DK162283B - L-TIN ACID O-MONOESTERS OF 3-MORPHOLINO-4- (3'-TERT-BUTYLAMINO-2'-HYDROXYPROPOXY) -1,2,5-THIADIAZOL AND THEIR PREPARATION AND USE - Google Patents

Description

in

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The present invention relates to novel compounds which can be used as intermediates in the preparation of the pharmacologically active β-blocker S-3-morpholino-4- (31-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole and acid addition salts thereof, and their preparation and use.

The preparation of S-morpholino-1-β-tert-butylamino (hydroxypropoxy) -1,2,5-thiadiazole, either as the racemic mixture, i.e. in the R, S configuration, or as the R or S enantiomer, also known by the term timolol, and having the formula /

'IK, O-CH, -CH-CH, -NH-C (CH,), I

\ / 2 I 2 33

Π 0H

is known. Thus, from US Patent Nos. 3,655,663 and 3,729,469, it is known to prepare R, S-timolol by the process illustrated in Reaction Scheme 1 below.

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2

Reaction Scheme 1 R OH R D-CHO-CH-CHOCl

W (Na) ° H

II II + H C-CH-CH Cl -5. [I I

N N V NN

Epichlorohydrin / l III

// Base (ch3) 3c-nh2 / \ / r \ o-ch0-ch-ch-

/ "J

/ NN

/ '' S '' IV

(CH₂C- ^HI / / O-CH₂ -CH-CH₂-NH-C (CH,))

ΓΊΙ 08 NB

N N ^ N. J

V

X. R 2 O-CH 2 -CH-CHO-NH0 (CH.J-C-C1 \ f / 1

\ W

N N XSX

WE

In this known process, a 3-Rq-4-OH-substituted 1,2,5-thiadiazole of formula II is first reacted wherein Rq of formula III, or the epoxide of formula IV formed from the hydroxy halide under basic conditions, is reacted with tert-butylamine to give an R, S-alkanolamine of formula V

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3 with R, S-timolol when Rq is a morpholino group. When R in formula V means chlorine, this can be exchanged with a morpholino group by treatment with excess morpholine.

From the hydroxy halide of formula III or the epoxide of formula IV of Scheme 1, the alkanolamines of formula V can also be formed by first reacting with ammonia, thereby forming a primary alkanolamine of formula VI which forms with the tert-butyl chloride the alkanolamine of formula V .

According to Japanese Patent Specification No. 7413176, 10 R / S-timolol is prepared by reacting a sulfonyl ester of the formula 0 NV O-CHO-CH-CHo-O-SOO-R, (VII)

We in v wherein R 1 represents an alkyl or aryl group, with tert-butylamine.

From Spanish Patent Specification No. 486,629 it is known to prepare R / S timolol as illustrated in Scheme 2.

Reaction Scheme 2 R p 'P ONa 0 o .0-CH 2 -CH-CH (OC 2 H 5) 2

jj jj + CH + -CH-CH (OC «H (.) ~ -> \\ 1 | OH

NN N N

XS /

II VIII IX

R (CH3) 3C-NH2 r

-> \ O-CH - CH-CHO> £ »-CHO-CH-CH = N-C (CH_L

We t We L

NN NN

Xs / X ^ XI

reduction. 0, -> R, S-timolol

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4

According to this known process, the diethyl acetal of glycidaldehyde of formula VIII is reacted with an alkali metal salt of 1,2,5-thiadiazole of formula II wherein R is as defined above and the resulting acetal of formula IX is hydrolyzed to the corresponding aldehyde of formula X, from which, upon reaction with tert-butylamine, a Schiff base of formula XI is formed which is reduced to R, S-timolol.

U.S. Patent No. 3,655,663 discloses a process for resolving a racemic alkanolamine of formula V wherein 10 Rq is chlorine over optically active salts such as 0.0-di-p-toluoyl- (+) - or (-) tartaric acid, 0,0-dibenzoyl- (+ -) - or - - (-) - tartaric acid or (+) - or (-) - tartaric acid. The S-enantiomer of formula V, wherein Rq means chlorine, which upon reaction with morpholine gives S-timolol, is recovered from the mother liquor, which remains after the separation of these salts, under the circumstances described for the R-enantiomer. which is more easily precipitated. The yields of the resolution are low and the R form is not used. The preparation of optically pure or almost optically pure enantiomers, viz. of an S-enantiomer which satisfies the requirements of a drug by means of such salt crystallization requires fractional crystallisations which are difficult to conduct in practice and which further reduce the yield.

The preparation of the enantiomers of formula I from starting materials having the desired stereoconfiguration is described, for example, in U.S. Patent Nos. 3,655,663, Nos. 3,657,237 and Nos. 3,729,469. This known process is illustrated in Reaction Scheme 3 below.

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Scheme 3

CHO CHO

I I

HC-OH HC-D. CH ~ i N / ch9oh / \ Å H2c-D CH3

D-Glyceraldehyde XII XIII

^ + (ch3) 3c-nh2 ^

Reduction \ y '1. Reduction \ 2' R0 CH2-CH-CH2-NH-C (CH3) 3 OH OH \ R3- ^ -SO2C1 v '' S-XIV \ r2cho \ CH2-CH-CH2-NH -C (CH3) 3 ,, \ I lH ho-ch2-ch-ch2 \ S02 o ^ -cm3) 3 \ 1 1 \ S-XV R9 \ I \ xvi I S-XIV-A / \ \ V \ / Λ \ I \ / o'V \ \ R3 R „CHCk / t * \ / ° \ \ \ M \ 0 \ ~ V \ VY / R3 - <^^ - S02- ° -CH2- = H- ™ 2 \ \ / / S-XV-A 0 ^ -C (CH3) 3 \ XVI / 1. II \ / O n® \, / II ^ 2. H * v -> S-timolol

