2-epoxide prepared from the tosylate of the formula S-XIV-A (R 3 = CH 3) with 3-morpholino-4-hydroxy-1,2,5-thiadiazole ( Formula II, Na-SaIz) to give S-timolol as a product.

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

S-timolol is also obtained by treatment with sulfur monochloride of the obtained by reacting 1-morpholino and oxazolidine of the formula S-XV S-Diiitrils the Formal XVII

-CH-CH ₂ -NH-C (CH) XVII) H

been prepared.

U.S. Patent No. 3,619,370 discloses a process for preparing timolol by reducing a corresponding ketone according to Scheme 4, either chemically with sodium borohydride or aluminum alkoxides, to give racemic

Scheme 4

R, S-I 0.

-IN N

XVlIl

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

Owing to the very labile nature of both the ketone and some intermediates used in the reaction, we have failed to repeat the process of making the ketone of formula XVIII cited in said patent, so that the said

y -

Production method of the ketone (XVIII) at least not suitable for the scale of an industrial production.

Object of the invention

The invention relates to a process for the preparation of S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) 1,2,5-thiadiazole (formula I), ie of S-timolol, from the - ^ ^r>, sen racemate by at whose Dialkanoyl-, Diaroyl- or alkanoyl aroyl-L-tartaric acid-O-monoestern according to the formula R, SIL-XIX, scheme 5, a decomposition is performed, in which formula R 4, and R5 independently represent a straight or branched alkanoyl group having 1 to 5 carbon atoms in the alkyl group, a benzoyl or p-methylbenzoyl group.

Accordingly, R4 and R5 represent, as an alkanoyl group, the acetyl, propionyl, butyryl, pentanoyl or hexanoyl group which may be a straight or branched group, and preferably represents the acetyl group.

CD Presentation of the essence of the invention

The monoesters of the formula R, SIL-XIX, the novel compounds and as such are the subject of the invention, can easily be prepared by reacting the R, S-timolol base (R, SI) with a dialkanoyl, diaroyl or alkanoyl-aroyl L-tartaric anhydride of the 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 0 -. 70 ⁰ C for a reaction time of 10 minutes to 3 STUN

to be made. Evaporation of the solvent gives the dialkanoyl, diaroyl or alkanoyl-aryl-L-tartaric acid O-monoester of R, S-timolol pure and with a quantitative yield. We have already found that the substitution under the given conditions is only as an O substitution, as confirmed by the mass spectra measured on the products, in which there are no fragments characteristic of the N-substituted molecule, whereas the fragment m / z 86 (CH ₂ = ^ JH-C (CH ₃ ) ₃ , also the morpholino group) occurs strongly. If the product were N-substituted, ie an amide, it would not hydrolyze appreciably under the hydrolysis conditions typical of an O-substituted product, ie an ester.

Very surprisingly, it was found that the decomposition of an R, S-timolol dialkanoyl, -diaroyl or -alkanoylaroyl-L-tartaric acid O-monoester (Formula R, SIL-XIX) with a very good both chemical and optical yield can be carried out by the racemate

like methanol,

Scliena 5

4 H »-

H H

- It

L-XIX

H ₁ SIL-XIX

O-CH.-C-CH-NH-C (CH ₁ ), O-CH-C-CH.-MH-t (CHJ

N N

»I - R.0 -

R-I-L-XIX S-I-L-XIX

-0

- H

TOOH

R tolnol base

H ₂ -C-

OH

S-Tirolol base

Ethanol, n-propanol or isopropanol or from their mixtures or aqueous solutions in a pH range of 7 to 2 and in a temperature range of 0 to 30 ° C is crystallized, wherein the S-enantiomer of Timololdialkanoyl-, -diaroyl- or - alkanoyl-aroyl-L-tartaric acid O-monoester (formula SIL-XIX) due to its lower solubility in the above solutions or solution mixtures, can be crystallized and separated from the mother liquor by known methods.

Crystallization of the R, S-timololdiacetyl-L-tartaric acid O-monoester (formula R, SIL-XIX; R4 = R5 = CH3-CO-) has been found to be a particularly advantageous manner for carrying out the decomposition from a mixture of water and Methanol in a pH range of about 4 to 5 at room temperature or in a temperature range of 0 to 30 ⁰ C, wherein the S-enantiomer with a yield of about 75% and with an optical purity of the product of> 97% crystallized. Recrystallization gives optically pure S-timolol diacetyl-L-tartaric acid O-monoester. This very advantageous optical yield may be due primarily to the strong tendency of the S-form of the timolol-L-tartaric acid derivative to form an internal salt under the existing crystallization conditions due to the stereochemical structure, as well as the poor solubility of this salt the crystallization solution mixture.

