FI71933B - NYA L-VINCYRA-O-MONOESTRAR AV 3-MORPHOLINO-4- (3'-TERT-BUTYLAMINO-2'-HYDROXIPROPOXY) -1,2,5-THIADIAZOLE FOR DERAS ANVAENDNING SAOSOM MELLANPRODUKTER - Google Patents

Description

71933

Novel L-tartaric acid O-monoesters of 3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole and their use as intermediates - Nya L-vinyl-O- The present invention relates to novel intermediates in the preparation of a pharmacologically valuable β-blocker, S (-) - monoestrar of 3-morpholino-4- (3'-tert-butylamino-2'-hydroxypropoxy) - 1,2,5-thiadiazole and other alternatives of the present invention 3-Morpholino-4- (3'-tert-butylamino-2'-hydroxy-propoxy) -1,2,5-thiazolazole and its acid addition salts.

This compound - also known as Timolol I And having the formula o O-CH_-CH-CH_-NH-C (CH 2),]

W

N N

preparation as either a racemic mixture, i.e. the R, S-form or the S-enantiomer, has been described in numerous patents.

The U.S. in U.S. Pat. means a chlorine or morpholine group or a metal salt thereof reacted with epichlorohydrin in the presence of a base, followed by reaction with an intermediate butoxide of formula IV or an epoxide of formula IV formed therefrom under intermediate conditions. , yielding 2,71933

Figure 1.

Rn OH R O-CH.-CH-CH.CI

1 T * 3 '* h2c-ch-ch2c, - "" j {iH

N N o NN

Epi chloro i hydr i in i Ml vVXq / \ Base J V * X \ w \ ^ Y R0 ° -CH2-C ^ H2 n n

Rn is 0-CH - CH-CHo_NH-C (CH_) ^ \ c ^ w ι ·: N N 'N. / Ν '"/ NH3 v * 0 / \ 0-CH - CH-CH - NH_ XW -

N N

VI

an R, S-alkanol of formula V which, if Rq is a morpholino group, is identical to R, S-timolol. If RQ in formula V represents chlorine, this can be replaced by a morpholino group11 by treating with an excess of morpholino.

The hydroxide halide III or epoxide IV of Scheme 1 can also be obtained by treating a 1-canoamine of formula V first with ammonia to give a primary α-canonium of formula VI which, together with tert-butyl or Id, forms a 1kano1 i ami in I n.

71933 3

In Japanese Patent Publication No. 7 * 413176, R, S-t I mo 1 o 1 1 a is prepared from a sulfonyl ester of Formula VII, wherein R 1 represents an alkyl or aryl group - and tert-butyl 1 - 0 ...

li-f Ah

N N

through the reaction between the amine.

Spanish Patent Publication * 486629 discloses a process for the preparation of R, S-thiololo I according to Scheme 2, in which g 1ysIdide aidehydryl diethylacetate (Formula Vili) is reacted with 1,2,5-thiolide according to formula II. ka 1 I with meta 11 I salt (where R 1 is as defined above), after which the acetal formed (formula IX) is hydrolyzed to the corresponding aldehyde (formula X),

Figure 2.

R „ONa o * o o-ch2-ch-ch (oc2h5) 2

\ - / ♦ ch ^ h-ch (oc2h6) 2-> N || f ° H

N "V /

Il Vili IX

-> R0 O-CH.-CH-CHO -—ώ-2> R0 O-CH2-CH-CH = N-C (CH3) 3

W * W 0H

NN NN

S s

X XI

Pel k.

-> R, S-Timo1oli 71933

The Schlff base (formula XI) formed with tert-butyl amine is reduced to R, S-11 mo 1 o 1 IksI.

The U.S. U.S. Pat. No. 3,655,663 describes the resolution of a racemic a 1-cananol of formula V (Rg = chlorine) with optically active salts such as o, o-dl-p-toluyl - (+) - hydrochloric acid, o, o-dibenzoyl via - (+) - tartaric acid or (+) - VIII acid. The S-enantiomer of formula V (Rg = chlorine) - from which S-tmmolol can be prepared by treatment with morphol I11a - is obtained from the base 11 obtained after separation of the above salts, the R-enantiomers which precipitate more easily under the conditions shown. Resolution yields are low and the R-form has not been utilized. In addition, the preparation of an optically pure or nearly pure ell-enantiomer S-enantiomer by this type of salt crystallization requires difficult-to-practice fractional crystallization, which further reduces the yield.