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As starting material, D-glyceraldehyde of formula XII or its 2,3-acetonide is used with formula XIII, which, by reducing amination in the presence of tert-butylamine, and in the case of the 2,3-acetonide after acidic hydrolysis gives S1, 2 -dihydroxy-3-5 tert-butylamino-propane of formula S-XIV, which as such or activated in the 1-position with e.g. a benzenesulfonyl group or a tosyl group (formula S-XIV-A, R 2 = H, CH 2, NO 2, Br) or as the corresponding S-oxazolidine (formula S-XV, R 2 = H, (CH 3) 2 CH-, C2H5-, etc.), which may also be activated (formula S-XV-A), is reacted with the 1,2,5-thiadiazole of formula II (Rq = morpholino) or with 3-chloro-4-morpholino-1 , 2,5-thiadiazole of formula XVI in the presence of basic agents, after which, in the case of oxazolidine intermediates, hydrolysis with an acid is obtained, thereby obtaining in all cases IS S-timolol as the final product. Some of these methods provide satisfactory or good yields, but a limiting factor for the widespread use of these methods is the high cost and often difficult availability of starting materials with the right stereo configuration.

In addition to the methods described above, some alternative methods for preparing s-timolol from U.S. Patent No. 3,657,237 are known. The D-10 Camphor sulfonate salt of the S-1,2 epoxide prepared from the tolysate of formula S-XIV-A (R 3 = CH 2 J can thus be reacted with 3-morpholino-4-hydroxy-1,2,5-thiadiazole of formula II (Na salt) to form S-timolol.

According to a modified method, the morpholine ring of the compound of formula I is formed in two steps by first reacting the alkanolamine of formula V with S configuration (RQ = chlorine) with diethanolamine, then forming 3- (3'-dihydroxy) - diethylamino group is cyclized to form the morpholino group.

S-Timolol can further be prepared by reacting the S-dinitrile of the formula

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7

ISLAND

/ V

XVII

NC - C - O - CH0 - CH - CH0 - NH - C (CH2) ^ I! Il 2 I 2 33

NH NH OH

which is prepared by reaction of 1-morpholinodicyan and the oxazolidine of formula S-XV with sulfur monochloride.

U.S. Patent No. 3,619,370 also discloses a process for preparing timolol by reducing the corresponding ketone of formula XVIII either chemically with sodium borohydride or aluminum alkoxides to form racemic timolol, or microbiologically with reductase to obtain a product with S configuration. This procedure is illustrated in Reaction Scheme 4 below.

Reaction Scheme 4 / chemical reduction. J - »R, S-1 N O-CHo-C-CHo-NH-C (CHO) 'YY 11 J' 1 ^ reduction by \ s / [reductase_ S-1

XVIII

In connection with the present invention, it has been attempted to prepare the ketone of formula XVIII by the methods described above. However, since both the ketone and some of the intermediates in the reaction are very unstable, this has not been possible and this known method for preparing the ketone of formula XVIII is obviously not applicable, at least not on an industrial scale.

It is the object of the present invention to provide a process for the preparation of S-3-morpholino-4- (3'-tert-butylamino-21-hydroxypropoxy) -1,2,5-thiadiazole of formula I,

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8 ie S-timolol, from the racemate by resolving the dialkanoyl, diaroyl or alkanoyl-aroyl-L-tartaric acid O-monoester of formula R, SIL-XIX, wherein and R ^ each represent a straight-chain or branched alkanoyl group having 1 5 carbon atoms in the alkyl group or a benzoyl or p-methylbenzoyl group.

Thus, as the alkanoyl group, R 4 and R 2 may mean an acetyl, propionyl ·, butyryl ·, pentanoyl · or hexanoyl group which may be straight chain or branched, preferably the acetyl group.

The mono esters of formula R, SIL-XIX, which are novel compounds and also encompassed by the present invention, can be readily prepared by reacting the R, S-timolol base (R, SI) with a dialkanoyl, diaroyl - or alkanoyl-aroyl-L-tartaric anhydride of formula L-XIX, wherein R R and R, have the above meanings, in an inert anhydrous organic solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran , benzene or toluene, advantageously at room temperature or in a temperature range of 0-70 ° C at a reaction time of from 10 minutes to 3 hours. Evaporation of the solvent gives the dialkanoyl, diaroyl or alkanoyl-aroyl-L-tartaric acid O-monoester of R, S-timolol in pure form and in quantitative yield. It has been found, according to the invention, that under these conditions the substitution takes place only as an O-substitution, which is confirmed by mass spectroscopy 25 of the compounds prepared, since the spectra do not contain fragments characteristic of N-substituted molecules, whereas the fragment m / z 86 (CH 2 = NH-C (CH 2) + / also the morpholino group) is strong. If the product had been N-substituted, e.g. an amide, this would not appreciably be hydrolyzed under hydrolyzing conditions characteristic of an O-substituted product, i.e. an ester.

Surprisingly, it has been found that the R, S-timolol-dialkanoyl, -diaroyl or -alkanoyl-aroyl-L-tartaric acid O-monoester of formula R, S-I-L-XIX can be resolved in very good yield.

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9, both chemically and optically, by crystallizing the racemate from C --C C alcohols, such as methanol, ethanol, n-propanol or isopropanol or from mixtures or aqueous solutions thereof, at a pH in the range of 7 to 5 2 and at a temperature in the range of 0-30 ° C, the S-enantiomer of the timolol-dialkanoyl, -diaroyl or -alkanoyl-aroyl-L-tartaric acid O-monoester of formula SIL-XIX, which is the more heavily soluble compound in these solvents or solvent mixtures, crystallizes and can be isolated from the mother liquor in known manner.