The peaks found in the IR spectra are typical in the ranges of 1575 to 1600 cm -1 and 2250 to 2700 cm -1 (1 to 5 peaks) and the perception made in the 13 C NMR spectra that the Carbon atom 2 signal (see the structural formula and the values of Table 1) has shifted by 5 - 7 ppm in the lower field, which is characteristic when an acid group

Salt structure (- + NH ₂ -) (see Acta Chem. Scand. B 38 (1984) 67) are an indication that the S-timolol-L-tartaric acid derivative occurs as an internal salt. These perceptions based on the salt structure in the IR and 1 ³ ONMR spectra also show that the reaction of the R, S-timolol with the dialkanoyl, diaroyl or alkanoyl-aroyl-L-tartaric anhydride as an O Substitution and not as an N substitution, since in the latter case, no formation of an inner salt would occur. Table 1 lists the chemical shifts in the ¹³ C-NMR spectra of the S and R, S-timololdiacetyl-L-tartaric acid O-monoesters and the corresponding dibenzoyl esters as well as the S-timolol base. The S-timolol base can be prepared from said O-esters by acid hydrolysis in aqueous solution for 1 to 24 hours in a pH range of 0 to 5 and in a temperature range of 25 to 100 ⁰ C using, for example, mineral acid such as sulfuric acid or Phosphoric acid to be released.

It has proved advantageous to boil an aqueous solution, adjusted to pH 2 with sulfuric acid, for 10 hours under reflux. The recovery of the S-timolol base is carried out by precipitating it from e.g. with alkaline hydroxide or ammonia alkalized (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 distilling the solvent in almost quantitative yield can be obtained with an optical purity of> 97%. Optionally, the S-timolol base may be further purified by crystallization from an organic solvent, or it may be converted to the corresponding acid addition salt, such as the hydrochloride or hydrogen maleate, in a manner known per se.

Table 1

ct

0 - CH - CH -

I ₁

 CH

10. CH - CH

0 0

1 I C-O C-O

CH,

- NH

2.1 ^J 1.

• L; ^c "

Formula I-L-XIX

• R Configuration Solvent medium ^C 1 ^C 2 ^C 3 69.5 ^C 5 6 9 ^C 6 9 8th C 7 7 ^C 8 C 3 So ^ i Other , C - 0 β sign. CH ₃ R ₁ S ((COJ-SO + 1 (COj) JCO 25.2 • 55.8 56.1 ttsign.) D 69.3 73 6 7 152nd 8th Il hg .67 5 Ί7.5 65 .8th 73.0 75.0 2) R-CH- 166.3-169 .9. t. sign. CH S K 25.1 55.8. 0 69-75 73 70-75 152nd 153.9 (2s <n.) 1 ' "9 I Ί7.Ί 65 .7 75.0 166.6-168 .9. 5 sign. Vs R, S (CO ₃ J ₂ CO 26.2 57.Ί (2 signed) 69-71 73 152nd 150.6 (2signy · Ί8.6 66 .8th 67-75 (π) 3) 129.2- 166.0-170 .-. 5 s ίςη. V ₅ S J (COJ ₂ SO * 25.7 5 * .S 1) 67.8 72 153rd ng ! • 7/3 65 5 ' 69-75 3) 128.1- 133.9 164.9-167 .8th. Tinoial Base S and R, S CDC ₃ 28.9 50.3 * * * lie to 1.7.8 66 3 - - -

^C 3. remains covered by the solvent

2) remains covered by the solvent

R w C * ·

The decomposition of the R, S-timolol by crystallization of the corresponding dialkanoyl, diaroyl or alkanoylaroyl-L-tartaric acid O-monoester (formula R, SIL-XIX) preferably the diacetyl ester from an alcohol or an alcohol-water mixture in a pH range <J and in a temperature range of 0 to 30 ⁰ C, wherein the L-tartaric acid O-monoester (formula SIL-XIX) of S-timolol can be separated in a good yield and optically almost pure, and hydrolysis of it in a pH range of 0 to 5 to S-timolol has been found to be a very advantageous process for the preparation of the substance in question, and to the best of our knowledge in the literature to date for alkanolamines of this type did not disclose such a decomposition in which, by a single crystallization, one of the enantiomers would have been obtained in good yield or even optically pure.