The preparation of enantiomers of formula I from starting materials having the desired stereochemistry is described, e.g., in U.S. Pat. U.S. Pat. Nos. 3,655,663, 3,657,237 and 3-729-6-6-S-tmmolol (cf. Scheme 3) use D-glyceraldehyde (Formula XII) or its 2,3-acetonide (Formula XIII) as a starting material. in the presence of tert-butylamine, and in the case of 2,3-acetonide. After acid hydrolysis, S-1,2-dihydroxy-3-tert-butylpropane (formula S-XIV) has been obtained, which as such or 1- in position e.g.

a benzenesulfonyl or tosyl group activated (formula S-XIV-A, R 1 = H, CH 2, NO 2, Br) or the corresponding S-oxazolide (formula S-XV, R 2 = H, (CH 2) 2 CH-, C 8 H 2 and the like) .), which may also be activated 71933 5

Figure 3.

CHO CHO

I I

HC-OH HC-0. XH, I 3 CH2OH H2C-O / VCH3

D-Glyceraldehyde (X I I) XIII

+ (ch3) 3c-nh2.

Pel k. \ / 1. Pel k.

\ / ®

\ / 2. H

CH -CH-CH -NH-C (CH-).

I 2 I 2 3 3 OH OH v r3 / As „2ci / S-XIV \ r2cho \ v \ CH - CH-CH.-NH-C (CH -) - ho-ch -ch-ch„ \ i 2 I 2 33 il \ 0 OH o NC (CH-), \ 1 \ / 33 \ J ° 2 fH \ rn s "xv ^ \

LI S-XIV-A \ XVI

* 3 / cx \ \ ° \ Jo \ c °) \ \ V \) _ S02 '°' CH2'fH1H2 \ N i / \ \ - = / 0 NC (CH -) - \ / \ \ / 3 3 \ s XVI / \ S-XV-A iH \ / ~~ ---> S-Timolol 71933 6 (formula S-XV-A) is reacted according to formula 1,2,5-tI ad I at so 1I n ( R 2 = morpholino group) or 3-chloro-4-morpholino-1,2,5-thiazolazole (formula XVI) in the presence of time, After which, when used as an intermediate, the oxazolide is hydrolyzed by acid treatment, whereby the product is obtained in lime cases. S-tlmololla. Some of these methods give satisfactory or good yields, but the limitation of their widespread use is the high cost and often difficult availability of the starting materials necessary for the methods, which have the correct terteochemistry.

The U.S. U.S. Patent No. 3,657,237 discloses, in addition to the above methods, a number of alternative methods for preparing S-tlmololI. Thus, the D-10-camphorsulonate salt of S1,2-epoxide of the tosylate of formula S-XIV-A (R1 = CH2) is reacted with 3-morpholino-4-hydroxy-1,2,5-thiol. With Iazol I (Formula 11, Na salt) to give S-timolol.

In one variation, the morpholino ring of formula 1 is formed in two lies by first reacting the S-form a 1-cananol of I 1 (R 2 = chlorine) with diethanol and then forming the 3 - (β, / 5'-dihydroxy) The ethyl group is cyclized to the morphol group I.

S-tlmolo has also been prepared by treating 1-morphol with 1-cyanogen and a compound of formula S-XV.

branches so obtained by the reaction between IdiI n I n, of formula XVII

according to S-dln 11r I I 1 I ä 0

- C-O-CHn-CH-CH_-NH-C (CH) _ XVII

il K 2 1 2 53

NH NH OH

sulfur monochloride 1 la.

71933 7 U.S. U.S. Pat. No. 3,619,370 discloses a process for the preparation of tlmololl by reduction of the corresponding ketone of formula XVI I I according to Scheme 4, either chemically with sodium borohydride or with sodium oxide, to give racemic

Chart * +.

\ V '° e ° J * R’S_I

Ό-CH -C-CH -NH-CCCH,), \ / 1 (I 1 5 3 ^ I — I 0

Re / N

XVI I I c * s »s-1 tlmolol, or microbiologically reductase I11a to give the S-form product.

However, we have not been able to repeat the methods for preparing ketones of formula XVII1 mentioned in the above patent, due to the highly labile nature of both ketones and some of the intermediates used in the reaction, so the above methods for preparing ketones (XVIII) are at least suitable for production scale.