Accordingly, the process of the invention for the preparation of S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole is characterized in that a racemic compound of the formula o C3 O-CHo-CH-CHO-NH ~ C (CH2).

YY °

N N C = 0 R, S-I-L-XIX

S H «*» C "• OR.

«** R50 ^ * C · * · η

COOH

wherein and are the same or different and means a straight or branched alkanoyl group having 1-5 carbon atoms in the alkyl group, a benzoyl group or a p-methylbenzoyl group, is resolved by crystallization of the compound from an alcohol containing 1-5 carbon atoms or from a aqueous solution of such alcohol at a pH in the range of 7-2 and at a temperature in the range of 0-30 ° C, upon which formed the crystalline S compound of the formula / \ 1 J h \ N / f -C-CH7-NH-C (CH,), / * é z J 3 nr?

\ S-I-L-XIX

S H »^ C- <OR4

rso ^ - c * ^ h COOH

Wherein R R and R ^ are as defined above, acidic hydrolysis is subjected to an aqueous solution to give the desired compound.

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Reaction Scheme 5 s o-ch 2 -ch-ch 2 -nh-c (ch 3) 3 - ^

Vif όΗ + i 4 ^ ro

J 'A C- ^ H

NN 5 J

\ a / I

R, S-timolol base (R, S-1) C

x) o - ^

Vsr 0-CH_-CH-CHo-NH-C (CH-.) Q

v / 2, 2. i j 11?

N N C = 0 R, S-I-L-XIX

Ns ^ '__ H ^ -C - «OR4 \ rcOI ^ C« * · η i

V. COOH

Resolver ingN.

COOH O.

'_ / \ H ^ C- ^ OR.

I ^

Ov R.O *> C- ^ H li H

/ \ έ = 0> h ^ », 0-CH9-C-CH9-NH-C (CH,) ^ kN /? ri ° o-ch2-j-ch2-hh-c «ch3,3 H i = 0 s_i_l_xix rt h» c-0r4

N N R O ^ C «<H

Ns / E-I-I.-XIX ioOH

/ H® / H20 / 3® / H20 / Λ /

H

1 R-Timolol Base No. O-CH 2 -C-CH 2 -NH-C (CH 3) 3 YY oh

N N

S-timolol base

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11

In a particularly advantageous embodiment, the resolution is carried out by crystallization of the R, S-timolol diacetyl-L-tartaric acid O-monoester (formula R, SIL-XIX, where R4 and R5 both represent CH 2 -CO-) from a mixture of water and methanol at a pH of 4-5 at room temperature or a temperature in the range of 0-30 ° C, whereby the S enantiomer crystallizes with a yield of approx. 75% and with an optical purity of more than 97%. Upon repeating the crystallization, optically pure S-timolol diacetyl-L-tartaric acid O-monoester is obtained. This particularly advantageous optical yield is probably due primarily to the high affinity of the S-form of the timolol-L-tartaric acid derivative to form an inner salt under the crystallization conditions used as a result of its stereochemical structure and the low solubility of this salt. the solvent mixture used for the crystallization.

The presence of the S-timolol-L-tartaric acid derivative in the form of an inner salt is indicated by the peaks found in the IR spectrum which are characteristic of such salts in the range 1575-1600 cm 2 and 2250-2700 cm 2 ( 1-5 peaks) and of observed 13 20 C-NMR spectra, which show that the signal for carbon atom 2 (cf. the structural formula in Table 1 and the values in this table) is offset 5-7 ppm against it smaller field, which is characteristic of an acidic group which forms a salt structure (- + NH5-), cf. Acta Chem.Scand. B 38 (1984) 67. These observations on the basis of the IR and C spectra, which indicate the existence of a salt structure, also indicate that the reaction between R, S-timolol and dialkanoyl, diaroyl or the alkanoyl-aroyl-L-tartaric anhydride proceeds as an O-substitution and not as an N-substitution, since in the latter case no internal salt formation would occur.

Table 1 below lists the chemical shifts in the 13 C-NMR spectra for S and R, S-timolol diacetyl-L-tartaric acid O-monoesters and corresponding dibenzoyl esters as well as for the S-timolol base. The S-timolol base can be released from the aforementioned O-esters 35 by acidic hydrolysis in an aqueous solution for from 1 to 24 hours

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12 at a pH in the range 0-5 and a temperature in the range 25-100 ° C using e.g. mineral acid such as sulfuric acid or phosphoric acid.

It has been found advantageous to boil at reflux for 10 hours with sulfuric acid in an aqueous solution adjusted to pH 2. The recovery of the S-timolol base is effected by extraction from the reaction mixture which is made basic (pH value 10-13) with e.g. one alkali metal hydroxide or ammonia, in an organic solvent such as methylene chloride, 1,2-dichloroethane, benzene, toluene or ethyl acetate, after which the S-timolol base is recovered after distillation of the solvent in almost quantitative yield and with an optical purity of more than 97%. The S-Timolol base can, if desired, be further purified by crystallization from an organic solvent or it can be converted to the corresponding acid addition salt, such as the hydrochloride or hydrogen maleate, in known manner.