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

Since the S-esters can be hydrolyzed easily and with very good yield without racemization to S-timolol, the decomposition is also suitable for production on an industrial scale. This process for the preparation of the S-timolol is also advantageous in that the dialkoxylic, diaroyl or alkanoyl-aroyl-L-tartaric acid O-monoesters of R, S-timolol to be used as starting materials for the decomposition using racemic timolol and known from the literature, easy to produce L-Teinsäureanhydriden, can be prepared, and that as starting materials not such substances, as in most

literature processes are known in which the chiral center is already present in the correct stereochemical configuration and which are usually difficult to manufacture and expensive.

Another fact which makes the process of the present invention very advantageous is that of the mother liquor obtained by separating the S-timolol-L-tartaric acid O-monoester, which contains mainly the above R-enantiomer, the "valuable" part ie 3-morpholino-4-hydroxy-1,2,5-thiadiazole can be readily regenerated by hydrolyzing the stearic bond of timolol (see Example 5).

In the case of the R enantiomer of timolol, it is also possible to carry out inversion in the manner known in principle from the literature (cf., for example, Japanese Patent 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, J. Chem. Soc., Chem. Commun. (1974) 309) and using the racemate as the starting material for the above decomposition.

In addition to the processes described in the literature, the R, S-timolol can also be prepared by the process known per se in Scheme 6 (cf., for example, Japanese Patent 72 19 259 or Spanish Pat. No. 459,725) using 3-hydroxy-4-. morpholino-1,2,5-thiadiazole or, preferably, its alkali metal salt (formula XX, R ₆ = H, Na, K) and also L-tert-butyl-3-azetidinol or its hydrochloride (formula XXI) or another acid addition salt as starting materials become.

Scheme g

χ HCI> R _f 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 of 40 to 160 ^° C. with a reaction time of 1 to 24 hours. It is advantageous to use in the reaction the equivalent amounts of starting materials or an excess of from 5 to 10% of azetidinol (formula XXI). 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 recovered by extracting its acid addition salt into the water and the alkali liberated base thereof into an organic solvent and evaporating 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 due to the presence of tautometal species in the 3-hydroxy-1, 2,5-thiadiazoles

In the reaction according to Scheme 6, an N-substitution is possible even under the above reaction conditions, but the O-substitution has proved to be the main reaction. The small amount of by-product resulting from the N-substitution can easily be hydrolyzed by addition of water at the end of the reaction and by continuing reflux for a further 1 to hours, with hydrolysis of the N-substituted by-product being quantitative and among those used Conditions does not affect the recovery or purification of the desired product.

The 3-hydroxy-4-morpholino-l, 2,5-thiadiazole (formula XX) used as the 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, for example, J. Org. Chem. 41 (1976) 3121 and J. Org. Chem. 32 (1967) 2823 and DE Patent 1,914,496), some of which are set forth in Scheme 7.

Scheme 7

C -

N N

cyan

III Il '

NH

Alkylcyanoformimidat

t - C '

in II

H HCt

Alkylyanochloroform formimidate

SCl.

Cl

C- /

I

N NH ₂ cyanoformamide S ₂ Cl ₂

H H

Cl

XX) I

hydrolysis

OH

HN

3-chloro-4-hydroxy-1,2,5-thiadlazol

H.C.C.

² I III HX *

»J

α-aminoacetonitrile

SC

egg. * et

Ί-Ii

H H

3,4-Dlchlor-1,2,5-thiadiazole

Morptiolin

Cl

3-C3ilor-4! Tc> rpholino-1,2,5-thiadazol

DHS0 / NaOH-H ₂ O

OH

N N

3-hydroxy-4-niorpholino-1,2,5-thiadiazol

(XX)

An alternative, shown in Scheme 8 (see Example 1) for the preparation of 3-hydroxy-4-morpholino-1 , 2 , 5-thiadiazole is carried out by reacting 3-chloro-4-alkoxy-1,2,5-thiadiazole (Formula XXII, R ₇ = C ₁ - C ^ alkyl) with morpholine and by subsequent hydrolysis by known methods of the obtained as an intermediate

scheme

CJ

if

XXIl XXIM

3-morpholino-4-alkoxy-l _i 2, 5-thi.adiazols (Formula XXIII), Rj as above) to give 3-morpholino-4-hydroxy-l, 2,5-thiadiazole.