The present invention relates to a process for S (-) - 3-morpholino-** - (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole (Formula I) i.e. to prepare S (-) - thymolol I from its racemate by performing a resolution of this dI a 1kanoyl1I-, dlaroyl- or α1kanoyl1I-aroyl-L-tartaric acid-O-monoesterI11e (cf. Scheme 5, formula R, SIL-XIX, wherein R 2, R 2 = CH 2 -C 11 H 2 N -CO- (n = O- and which is straight-chain or branched), C 1 H 3 -CCO- or p-CH 2 -C 6 H 2 -CO-, wherein R 1 and R 2 ^ may be the same or different). These monoesters - which are novel compounds - can be readily prepared by reacting R, S-11 mo 1 o 1 I-base (R, SI) with a dia-kanoyl-I-, 71933 dlaroyl- or with 1-kanoyl-1-aroyl-11-yl acid acid anhydrous in an inert, anhydrous, organic solvent such as methylene or Id, 1,2-dichloroethane, tetrahydrofuran, benzene, toluene or the like. in the range of 0-70 ° C with a reaction time of 10 million to 3 h. Evaporation of the solvent gives R, S-thiololo In dialkanoyl, dlaroyl or alkanoyl-aroyl-L-vinyl acid O-monoester in pure and quantitative yield. We have found that the substitution under the above conditions occurs exclusively as an O-substituent, which is also confirmed by the mass spectra of the products in which the N-substI present gives fragments characteristic of the Idul1e molecule, while the fragment m 86 (CH 2 -NH-CCCH 3) also morpholIno group) occurs strongly. If the product were an N-substituent, i.e. an amide, this would also not be significantly hydrolyzed under the hydrolysis conditions typical of an O-substituent, i.e. an ester.

Very surprisingly, it has been found that the resolution of R, S-thiololo-1-dIa 1-canoyl, dlaroyl or alkanoyl-aroyl-L-vinyl acid-O-monoester (formula R, SIL-XIX) can be carried out with very good chemical and optical in yield by crystallization of the racemate from C 1 -C 4 alcohols such as methanol, 71933 q

Figure 5.

0 Ϊ / ° 0-CH_-C-CH_-NH-C (CH 3) _ / W i H * ^ ^ 0 NN R ^ O ► ^ ^ R, S-Timolol base (R, S-I) Ζζ ^^

\ L-XIX

I H

-> o-ch -c-ch - nh-c (ch,).

\ - (f

l K C = 0 R, S-I-L-XIX

N N j H - <j - OR ^

/ ioOH

/ Resolution

COOH

R ^ O ► C - H

H 2 C - OR 2 H 2 N H

0 \? - ° J I.

η o o-ch2-c-ch2-nh2-c (ch3) j

\ 0 - «= H2-C - ': H2-MH-C <CH3) 3" l I I S-I-L-XIX

\ - [f 4 N N C = 0

Il II H \ s / | NN H - C - OR,

\ c / I M

5 R 0 · - C - H

R-I-L-XIX {· 00θ / H * / H2 ° / h® / H20 i / / ° \

R-Timol oii base | I H

L J f 0-CH_-C-CH_-NH-C (CH_), w v

N N

ST i mol oii base 71 933 10 from ethanol, n-propanol or iso-propanol or mixtures thereof or aqueous solutions in the pH range 7-2 and in the temperature range 0-30 ° C, wherein thiololool I-dI a 1kanoyl1I-, dlaroyl - or the 1-enoyl of the 1-canoyl-aroyl IL-VIII monoester (formula SIL-XIX) in the above solvents or in a solvent mixture which crystallizes as a poorer solvent and can be separated from the mother liquor by known methods.

Crystallization of R, S-tmmololl-dla-ethyl-L-hydrochloric acid-O-monoester (formula R, SIL-XIX; R 2 = R 2 = CH 2 -CO-) from a mixture of water 1-methanol 1 in the pH range has proved to be a very preferred resolution method. 3.7-4 at room temperature or in the temperature range 0-30 ° C, wherein the S-enantiomer crystallizes in about 75% yield with> 97% optical purity of the product. By repeating the crystallization, optically pure S-tmmololl-diacetyl I-L-valine dic acid O-monoester is obtained. This highly advantageous optical yield is primarily due to the high tendency of the S-form of the IL-VIII acid derivative to form an internal salt due to the high tendency to form an internal salt under the prevailing crystallization conditions (cf. Scheme 5, formula SIL-XIX). as well as the low solubility of this salt in the crystallization 1 solvent mixture.