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13 σι cn ^ p co p - P »M - <u '“ i σιφ ro a) oh r ~ h O o h ro η r- rt rort

Hrt Hrt Hrt d g.

il IC ic i q> i θ '1 ro ϋι ro ό o -H σι h o «. η * ·· η «. ω * w y ro ω ro µ ro · µ * w ro ro ro ro ro ro h h ro Η Ό * H h +) rt

a) ro li S

c .—. te N <i ri 0) o

Ό «now co» ro «> * · P

C II o 'tf ro ro 1 rt rt & cm ro cm ro 1

Η r-l ^ r-l Π O

d o o '"" o ^ ro m II

O - r-> • µ. ro in in 1 S 1 1 κ y r * · »t'- i" r- w and ro ro f '· ro in ro ΓΛ · »W * * *>

o in a ro ro ro -P

> <; ro ro ro ro ro a> H * pn ro ^ ro ro ro -h

In co - - “· * * S

u t "Γ 'ro r ~ to I ^ 0 ro Η .3

d, ^ I C

HU H ror'p 'ro ui ρ t "mm 0 - - * h tu *' 5 ro I ro E υ 22g °« h oj 2 d, ί-ι H! J a ro rt ^ rlS-U- UH 0 HHH HCipjH H0 ra i «cn 00 cn * co ** ro

I ^ w * O 'J »| ** siU

U cm cm co 'ri <u Ϊ2 »\

o "minro" Hroro-P

g ^ Η Η H Cl rt H H 0)

lO rororor ^ enr ^ M

r \ O * · »* · I ** · ·“ Ό

rviV O Γ0 co o and CM

κ \ εο »„ ^^^^ S

ro U HU-O-U-Ρί ro h>

H soror''-r'-coH

1 I o * · * 1 1 “d n o σι and a σι r-, ρ b? s? ""> 10 10 * 10 g ^ U-O-U-U-O-U- (¾ ro ro%, - · »" ^ **

1 ^ «tf CM

CM 'O

j-jH. C · Ρ ID u cm ro Η η co «tf &> m ro aj

O - * “- H - * H

. roro.h ro c ~ - to * 5j * o <o

a ro m w ro ro m H

_ CM S

O cm κ '-'tn

^ I — H CM H CM n- and H

\ q * · * ·> ** · * h C / j LO Vø LO CO tø <J \ 00 _ / CM CM CN CM CM ”Θ · / - \ ty == s, o.

o ψ% é o O 5 O 0 \ s c_, mu u to o ro ......... * -Η ^ CM CM CM CM CM Π3

CT \ (Y> H (I) ^ S λ CO

M ro ro ro ro roeoH-P

• arooa a a a u 0 h2 u u a ου a ^

8's H3 “Ή ^ · υ I

ο. and S 'S

ho ro w o co> (Li .Η * * »Η

C +) p1 CO (¾ ω WpSH

Η rt -Η Μ Μ g Η I ιρ Η Η Ο Γη QJ Η 00

ω ^ o ro ro ro OHO

Λ a η w μ βω rt Ο υ ro ro η rt ^ øh U U Εη Λ Η

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The resolution of R, S-timolol by crystallization of the corresponding dialkanoyl, diaroyl or alkanoyl-aroyl-L-tartaric acid O-monoester (formula R, SIL-XIX), preferably the diacetyl ester, from an alcohol or an alcohol-water mixture at a pH 5 less than or equal to 7 and at a temperature in the range of 0-30 ° C, whereby the S-timolol-L-tartaric acid O-monoester (formula SIL-XIX) can be isolated in good yield and almost optically purely, and by hydrolysis thereof at a pH in the range of 0-5 to form S-timolol, has been found to be a particularly advantageous way of preparing this compound, and as far as is known, there are no indications in it. known literature on such resolutions of alkanolamines of this type, whereby, by a single crystallization, one of the enantiomers is obtained in extremely good yield and especially in an optically pure form.

The versatility of the process is also confirmed by the fact that when the resolution is carried out using the corresponding D-tartaric acid derivatives, R-timolol can be prepared in an analogous manner in good yield and in optically pure form (cf. Example 7).

Since the S-esters can be easily hydrolyzed to S-timolol without racemization easily and in very good yield, the resolution can also be carried out on an industrial scale. Furthermore, the process of the invention for the preparation of S-timolol also has the advantage that R, S-timolol-dialkanoyl-, -diaroyl- or -alkanoyl-aroyl-L-tartaric acid-O-monoestrehe is used as starting materials for the resolution. can be prepared using racemic timolol and L-tartaric anhydrides, which are known compounds that can be readily prepared, whereby, unlike the best known methods, it is not necessary to use starting materials where the chirality center of timolol already has the correct stereoconfiguration , which are often expensive and difficult to manufacture.

Furthermore, the process according to the invention has the particular advantage of being formed from the mother liquor by the separation of

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The S-timolol L-tartaric acid O monoester, which primarily contains the R enantiomer, can readily regenerate the "valuable" portion of the molecule, ie. 3-morpholino-4-hydroxy-1,2,5-thiadiazole, by hydrolyzing the ether linker in timolol, cf. Example 5.

An inversion reaction can be carried out with the R enantiomer of timolol in a manner known per se, cf. Japanese Patent Specification No. 7475545, J. Org.Chem. 46, 4321 (1981), and Tetrahedron Letters 1619 (1973). R-timolol can also be used in racemization thereof using methods known per se, cf. J.Chem.Soc., Chem.Commun. 309 (1974), and using the racemate as described above as the starting material for the resolutions described above,

In addition to the methods described in the literature, 15 R, S-timolol can also be prepared according to the procedure shown in Reaction Scheme 6, cf. Japanese Patent Specification No. 7219259 or ES Patent Specification No. 459,725 using as starting material 3-hydroxy-4-morpholino-1,2,5-thiadiazole or more preferably its alkali metal salt (Formula XX, Rg - H, Na, K) and the 1-tert-butyl-3-azetidinol or its hydrochloride (Formula XXI) or another corresponding acid addition salt.