The 1-tert-butyl-3-azetidinol used as the other starting material in the method for the preparation of R, S-timolol by Scheme 6 and its hydrochloride (Formula XXI) or another acid addition salt can advantageously of epichlorohydrin and tert-butylamine as claimed in any of Chem. 32 (1976) 2972), which we have improved to give pure 1-tert-butyl-3-azetidinol hydrochloride with a yield of 60% (see J. Org. Chem. see example 1).

-Zl-

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

Mass spectra: Jeol JMS D 300 / JMA 2000 H

iH NMR spectra: Varian EM 360 L

13c NMR spectra: Jeol JNM PFT-100

IR spectra: Perkin-Elmer 1420

The specific rotations were measured with an "ATAGO" polarimeter provided with a Na lamp and the melting points measured with a "Gallenkamp" melt point meter. The melting points have been corrected. The liquid chromatography (high-performance column chromatography HPLC) is carried out as follows:

Pumps - Waters M-45 G and 510 as well

automatic gradient control

Detector - Waters - Model 481 LC Spectrophotometer

Columns - e.g. Waters Bondapak

embodiments

The following examples illustrate the invention:

Example 1;

R _/ S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) - _f l 2,5-thiadiazole (= R, S-timolol)

93.6 g (0.5 mol) of 3-hydroxy-4-morpholino-l, 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 within about 10 minutes. After the addition, the mixture is stirred for 10 minutes and 91 g (= 0.55 mol) of 1-tert-butyl-3-azetidinol hydrochloride and 8.5 g (= 0.025 mol) of tetrabutylammonium hydrogen sulfate added. The mixture is heated to boiling and distilled to 90 ⁰ C, after which the mixture is stirred under reflux for 10 hours. Thereafter, 100 ml of water are added, and stirred under reflux for 2 hours, cooled and mixed at <20 ⁰ C 800 ml of 3N hydrochloric acid. The mixture is filtered fj ^ and the water phase of the filtrate is made alkaline with a concentrated sodium hydroxide solution at <20 ⁰ C. The mixture is extracted with 500 ml of methylene chloride and the extract is dried and evaporated in vacuo. The oily R, S-timolol base obtained as evaporation residue is purified by crystallization from a mixture of toluene and hexane to give about 100 g (= 63% of theory) of colorless R, S-timolol base. Content> 96% (HPLC). Sp 71 to 72 ° C. ¹ H-NMR (CDCl 3: Sl.1 (s, 9H), 2.4-3.0 (m 3H), 3.3-4.0 (m, 9H), 4.3-4.5 (d 2H), 13 C-NMR (CDCl 3): see 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 "l.

The starting materials used in Example 1 can be prepared as follows:

L-tert-butyl-B-azetidinol hydrochloride ;

92.5 g (= 1 mol) of epichlorohydrin are dissolved in 200 ml of ethanol, and to the solution 73.1 g (= 1 mol) of tert-butylamine are added dropwise with stirring over about 1 hour. After completion of the exothermic reaction, the solution is refluxed for 1 hour, after which about 90% of the ethanol is distilled off. 200 ml of acetone are added to the residue and stirred for 3 hours. The crystalline product is filtered, washed with acetone and recrystallized from isopropanol. The yield obtained is about 83 g (= 50% of theor.) Colorless L-tert-butyl-3-azetidinol hydrochloride. Content (HPLC)> 96%. B.p. 157 to 158 ° C.

1 H NMR (CDCl ₃ ): δ 1.4 (s, 9H), 4.1 (quintet, 4H), 4.4-5.0 (m, IH), 5.9 (br, s, IH)

3-hydroxy-4-morpholino-1,2,5-thiadiazole :

a. 3-Isopropoxy-4-morpholino-1,2,5-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 stirred at 100 to 110 ⁰ C for 16 hours, and the excess morpholine in vacuo distilled off. To the residue is added 100 ml of methylene chloride, after which the insoluble part is separated by filtration. The filtrate is washed with 1 N 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-1,2,5-thiadiazole as a yellow one gradually

receives crystallizing oil. The yield is 90 to 95% of the theoretical.

1 H NMR (CDCl ₃ ): 6 1.4-1.5 (d, 6H), 3.4-3.9 (m 8H), 4.9-5.4 (M, IH).

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 mixture with stirring and cooling 75 g (= 0.4 mol) of titanium tetrachloride added. The mixture is stirred for 20 hours under reflux, then cooled and treated with cooling with 80 ml of water.