S-thymolation of IL-v1 I n I acid Derivative The presence of it as an internal salt is indicated by the peaks characteristic of such salts in the IR spectrum in the regions 1575-1600 cm * and 2250-2700 cm * (1-5 peaks) and by 1 H-NMR the observation in the spectra that carbon atom 2 (cf. the structural formula in Table 1 and the table values) has shifted to a subfield of 5-7 ppm, which is characteristic of the acid group forming a salt structure (- + NH_-) (cf. Acta Chem. Scand., by weight).

... 13 * These observations supporting the salt structure in the IR and C-NMR spectra also show that R, S-tI mol o 1 I n and d1 a 1kanoyl1 I-, diaroyl- or α1kanoyl1i-aroyl1i-L - The reaction between tartaric anhydride takes place as an O-substitution and not as an N-substitution, since in the latter case the formation of the internal salt would take place.

Il

71933 U

Table 1 shows the * chemical shifts. The S-thiol mol base can be liberated from the above-mentioned O-ester acid by aqueous hydrolysis in an aqueous solution for 1-2 * 4 h at a pH in the range of 0-5 and at a temperature in the range of 25-100 ° C using e.g.

It has proven advantageous to reflux for 10 hours in an aqueous solution adjusted to pH 2 with sulfuric acid.

Recovery of the S-tI mo 1 o 1 I base is accomplished by extraction of this from an alkali (pH 10-13) e.g. n, benzene, toluene, ethyl acetate or the like, from which the S-t1 mo 1 o 1 1-base is recovered after distilling off the solvent in almost quantitative yield with an optical purity of> 97%. If desired, the S-thiolylating base can be further purified by crystallization from an organic solvent or can be converted into the corresponding acid addition salt such as hydrochloric acid or hydrogen acetate in a manner known per se.

c c c c 12 Ο) Ο) Oi O) 1 * (Λ i /> t / l KT> ^ 71933 Ο cn cn -3- oo

n cn co o r ^ - I

\ D vC lO

III I

m vO O cn vO \ C vO J-

\ 0 \ 0 \ C sC

I I

* -> · ~ · er \ <-vNJ Λ-m 3 Nj m · · pa · ·

3 C_> OO (Λ I

X Η (Μ (Λ (ΜΙΛ ce - -

o °° ° £ _ R

, Γ PA LA LTV J E Λ, "i

° - ^ ^ S

x oo r— co in m ε

^ '· ·· · «Q

X - LA LA \ £) LA νβ V- I \ β sO vO lO vO (0

J _-- S

LAJ-νθΓΑΟΟΙΙ ΓΑ (0 • x> '-'r'-r ^ oor ^ f ^ oe * “<->> 0 -3--3-3 3 3 (D__ ΓΑ 1 ΓΑ X _ .____ .XX · n ~ 3 ^ γα

• (_> - (J - <_) ’^ vO N vO c A LA

^ 1 ° CACT \ cn ο '* 1 CD <D

X 3 3 3 1 /) ^ - 33 Z - H -—- X - 'I o cn co cn £ oo 3 o · ·. ¢). c m <- / Ο, '"PM CM ΓΑ CM PA o

• X \ x II - LA LA LA LA LA O

PA C_>. <_> o — o — ce - _ _ nJ, _ _ ϋ

__ O J *

I * I (A - o O vXJvOp ^ enP ^ 4)

. X II X II.,. . CL

-3 "<-> —O-O— <_> -O— <_> -ce t ~ A ΓΑ PA ο ΓΑ PM

• 1-5 I— r · - r— r-- a- c I o oj CM LA - • x LA PA Γ · ». 00 4-> in o ·. ,,. 4.

·? cn en cn cn r ^. O

I ^ vO vD sD \ 0 \ D ZJ

O - II

\ -3- -T

* - \ --- 3 -5: -3 (/) ^ Φ-tpf "· =. *. / OO - £, oo § 3, la pa ^

/ '/ ° LA vO UI LA I— 1 /) -3 · O

O Z LALA- ^ LALAroLALA

w __ = _ = _ ολ co cm - cm σ \ 7 "LT> LT> vO LT \ oo CM CM CM CM CM c __o + + £ OOOOO« U »C (/) o CJ (/> <_> · - - CM CM CM CM CM 0> * -> ^ r * -> Cl 'OC ^ \ cr \ Z r * "\ cr \ cr \

3 O O Q OOO C

· - <_> <-> O O O O 0)