Reaction Scheme 6 / ° C (CH-).

NN / jOR6 + -N J J

^ -jj x HCl -> R, S-timolol

N N HCT

SS ^

XX XXI

The reaction is advantageously carried out in an inert organic solvent such as benzene, toluene, xylene, a chlorinated

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16 aliphatic or aromatic hydrocarbon, dimethylformamide or dioxane at a temperature of 40-160 ° C at a reaction time of 1-24 hours. It is advantageous to use equivalent amounts of the starting materials or an excess of 5-10% of azetidinol (Formula XXI). By adding a phase transfer catalyst to the reaction mixture in an amount of 2-20%, such as tetrabutylammonium bromide or hydrogen sulfate, the reaction can be accelerated and the yield can further be affected. The reaction product is recovered by extracting the acid addition salt with water, releasing the base by adding a basic agent and extracting the released base with an organic solvent. whereupon the solvent is evaporated. The R, S-timolol base, obtained in a yield of ca. 70%, can be purified by crystallization or by conversion to the desired acid addition salt, e.g. the hydrochloride or hydrogen maleate. It should be noted that although in the reaction of Scheme 6, an N-substitution reaction may also occur under the reaction conditions due to the tautomerism of the 3-hydroxy-1,2,5-thiadiazoles, it has been found that the primary reaction is 0 -substitutionen.

The small amounts of by-products formed by N-substitution can be readily hydrolyzed by adding water at the end of the reaction and continuing to reflux for 1-3 hours, whereby the hydrolysis of the N-substituted by-product proceeds quantitatively and does not affect the recovery or purification of 25 during the reverse reactions.

3-Hydroxy-4-morpholino-1,2,5-thiadiazole (FormulaXX) used in Reaction Scheme 6 as the second starting material for the preparation of R, S-timolol can be prepared using known methods described in the literature, cf.

E.g. J. Org. 41, 3121 (1976) and J. Org.Chem. 32, 2823 (1967) and DE Patent No. 1,914,496. Some of these known methods are illustrated in Reaction Scheme 7 below.

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Scheme 7 η μί. ""

N N NEL · N

Θ

Dicyan a-Aminoacetonitrile sc \ SC12 S2C12 / C12 S2C12 \ ✓OR-, -OR-, Cl * Cl C - C 7 C - c '7 \ _ / IB II III II ilf N NH N NCI N Jp

Alkylcyano-Alkylcyano-formimidate chloroformimidate 3,4-dichloro-1,2,5- [thiadiazole]

Cl OR-,

Yy C - C NN Morpholino

Hl I Ψ

N HH2 XXII

Cyanoformamide / \ Hydrolysis I χ / 1 C1 \ / 0H 1ΓΊ

Ml VN

N. N & 'S' '' 3-Chloro-4-morpholino-3-chloro-4-hydroxy-1,2,5-thiadiazole 1,2,5-thiadiazole ✓

MorpholinX / DMSO / NaOH-H-, 0 / \ / xn 'oh

Vf 3-Hydroxy-4-morpholino-1,2,5-thiadiazole (XX)

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In an alternative process (see Example 1) illustrated in Reaction Scheme 8 below to prepare 3-hydroxy-4-morpholino-1,2,5-thiadiazole, 3-chloro-4-alkoxy-1,2,5-thiadiazole is reacted ( Formula XXII, = C ^-Calk alkyl) with morpholine, and then the intermediate 3-morpholino-4-alkoxy-1,2,5-thiadiazole (formula XXIII, R ^ has the same meaning as above) is hydrolyzed on and off. known method for forming 3-morpholino-4-hydroxy-1,2,5-thiadiazole (Formula XX).

Reaction Scheme 8 C1. / / 7 A. / \ | j II Morpholine.

N \ s / N 0R7 TI 'OH

YY. Hydrolysis YrY

N N N Ν '.

XXII XXIII XX

10-Tert-butyl-3-azetidinol and its hydrochloride (Formula XXI) or another acid addition salt used as the second starting material in the preparation of R, S-timolol according to Scheme 6 can advantageously be prepared from epichlorohydrin and tert. -butylamine using a method known per se, cf. J. Org.Chem. 32, 2972 (1976). In the context of the present invention, this process has been improved and thus it is possible to prepare pure 1-tert-butyl-3-azetidinol hydrochloride in a yield of about * 60%, cf. Example 1.

The invention is further illustrated in the following examples in which the spectra set forth are recorded with the following apparatus:

Mass Spectra: Jeol JMS D 300 / JMA 2000 H

Y-NMR spectra: Varian EM 360 L

J | c NMR spectra: Jeol JNM PFT-100 25 film spectra: Perkin-Elmer 1420.

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The specific rotational power is determined by an "ATAGO" polarimeter equipped with a Na lamp and the melting points are determined by a "Gallenkamp" melting point apparatus. The melting points indicated are corrected. In liquid chromatography (HPLC) 5, the following equipment has been used:

Pumps - Waters M-45 G and 510 and automatic gradient adjustment detector - Waters model 481 LC spectrophotometer columns - e.g. Waters Bondapak C ^ g.

Example 1.

R, S-3-morpholino-4- (3'-tert-butylamino-21-hydroxypropoxy) -1 / 2,5-thiadiazole (R, S-timolol) - 93.6 g (0.5 mo]) 3 -hydroxy-4-morpholino-1,2,5-thiadiazole is mixed with 750 ml of toluene and to the mixture is added dropwise 90 g of 30% solution of sodium methylate over approx. 10 minutes.