The aqueous phase is basified with a 20% sodium hydroxide solution, mixed with water, stirred and filtered. The filtrate is acidified with hydrochloric acid to precipitate the 3-hydroxy-morpholino-1,2,5-thiadiazole. The product is separated by filtration, washed with water and dried. The yield obtained is about 12.5 g (= 67% of theor.) Of a light brown product, which is purified by recrystallization from absolute ethanol. B.p. 197 to 199 ° C

Ih NMR (CD ₃ J ₂ SO): 63.2-4.0 (m, 8H).

Example 2

The preparation and decomposition of diacetyl-L-tartaric acid O-monoester of

R, S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole

108 g (= 0.5 mol) of diacetyl-L-tartaric anhydride (preparation: "Organic Syntheses", Coll. 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 within 15 to 15 minutes at room temperature with stirring 158 g (= 0.5 mol) of R, S-timolol base added dropwise in 350 ml of methylene chloride and evaporated to dryness in vacuo. The yield obtained is 266 g (= 100% of theory) of pure diacetyl-L-tartaric acid O-monoester of R, S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1 , 2, 5-thiadiazoles.

Ih NMR (CDCl ₃ ): 6 1.5 (s, 9H), 2.1-2.2 (d, 6H), 3.0-4.0) (m, 10H), 4.3-5.8 (m, 5H). ,

13C NMR ((CD ₃ J ₂ SO + (CD ₃ J ₂ CO): 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, M + I 533, 317, 86 MS (EI, 70 EV): 517, 386, 130, 86

decomposition

266 g (= 0.5 mol) of diacetyl-L-tartaric acid O-monoester of R, S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole be in 430 ml of water, which is 2% with respect to acetic acid, and a pH of 4 to 5 (NH4OH), dissolved. The mixture is mixed with 290 ml of methanol, 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 about 93 g (= 70% of theor.) Diacetyl-L-tartaric acid O-monoester of S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1, 2,5-thiadiazoles with an optical purity of> 97% (HPLC).

Repeated crystallization gives the optically pure product. B.p. 191 ° C.

[α] 20 ° C = + 20.5 ° (c = 1 g / 10 ml, HOAc).

¹ H-NMR (CDCl ₃ : CD ₃ OD; 3: 1): δ 1.5 (s, 9H), 2.2 (s, 6H),

2.8-4.1 (m, 10H), 4.5-5.5 (m, 5H),

I ³ C-NMR ((CD ₃ J ₂ SO + (CD ₃ J ₂ CO): see 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-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole base (= S-timolol base).

106.5 g (= 0.2 mol) of diacetyl-L-tartaric acid O-monoester of S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole (optical purity> 97%) are mixed with 1 liter of water and the pH is adjusted to about 2 with 5% strength sulfuric acid. The mixture is stirred at 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. 63 g (= 100% of theor.) Of the oily, gradually crystallizing S-timolol base are obtained as the yield. Product content> 99% (HPLC) and optical purity> 97% (HPLC). 1 H NMR (CDCl ₃ ): 5 1.1 (s, 9H), 2.4-3.0 (m, 3H), 3.3-4.0 (m, 9H), 4.3-4.5 (i.e., 2H).

13C-NMR _(CDCl3): see FIG. Table 1. IR (KBr-FiIm): 3400, 2950, 2900, 2840, 1525, 1490, 1440, 1360, 1305, 1290, 1255, 1220, 1110, 1065, 1050, 1020, 995, 945, 920, 850 cm "!,

Example 4

Hydrogen maleate of S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole (= hydrogen maleate of S-timolol) .

63.3 g (= 0.2 mol) of S-timolol base (optical purity> 97%) are dissolved in 100 ml of tetrahydrofuran and to the mixture is added a solution of 23.2 g (= 0.2 mol) of maleic acid in 70 ml of tetrahydrofuran. The mixture is allowed to stand for 1 hour in ice-water and the precipitated product is separated by filtration and washed with tetrahydrofuran and dried in the air to give about 82 g (= 95% of theor.) Of S-timolol hydrogen maleate > 99% (HPLC) and optical purity> 97% (HPLC) The product can be recrystallized from absolute ethanol with a yield> 95%.