-1 (-) E

3 ‘Ίο σιο oe 3 O 14- * J 1 /) LO -

-) C C ID - 1 /) - (A

- * O »0 oe oe i / i: fo o se L-: ru 3 - j_I-

/? O

^ - Jz o * _r ^ _ U \ u 3: co x x ^ .m

o X vO so, E P

ooob * - 71 933 13 DI a 1kanoyl1 I- / dlaroyl-a a 1kanoyy1 I-aroyy1 ILv II n The resolution of the diacid O monoesters can also be carried out by liquid chromatography both analytically and the preparations I using a column of type C as well as the eluent. Ikaic acid in methanol-water solution in the pH range of about 3.5_1 + (cf. Example 6). The resolution of the preparations I Iv1 s in the same time has been very good, es ImerkIksl S-timololl-diacetyl-L-hydrochloric acid-O-monoesterI11 e se 1ektI IvI cause s-1.83 and the corresponding> dIbenzoyl1 I-Ester I11 e n - 2.3.

Resolution of R, S-thiololes by crystallization of the corresponding dI a 1-canoyl, dlaroyl or α-canoyl-aroyl-L-V-I Acid O-monoester (Formula R, SIL-XIX) - preferably diacetyl I-Ester I from alcohol or a 1 from a 1 i-water mixture in the pH range <7 and in the temperature range 0-30 ° C, whereby the L-tartaric acid O-monoester of S-timolol (formula SIL-XIX) can be separated in good yield and optically almost pure, and by hydrolysis of this to 0-5 S-thiolol in the pH range, has proved to be a very advantageous way of preparing substance and, to our knowledge, no such resolution has previously been reported in the literature for such an alcohol, in which a single crystallization would have obtained the second enantiomer in very good yield or especially in optically pure form.

Since the S-ester can also be easily and in very good yield hydrolysed to the S-thiolole without racemic acid, the resolution can also be applied to the production scale. This process for the preparation of S-tmmolol is also preferred by the fact that the R, S-thymoloyl diakanoyl, diaroyl or alkanoyl-aroyl-L-tartaric acid O-monoesters used as starting materials for the resolution can be prepared using racemic timolol and those known from the literature. , easily prepared L-vI 1 n Acid anhydrides and, as in most of the book 11, where no starting materials are needed in which the chiral center of timolol is already ready in its proper stereochemical form and which are generally difficult to prepare and expensive.

Another aspect which makes the method disclosed herein very advantageous is that the base obtained from the separation of S-tmmololl-L-v-I Acid O-monoester, which contains mainly the aforementioned R-enantiomer, is a "valuable" molecule. part, i.e. 3-morpholino-9-hydroxy-1,2,5-thiol adazol1, can be easily regenerated by hydrolysis of the Timolol In ether bond (cf. Example 5).

Timolol In R-enantiomer 11 e can also be inverted by methods known in the literature in principle (cf. e.g. Japanese Patent Publication No. 7975595, J. Org. Chem.

321 (1981) and Tetrahedron Lett. 1619 (1973)). R-tlmololl can also be utilized by racemic mole by methods known in principle from the literature (cf. e.g. J. Chem. Soc., Chem. Commun. 309 (1979)) and by using the racemate as a starting material for the resolution described above.

In addition to the methods described in the literature, R, S-timolol Ia can also be prepared according to the method shown in principle in Scheme 6 (cf. e.g. Japanese Patent Publication No. 7219259 or Spanish Patent Publication No. 959,725) using 3-hydroxy-9-morpholino-1,2 as starting materials, 5-Thiadiazole or, more preferably, a salt thereof (Formula XX, R 2 = H, Na, K) and 1-tert-butyl-3-acetolin a or its hydrochloride (Formula XXI) or other corresponding acid addition salts.

Figure 6.

O

N OR, + I x HCl -> R S-Timolol

N S

XX XXI

71933 15

The reaction is preferably carried out in an inert, organic solvent such as benzene, toluene, xylene, chlorinated aliphatic or aromatic hydrocarbon, dimethylformamide or doxane at a temperature in the range of 90 to 160 ° C. excess azetIdInol I a (Formula XXI). By adding 2-20% of phase I ns I bulk catalysts such as tert-butylammonium bromide or hydrogen sulfate, the progress of the reaction can be accelerated and the yield can also be affected.

The product is recovered by extracting this acid additive into water and the alkali-liberated base into an organic solvent and evaporating the solvent. The R, S-thymolyl base obtained in about 70% yield can be purified by crystallization or conversion to the desired acid addition salt such as hydrochloric acid or hydrogen acetate. It should be noted that although the tautomer present in 3-hydroxy-1,2,5-tI adlazole Due to the reaction in Scheme 6 also N-substituent is possible under the above reaction conditions, the O-substitution has proved to be the main reaction. The small amount of N-substituent formed can be easily hydrolyzed by adding water at the end of the reaction and continuing the reflux for a further 1-3 h, whereby the hydrolysis of the N-substituent by-product is quantitative and does not affect the recovery or purification of the desired product.