After the addition is complete, stirring is continued for a further 10 minutes, adding 91 g (0.55 mol) of 1-tert-butyl-3-azetidinol hydrochloride and 8.5 g (0.025 mol) of tetra-butylammonium hydrogen sulfate. The mixture is heated to boiling and distilled until the temperature reaches approx. 90 ° C, after which the mixture is stirred at reflux for 10 hours. Add 100 ml of water and stir the mixture under reflux for an additional 2 hours, then cool, and add 800 ml of 3 N hydrochloric acid at a temperature not exceeding 20 ° C. The mixture is filtered and the aqueous phase of the filtrate is basified with concentrated sodium hydroxide solution at a temperature not exceeding 20 ° C. The mixture is extracted with 500 ml of methylene chloride and the extract is dried and evaporated to dryness under vacuum. The oily R, S-timolol base obtained as the evaporation residue is purified by crystallization from a mixture of toluene and hexane to give ca. 100 g (63% of theory) of colorless R, S-timolol base with a purity greater than 96% (HPLC). Mp. 71-72 ° C. 1 H NMR (CDCl 3): δ 1.1 (s, 9H), 2.4-3.0 (m, 3H), 3.3-4.0 (m, 9H), 4.3

DK 162283B

4.5 (d, 2H), 13 C NMR (CDCl 3): see Table 1.

IR (KBr 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 material used in Example 1 can be prepared as follows: 1-Tert-butyl-3-azetidinol hydrochloride 92.5 g (1 mole) of epichlorohydrin are dissolved in 200 ml of ethanol and to the solution is added dropwise with stirring 73.1 g (1 mole) 10 tert-butylamine over approx. 1 hour. When the exothermic reaction is complete, the mixture is refluxed for 1 hour, then approx. 90% of the ethanol is distilled off. To the residue is added approx. 200 ml of acetone and stirring is continued for 3 hours.

The crystallized product is filtered off and washed with acetone and then recrystallized from isopropanol. The yield is approx. 83 g (50% of theory) colorless 1-tert-butyl-3-azetidinol hydrochloride. Purity (HPLC)> 96%. Mp. 157-158 ° C. 1 H-NMR (CDCl 3): δ 1.4 (s, 9H), 4.1 (quintet, 4H), 4.4-5.0 (m, 1H, 5.9 (br, s, 1H)).

3-Hydroxy-4-morpholino-1,2,5-thiadiazole a. 3-Isopropoxy-4-morpholino-1,2,5-thiadiazole.

17.9 g (0.1 mole) of 3-isopropoxy-4-chloro-1,2,5-thiadiazole are dissolved in 65 ml of morpholine and the mixture is stirred for 16 hours at 100-110 ° C, then the excess morpholine is distilled off vacuum. To the residue is added 100 ml of methylene chloride and the undissolved material is removed by filtration. The filtrate is washed with 1N hydrochloric acid and with water, dried over magnesium sulfate and filtered. The filtrate is evaporated to dryness in vacuo to give 3-isopropoxy-4-morpholino-1,2,5-thiadiazole 30 as a yellow slow crystallizing oil. the yield is 90-95% of the theoretical.

DK 162283 B

1 H NMR (CDCl3): δ 1.4-1.5 (d, 6H), 3.4-3.9 (m, 8H), 4.9-5.4 (in, 1H).

b. 3-Hydroxy-4-morpholino-1,2,5-thiadiazole 22.9 g (0.1 mole) of 3-isopropoxy-4-morpholino-1,2,5-thiadiazole are dissolved in 400 ml of 1.2 -dichloroethane, to which 75 g (0.4 mole) of titanium tetrachloride is added with stirring and cooling. The mixture is stirred at reflux for 20 hours, then 80 ml of water is added under cooling. The aqueous phase is made basic with a 20% sodium hydroxide solution, then water is added and stirred and the mixture is filtered. The filtrate is acidified with hydrochloric acid to precipitate 3-hydroxy-4-morpholin-1,2,5-thiadiazole. The product is isolated by filtration, washed with water and dried, the yield is approx. 12.5 g (67% of theory) in the form of a light brown product which is recrystallized from absolute ethanol. Mp. 197-199 ° C. 1 H-NMR ((CD 3) 2 SO): δ 3.2-4.0 (m, 8H).

Example 2.

Preparation and Resolution of Diacetyl-L-Tartaric Acid O-Monoester of R, S-3-morpholino-4- (31-tert-butylamino-2'-hydroxypropoxy) -20 1,2,5-thiadiazole-108 g (0, 5 moles) of diacetyl-L-tartaric anhydride (preparation: "Organic Synthesis", Coll. Vol. IV, 2nd ed. 1967, page 242 using L-tartaric acid instead of D-tartaric acid) is dissolved in 750 ml of methylene chloride, whereupon to the solution dropwise 25 and with stirring, 158 g (0.5 mole) of R, S-timolol base is added in 350 ml of methylene chloride over 10-15 minutes at room temperature and the mixture is evaporated to dryness in vacuo. The yield is 266 g (100% of theory) of pure diacetyl-L-tartaric acid O-monoester of R, S-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5 -thiadiazole.

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

DK 162283 B

22 C NMR ((CD3) 2 SO + (CD3) 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.

5 MS (CI, I-butane): M + 57 589, M + 1,533, 317, 86 MS (EI, 70 EV): 517, 386, 130, 86.

Resolution 266 g (0.5 mole) of diacetyl-L-tartaric acid O-monoester of R, S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5 -thia-10 diazole is dissolved in 430 ml of water containing 2% acetic acid and adjusted to pH 4-5 with ammonium hydroxide.