[α] 20 ^o C = _7. ₅ o ( _C = 2 g / 10 ml, in HCl). Sp 198 to 199 ° C.

iH NMR ((CD ₃ J ₂ SO): δ 1.3 (s, 9H), 2.5 (s, IH), 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, 2450, 1690, 1615, 1570, 1530, 1490, 1445, 1380, 1350, 1310, 1290, 1255, 1225, 1200, 1115, 1065, 1050, 985, 950,

860 cm " ¹ .

Example 5 Regeneration of 3-hydroxy-4-morpholino-l, 2,5-thiadiazole Hydrolysis of L-tartaric acid O-monoester

From the decomposition of the diacetyl-L-tartaric acid O-monoester of R, S-3-morpholino-4- (3'-tert-butyl-amino-2'-hydroxypropoxy) -1, 2,5-thiadiazole (see Example 2), the methanol and ethanol are evaporated in vacuo, and the residue is hydrolyzed according to Example 3. The liberated timolol is extracted from an alkaline solution with methylene chloride, and the extract is washed with water, dried and evaporated. The yield is about 100 g (= 95% of theor.) Oily timolol base containing R and S enantiomers in the ratio of about 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 to the mixture 100 g of a 30% sodium methylate solution (= 0.55 mol) was added and refluxed for 1 hour. The methanol is distilled off, after which the mixture is refluxed for a further 3 hours. 135 ml of water are added to the mixture and the pH is adjusted to about 2 with concentrated hydrochloric acid, after which the mixture is stirred for 2 to 3 hours in ice-water. The product is filtered, washed with water and dried in the air. 54 g (= 90% of theor.) Of colorless 3-hydroxy-4-morpholino-1,2,5-thiadiazole having a content of about 92 to 94% (HPLC, contains inorganic salts) are obtained from the yield. After the recrystallization from ethanol

The content is> 98%. Sp 192-194 ° C ((CD ₃ ) ₂ SO): 63.2-4.0 (m, 8H).

Example 6

Preparation and decomposition of the dibenzoyl-L-tartaric acid O-monoester of R, S-3-morpholino-4- (3'-tert-butylamino-2 ¹ -hydroxypropoxy) -1,2,5-thiadiazole

The dibenzoyl-L-tartaric acid O-monoester of R, S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -l, 2 , 5-thiadiazole is prepared by the method described in Example 2 but using dibenzoyl-L-tartaric anhydride instead of diacetyl-L-tartaric anhydride (manufactured by J. Am. Chem. Soc. 55 (1933) 2605, in which the D-tartaric acid is replaced with L-tartaric acid becomes). The yield obtained is 312 g (= 100% of theory) of pure product.

IH-NMR _(CDCl3): 61.1-1.5 (2s, 9H), 2.8-4.0 (m, 10H), 4.2-5.0 (s, 2H), 5.0-5.9 (m, 3H), 7.0-8.3 (m, 10H). 13c-NMR (CD ₃ J ₂ SO + (CD ₃ J ₂ CO): see 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 .

decomposition

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 Methanol mixed and the mixture filtered hot. The precipitate is dried, whereby about 4 g (= 80% of theor.) Dibenzoyl-L-tartaric acid 0-monoester of S-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -

1,2,5-thiadiazoles whose optical purity is> 97%

(HPLC).

B.p. 92 to 93OC. [a] 20 ° C = + 4.0 ° (c = 1 g / 10 ml HOAc).

IH-NMR (CDCl ₃ ): 61.4 (s, 9H), 2.8-3.9 (m, 9H), 4.7 (m, 2H), 5.2 (s, IH), 5.5 (q, 2H) 7.2-8.2 (m, 10H), 9.0 (s, IH) 13C NMR _(CD3) 2SO + (CD ₃ J ₂ CO): see FIG. Table 1

 IR (KBr tablet): identical compared to the corresponding racemic compound (see above).

The residue formed on cooling the filtrate after filtration above is filtered and dried, whereby about 3.5 g (= 70% of theor.) Dibenzoyl-L-tartaric acid O-, monoester of R-morpholino-4 (3'- tert-butylamino-2'-hydroxypropoxy) -l , 2, 5-thiadiazoles having an optical purity of> 97% (HPLC). Repeating the treatment with methanol gives both the S and R enantiomers with an optical purity> 99.5%. The S and R esters can be hydrolyzed by the procedure given in Example 3 to give S- and R-timolol.