The 3-hydroxy-9-morpholine-1,2,5-11 adazole (Formula XX) used as a second starting material for the process for the preparation of R, S-tI mol oi according to Scheme 6 can be prepared by methods known from the literature (cf. e.g. J. Org. Chem. 9J, 3121 (1976) and J. Org. Chem. 37, 2823 (1,967) and West German Patent 1,919,996), some of which are described in Scheme 7.

Figure 7.

71 933 16

C - C H.C - C

I) Il 2 | III x x

NN hH, N

»>

Cyanogen q- ^ m; noacetone j tr j; ]; SCI2 \ SC 12 or S2C12 / C12 or s2C, 2 N.

Cl V Cl C - c'0R> C - e-0 * 2 'll-Ti' "III II III II V J1 N NH N NC1 AI kyy 1cyano- AI kyy 1cyano- 3 · chloro-1,2,5 ~ formimidate chloroformime - thiadiazole date i SC12 \ / s ^ J, Morpholine C '\ ^ / Tl-f

C - C NN

III I \ / *

N NH S

1 XXII 0

Cyanoformamide S '"' N

N. Hydrolysis l J

S2C12 \ ^ N ^ Cl c \ _ / H) {

1ί V S / N

NN 5 3-Chloro-N-morpholino-1,2,5 "thiadiazole 3-K-chloro-N-hydroxy-1,2,5-thiadiazole / DMSO / NaOH-H 2 O n /

O

OH

W

N N

\ /

S

3 "Hydroxy-N-morpholino-1,2,5" thiadiazole (XX)

II

71 933 17

An alternative method for preparing 3-hydroxy-4-morpholino-1,2,5-thladiazole shown in Scheme 8 is to carry 3-chloro-4-alkoxy-1,2,5-thiazol I (Formula XXII, = Cj - -alkyl) to the reaction with morpholine and then hydrolyze the intermediate

Figure 8.

n or? .o \ [| Morpholilni> or? oh \ ^ {Hydrolysis \ /

Ä NN NN

XXII XXIII XX

3-Morpholin-4-alkoxy-1,2,5-11 adol azol (Formula XXIII, R 1 as above) by known methods 3-Morpholin-4-hydroxy-1,2,5-11 adol iksi (formula XX).

The 1-1 e tert-butyl-3-acetyl Idino 11a and its hydrochloride (Formula XXI) or other acid addition salt used as a second starting material for the process for the preparation of R, S-1I mo 1 o 1 I can advantageously be prepared from epI chlorohydrin. and tert-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1-butyl-1- azetide InolI to the hydrochloride in about 60% yield.

71,933 18 The spectra presented in this publication are driven by the following 1a ItteI1 la:

Mass spectrum: Jeol JMS D 300 / JMA 2000 H

1 H NMR Spectrum: Colors EM 360 L

13 C NMR Spectrum: Jeol JNM PFT-100 IR Spectrum: Perklin-Elmer m 2 O

Omina I sk Ierrot is measured with a Na-lamp "ATAGC-pol ar Imetr I 1 1 a And melting points" "Ga 1 1 enkamp" '- sul ami sp I stene quotient 1 1 a l ttee 1 1 a. Melting points have been corrected. Liquid chromatographic (HPLC) runs were performed as follows: preparations I I v I set runs:

Waters Prep. LC / System 500 A

analytical runs: pumps - Waters M- ^ 5 G And 510 with automatic gradient adjustment detector - Waters model A81

LC spectrophotometer

column - e.g. Waters Bondapak Cjg The following examples illustrate the invention: 71933 19 EXAMPLE 1.

RS-3-Morpholino-N-C31-tert-butylamino-2H-hydroxy-propoxy) -1,2,5-t-adiazol1 (-RtS-thiolol) 93.6 g of C = 0.5 mol) 3-Hydroxy- 4-Morpholino-1,2,5-tladlazole is stirred in 750 ml of toluene, and 90 g of a 30% solution of sodium methyl methylate are added dropwise over a period of about 10 minutes. After the addition, stir for a further 10 min and add 91 g (-0.55 moles) of 1-tert-butyl-3-acetylidene hydrochloride Id 1a and 8.5 g (= 0.025 moles) of tetrabutylammonium hydrogenate 1 a. The mixture is heated to reflux and distill until the temperature is about 90 ° C, then stir at reflux for 10 h. Add 100 ml of water, and stir at reflux for a further 2 h and Cool and add 800 ml of 3 norm, hydrochloric acid at <20 ° C. The mixture is filtered and the aqueous phase of the filtrate is basified with concentrated sodium hydroxide solution at <20 ° C. The mixture is extracted with 500 ml of methylene or Id1a, and the extract is dried and evaporated to dryness in vacuo.