To the solution is added 290 ml of methanol and the solution is allowed to crystallize with stirring for 15-20 hours at room temperature. The product is filtered off and washed with cold 50% ethanol and then dried. The optical yield is approx. 93 g (70% of theory) of diacetyl-L-tartaric acid O-mono ester of S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole , which has an optical purity greater than 97% (HPLC). Upon repeating the crystallization, the optically active product is obtained with m.p. 191 ° C.

λλΟ [α] £ υ = + 20.5 ° (c = 1 g / 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 , Δ (m, 5H).

13 C-NMR ((CD3) 2 SO + (CD3) 2CO): 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, 970, 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) diacetyl) L-tartaric acid O-monoester of S-3-mor 23

DK 1b ': 283 B

pholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thi-diazole (optical purity greater than 97%) is mixed with 1.1 liters of water and the pH is adjusted to approx. . 2 with a 5% sulfuric acid solution. The solution is stirred at reflux for 15 hours and cooled to room temperature, then the pH is adjusted to approx. 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. The yield is approx.

63 g (100% of theory) oily slow crystallizing S-timolol base. The purity of the product is greater than 99% (HPLC) and the optical purity is greater than 97% (HPLC).

1 H NMR (CDCl 3): δ 1.1 (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 (KBr film): 3400, 2950, 2900, 2840, 1525, 1490, 1440, 1360, 1305, 1290, 1255, 1220, 1110, 1065, 1050, 1020, 995, 945, 920, 850 cm *.

Example 4

S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy)-1,2,5-thiadiazole hydrogen maleate (S-timolol hydrogen maleate) 63.3 g (0.2 mole) -timolol base (optical purity> 97%) is dissolved in 100 ml of tetrahydrofuran and to the solution is added a stirring solution containing 23.2 g (0.2 mole) of maleic acid in 70 ml of tetrahydrofuran. The mixture is left in ice water for 1 hour, 25 and the precipitated product is filtered off and washed with tetrahydrofuran and then air dried. The yield is approx. 82 g (95% of theory) of S-timolol hydrogen maleate with a purity> 99% (HPLC) and an optical purity> 97% (HPLC). The product can be recrystallized from absolute ethanol with a yield of more than 95%.

DK 162283 B

24 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

5 Recovery of 3-hydroxy-4-morpholino-1,2,5-thiadiazole Hydrolysis of the L-tartaric acid O-monoester

From the mother liquor obtained from the resolution of the diacetyl-L-tartaric acid O-monoester of R, S-3-morpholino-4- (3'-tert-butylamino-hydroxypropoxy) -1,2,5-thiadiazole (cf. Example 2) The methanol and ethanol are evaporated in vacuo and the residue is hydrolyzed analogously to the procedure described in Example 3. The released timolol is extracted with methylene chloride from a solution made basic and the extract washed with water, dried and evaporated. The yield is approx. 100 g (95% of the theoretical) oily timolol base, wherein the ratio of the R to S enantiomer is approx. 4: 1.

Hydrolysis of the timolol base

The above residual evaporation residue (100 g, 0.32 mol) is dissolved in 270 ml of isopropanol, then 20 100 g of 30% sodium methylate solution (0.55 mol) is added and the mixture is refluxed for 1 hour. The methanol is distilled off and the mixture refluxed for an additional 3 hours. To. the mixture is added 135 ml of water and the pH is adjusted to approx. 2 with concentrated hydrochloric acid, then mixed under cooling 25 in ice water for 2-3 hours. The product is filtered off, washed with water and air dried. The yield is approx. 54 g (90% of theory) of colorless 3-hydroxy-4-morpholino-1,2,5-thiadiazole, which has a purity of approx. 92-94% (HPLC, contains inorganic salts).

After recrystallization from ethanol, the purity is> 98%, m.p.

Mp 192-194 ° C.

HI NMR ((CD 3) 2 SO): δ 3.2-4.0 (m, 8H).

t

DK 162283 B

25

Example 6

Preparation and Resolution of Dibenzoyl-L-Tartaric Acid-O-Monoester of R, S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxy-propoxy) -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 prepared analogously to that described in Example 2 above. method using dibenzoyl-L-tartaric anhydride instead of diacetyl-L-tartaric anhydride (Preparation J. Am.Chem.Soc. 55, 10 2605 (1933), replacing D-tartaric acid with L-tartaric acid). The yield is 312 g (100% of theory) of pure product.

1 H NMR (CDCl 3): δ 1.1-1.5 (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).

13 C-NMR ((CD3) 2 SO + (CD3) 2CO): 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.

Resolution 10 g of the above-prepared dibenzoyl-L-tartaric acid O-mono-ester of R, S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2, 5 Thiadiazole is mixed with heating with 200 ml of methanol and the mixture is filtered hot. The precipitate is dried to give approx. 4 g (80% of theory) of dibenzoyl-L-tartaric acid O-monoester of S-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole with an optical purity greater than 97% (HPLC).

Mp. 92-93 ° C. [α] p0 = + 4.0 ° (c = 1 g / 10 ml HOAc).

1 H-NMR (CDCl3); δ 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).

13 C-NMR ((CD3) 2 SO + (CO 3) 2 CO): see Table 1.

IR (KBr tablet): identical to the corresponding racemic product, cf. above.

DK 162283 B

26

Upon cooling of the filtrate obtained above, a precipitate is formed which is filtered off and dried to give approx. 3.5 g (70% of theory) of dibenzoyl-L-tartaric acid O-monoester of R-morpholino-4- (31-tert-butylamino-21-hydroxypropoxy) -1,2,5-5 thiadiazole with an optical purity greater than 97% (HPLC).