Example 7 Preparation of the hydrogen maleate of R-timolol

Step 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, Coll. Vol. IV, 2nd Edition 1967, p 242) are dissolved in 750 ml of methylene chloride and the solution within 10 to 15 minutes at room temperature 158 g (= 0.5 mol) of R, S-timolol base in 350 ml of methylene chloride was added dropwise and evaporated to dryness in vacuo. you

the yield is 266 g (= 100% of theory) of pure diacetyl-D-tartaric acid O-monoester of R, S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1, 2,5-thiadiazole.

decomposition

266 g (= 0.5 mol) of diacetyl-D-tartaric acid-O-monoester of R, SS-morpholino - ^ - (3'-tert-butylamino-2'-hydroxypropoxy) -1, 2, 5-thiadiazole be in 430 ml Water, which is 2% with respect to acetic acid, dissolved. The solution is mixed with methanol, whereupon the solution is allowed to crystallize with stirring for 15 to 20 hours at room temperature. The product is separated by filtration and washed with cold, 50% ethanol and dried. 100 g (= 75% of theor.) Of diacetyl-D-tartaric acid O-monoester of R-3-morpholino-4- (3'-tert-bulylamino-2'-hydroxypropoxy) -1 are obtained as optical yield 2,5-thiadiazole with an optical purity of> 97% (HPLC). Repeating the crystallization gives optically pure substance.

[ _a ] 20 ° C ₌ _20.5 ° (c = 1 g / 10 ml, HOAc).

Level 2 ; R-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -l, 2, 5-thiadiazole base (= R-timolol base):

106.5 g (= 0.2 mol) of diacetyl-D-tartaric acid O-monoester of R-3-morpholino-4- (3'-tert-butyl- ^1- amino-2'-hydroxypropoxy) -1,2,5-thiadiazole (optical Purity> 97%) are mixed with 1.1 liters of water and the pH is adjusted to 2 with 5% sulfuric acid. The solution is stirred at reflux for 15 hours and cooled to room temperature, and the pH is adjusted with a sodium hydroxide solution

about 12 asked. 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. As a yield about 63 g '(= 100% of theor.) Oily R-timolol base. Content> 99% optical purity> 97% (HPLC).

Step 3 : Hydrogen maleate of R-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole (= hydrogen maleate of R-timolol):

63.3 g (= 0.2 mol) of R-timolol base (optical purity> 97%) are dissolved in 100 ml of tetrahydrofuran and to the mixture is added a solution of 23.2 g (= 0.2 mol) of maleic acid in 70 ml of tetrahydrofuran. The solution is allowed to stand for 1 hour in ice-water and the precipitated product is separated by filtration, washed with tetrahydrofuran and dried in air. The yield obtained is about 84 g (= 97% of theor.) Of R-timolol hydrogen maleate. Content> 99% (HPLC) and optical purity> 97% (HPLC).

The product can be recrystallized from absolute ethanol with a yield of> 95%.

[α] ² ° ^Oc = + 7.5 ° (c = 2 g / 10 ml, In HCl). Sp 193-194 ° C.

Claims (2)

claim A process for the preparation of S- (3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole of the formula 3'3 characterized in that R / S-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole of the formula 0 ν O-CH ₂ -j: H-CH ₂ -NH-C (CH ₃ ) ₃ Ti ^0H (RRS-I) with a dialkanoyl, diaroyl or alkanoyl-aroyl-L-tartaric anhydride of the formula H"- (L-XIX) wherein R4 and R5 are the same or different and are a straight-chain or branched alkanoyl group having 1 to 5 carbon atoms. IH lenstoffatomen in the alkyl group, a benzoyl or a
p-methylbenzoyl group, is reacted in an inert anhydrous organic solvent in a temperature range of 0 - 70 ⁰ C, and the resulting compound
the formula 0-CH-CH-CH ₂ -NH-C (CH ₃ ) 3 -O
- OR ₁ -· H
ODH R, S-I-L-XIX wherein R4 and R5 have the same meaning as above, a
Dissolution is carried out by crystallizing the compound from an alcohol having 1 to 5 carbon atoms, or from an aqueous solution of such alcohol, in a pH range of up to 2 and a temperature range of 0 to 30 ⁰ C, and in crystallized form obtained compound of the formula O-CH, -C-CH, -NH-C (CH ₁ ) ₃ V s -i-L-xix -D R.Ο - - H : ooii 2> 5 by acid hydrolysis from an aqueous solution to form the desired product.