The oily, impure molar base of R, S-tI obtained as a cooling residue is purified by crystallization from a mixture of toluene and hexane to give about 100 g (= 63% of theory) of a colorless R, S-Timo 1 o 1 I base. Concentration> 96% (HPLC). Mp 71-72 ° C. 1 H-NMR (CDCl 3): 61.1 (s, 9H), δ 2.4-3.0 (m, 3H), 63.3-4.0 (m, 9H), 64.3-4.5 Cd, 2H).

13 C-NMR (CDCl 3): see Table 1.

IR (KBr tablet i): 3280, 3120, 301 5, 2950, 291 0, 2850, 1525, 1490, 1445, 1415, 1375, 1360, 1325, 1310, 1290, 1255, 1220, 1170, 1120, 1110, 1060, 1022, 99C, 940, 920, 900, 850.

2 O

71933

The 1-tert-butyl-3-acetyldinol hydrochloride used as the second starting material in Example 1 is prepared as follows: 92.5 g (= 1 mol) of epichlorohydride are dissolved in 200 ml of ethanol, and 73.1 g (= 1 mol) of tertiary acid are added dropwise to the stirred solution. -butyl I am Inla within about 1 hour. At the end of the exotherm, the reaction is refluxed for 1 h, after which about 90% of the ethanol is distilled off. 200 ml of acetone are added to the residue, which is stirred for 3 h. The crystalline product is filtered off and washed with acetone and extracted with isopropanol. The yield is about 83 g (= 50% of theory) of colorless 1-tert-butyl-3-acetyl no. 1 L hydrochloric acid (CHPLC content)> 96%. Mp 157-158 ° C.

1 H-NMR (CDCl 3): 01.9 (s, 9H), 69.1 (quintet, 9H), 69.9-5.0 (m, 1H), 65.9 (br. S, 1H).

21, 71933 EXAMPLE 2.

Preparation of R.S-3-Morpholino-4- (31-tert-butylamino-2 1-hydroxypropoxy) -1,2,5-thliazolazine diacetyl-L-valine acid O-monoester. resolution ♦ 108 g (= 0.5 moles) of D-acetyl-IL-1-n-acid anhydride (prepared by "Organic Syntheses", Coll., Vol. IV, 2nd edition 1967, p. 242, in which D-tartaric acid is replaced by L-vI Inic acid ) are dissolved in 750 ml of methylene chloride IdI a and 158 g (= 0.5 mol) of R, S-tI mol oI base in 350 ml of methylene chloride or IdI a are added dropwise with stirring 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 R, S-3-morpholino-4- (3'-tert-butylamino-2'-hydroxy-propoxy) -1,2,5- dlacetyl-L-vl I n Iacid-O-monoester.

1 H-NMR (CDCl 3): 61.5 (s, 9H), 62.1-2.2 (d, 6H), 63.0-4.0 (m, 10H), 64.3-5.8 (m, 5H).

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

1R (KBr tablet I): 3420, 2970, 2840, 1745, 1635, 1530, 1495, 1445, 1370, 1310, 1290, 1255, 1220, 1115, 1060, 970, 950, 925.

MS (CI, 1-butane): M + 1-butane-589, K + 1 533, 317, 86 MS (EI, 70 EV): 517, 386, 130, 86 71933 22

Reso 1uutIo.

266 g (= 0.5 mol) of R, S-3-Morpholino-4- (3'-tert-butylamino) -2'-hydroxypropoxyO-1,2,5-thiazolyl-1-diacetyl-L- The acid O-monoester is dissolved in 430 ml of water, 2% acetic acid and the pH is adjusted to 3.7 (NH 4 OH), 290 ml of methanol are added to the solution, and it 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 dried.

The optical yield is about 93 g (= 70% of theory).

S-3-Morpholinyl-4- (3 * -tert-butylamino-2'-hydroxy-propoxy) -1,2,5-thiazololine diacetyl-L-formic acid O-monoester, optical purity> 97% (HPLC). Repeated crystallization gives an optically pure product.