Repeating the methanol treatments yields both the S and R enantiomer with an optical purity greater than 99.5%. The R and S esters can be hydrolyzed by analogy to the process described in Example 3 to give S and R timolol.

Example 7.

Preparation of R-timolol hydrogen maleate

Step 1.

Preparation and Resolution of Diacetyl-D-Tartaric Acid-O-Monoester of R, S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -15 1,2,5-thiadiazole.

Dissolve 108 g (0.5 mole) of diacetyl-D-tartaric anhydride (Preparation: Organic Synthesis, Coll. Vol. IV, Second Edition 1967, page 242) in 750 ml of methylene chloride and add to the solution dropwise with stirring 158 g (0 , 5 mol) R, S-timolol base in 350 ml of methylene chloride over 10-15 minutes at room temperature, then evaporate the mixture to dryness in vacuo. 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.

Resolution 266 g (0.5 mole) of diacetyl-D-tartaric acid O-monoester of R, S-3-morpholino-4- (3'-tert-butylamino-21-hydroxypropoxy) -1,2,5 -thiadiazole is dissolved in 430 ml of water containing 2% acetic acid.

To the solution is added 290 ml of methanol and the solution is allowed to crystallize with stirring for 15-20 hours at

DK 1 h 2 2 8 3 B

27 room temperature. The product is filtered off, washed with cold 50% ethanol and dried. The optical yield is approx. 100 g (75% of theory) of diacetyl-D-tartaric acid O-monoester of R-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole 5 with an optical purity greater than 97% (HPLC). Recrystallization gives the optically pure product.

[α] p = -20.5 ° (c = 1 g / 10 ml, HOAc).

Step 2, R-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-10 thiadiazole base (R-timolol base) 106.5 g (0.2 mole) diacetyl-D-tartaric acid O-monoester of R-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole (optical purity> 97%) mix with 1.1 liters of water and adjust the pH to approx. 2 with 5% sulfuric acid. The mixture 15 is stirred under reflux for 15 hours, after which the solution is cooled to room temperature and adjusted to pH approx. 12 with 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. The yield is approx. 63 g of 20 (100% of theory) oily R-timolol base. The product has a purity greater than 99% (HPLC) and an optical purity greater than 97% (HPLC).

Step 3.

R-3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy)-1,2,5-thiadiazole hydrogen maleate (R-timolol hydrogen maleate).

63.3 g (0.2 mole) of R-timolol base (optical purity> 97%) are dissolved in 100 ml of tetrahydrofuran and to the solution is added, with stirring, a solution containing 23.2 g (0.2 mole) of maleic acid in 70 ml. ml of tetrahydrofuran. The mixture is left in ice water for 1 hour, 30 and the precipitated product is filtered off, washed with tetrahydrofuran and air dried. The yield is approx. 84 g (97% of theory) of R-timolol hydrogen maleate. The product has a purity greater than 99% (HPLC) and an optical purity greater than 97% (HPLC).

DK 162283 B

28

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

[α] p ° = + 7.5 ° (c = 2 g / 10 ml, 1 N HCl). Mp. 193-194 ° C.

Claims (3)

1. L-tartaric acid O-monoesters of 3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole, characterized in that they have the general formula O No. y0-CHo-CH-CHo-NH-C (ΟΗ-, Κ \ / 2, 2 oj 5 We? NNC = 0 pon 2 vs /, 00H HC-CHO \ II R-Rc 45 wherein R 1 and R 2 are the same or different and mean a straight-chain or branched alkanoyl group having 1 to 5 carbon atoms in the alkyl group, a benzoyl group or a p-methylbenzoyl group. A process for the preparation of S-3-morpholino-4- (3 '-10 tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole of the formula / ° \ H k J T O-CH, -C-CH9-NH-C (CH,) o / Δ kz 00 Ϊ il OH NN or acid addition salts thereof, characterized in that a racemic compound of formula DK 162283B on O-CH CH_-NH-C (CH2, YY ° NNC = 0 R, SIL-XIX H ** »C ~ ^ OR4 Rj-OI ^ C - * · Η PI COOH wherein R ^ and Rg are the same or different and mean an equal -chained or branched alkanoyl group having 1-5 carbon atoms in the alkyl group, a benzoyl group or a p-methylbenzoyl group, is resolved by crystallization of the compound from an alcohol containing 1-5 carbon atoms or from an aqueous solution of such alcohol at a pH of in the range 7-2 and at a temperature in the range 0-30 ° C, upon which formed the crystalline S compound of formula Λ! 0-CH2 -C-CH2-NH-C (CH2) - / 2 ^ 2 33 µl? 10. N ^ 0 S-I-L-X1X s h ** c- * or4 R_0 * -C ^ H 3 1 COOH wherein R4 and Rg have the meaning given above are subjected to acidic hydrolysis in an aqueous solution to give the desired compound. Process for the preparation of L-tartaric acid O-mono esters of 3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) - 1,2,5-thiadiazole according to claim 1, characterized in that R, S-3-morpholino-4- (31-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole with the alkene DK 1 (-. 2 2 8 3 B / \ N O-CH, -CH- CH, -NH-C (CH,), (R, S -1) \ sz I Δ J -3 ilf NN is reacted with a dialkanoyl, diaroyl or alkanoyl-aroyl-L-tartaric anhydride of the formula H -XIX) wherein R 4 and R 1 have the meanings set forth in claim 1 in an inert anhydrous organic solvent at a temperature of 0-70 ° c.