Mp 191 ° C.

20 ° C

α D = + 20.5 ° (C = 1 g / 10 ml, HAc).

D

1 H-NMR (CDCl 3: CD 3 OD; 3: 1): δ 1.5 (s, 9H), 62.2 (s, 6H), δ 2.8-4.1 (m, 10H), 64.5-5.5 (m, 5H) 13 C-NMR C (CD3) 2SO + (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, 870, 840.

23 71077 EXAMPLE 3 ♦ 5 ° S-3-Morpholino-9- (3-tert-butylamino-2 * -hydroxypropoxy) -1,2,5-thiol 1azole I base (= S -tI mo I o 1 I base).

106.5 g of C - 0.2 moles) S-3-Morpholino-9- (3'-tert-butylamino-2'-hydroxypropoxy) -1,2,5-thiazolazinacetyl-1-L-acid -O-monoester (optical purity> 97%) is mixed with 1.1 liters of water, and the pH is adjusted to about 2 with 5% sulfuric acid. Stir at reflux for 15 h,

The solution is cooled to room temperature and the pH is adjusted to about 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 about 63 g (= 100% of theory) of an oily, gradually crystallizing S-thymol base. The product content is> 99% (HPLC) and the optical purity is> 97% (HPLC).

1 H-NMR (CDCl 3): 61.1 (s, 9H), 62.9-3.0 (m, 3H), δ 3.3-9.0 (m, 9H), 69.3-9.5 (d, 2H).

13 C-NMR (CDCl 3): see Table 1. IR (KBr filml): 3900, 2950, 2900, 2890, 1525, 1990, 1990, 1360, 1305, 1290, 1255, 1220, 1110, 1065, 1050, 1020 , 995, 995, 920, 850.

29 EXAMPLE 9.

71933 Hydrogenate of S-3-Morpholino-N-N'-tert-butylamino-2'-hydroxy-propoxy) -1,2,5-tladlazoline (= hydrogen maleate of S-tylmool).

63.3 g of C = 0.2 mol) of S-Thiol mol (optical purity> 97%) are dissolved in 100 ml of tetrahydrofuran, and a solution of 23.2 g (= 0.2 mol) of acid in 70 ml of tetrahydrofuran is added with stirring. ! a. Stand in ice water for 1 h, and the precipitated product is filtered off and washed with tetrahydrofuran Π 1a and dried in air. The yield is about 82 g (= 95% of theory) of S-tmmololl hydrogen maleate. Concentration> 99% (HPLC) And optical purity> 97% (HPLC).

The product can be re-used for abs. from ethanol> 95% yield.

20 ° C

[α] = -7.5 ° (C = 2 g / 10 ml, 1 n HCl). Mp 198-199 ° C.

D

1 H-NMR ((CD 5) 2 SO): 51.3 (s, 9H), * 2.5 (s, 1H), δ 2.7-1 + .0 (m, 9H), 59.1-9.7 (m, 3H), 56.1 (s , 2H).

1R (KBr tablet 1): 3380, 3290, 301 0, 2965, 2880, 2890, 2360, 2950, 1690, 1615, 1570, 1530, 1990, 1995, 1380, 1350, 1310, 1290, 1255, 1225, 1200 , 1115, 1065, 1050, 985, 950, 860.

EXAMPLE 5.

25 71933 3-Hydro k s I -9-morph oi no-1,2 t 5-t1 ad Iatsol In regenerolntl.

L-VI I n Iacid-O-monoesterIn hydrolysisl.

R, S-3-Morpholino Into-t4- (3'-tert-butylamino-2, -hydroxy-propoxy) -1,2,5-thladiazol-1-diacetyl-11-vinyl acid-O-monoester in resolution (cf. Example 2) The resulting mother solution is evaporated off methanol and ethanol in vacuo, and the residue is hydrolyzed as described in Example 3. The liberated tlmololl is extracted from a solution made up of methylene or IdI I, and the extract is washed with water, dried and evaporated.

The yield is about 100 g (= 95% of theory) of an oily thiol of a base having a ratio of R to S enantiomers of about 3: 1.

TI mo 1 o 11 base hydrolysisl.

The residue obtained above (100 g = 0.32 mol) is dissolved in 270 ml of isopropanol and 100 g of a 30% sodium methylate solution (= 0.55 mol) are added and the mixture is refluxed for 1 h. The methanol is distilled off and then refluxed for a further 3 h. 135 ml of water and the pH is adjusted to about 2 with concentrated hydrochloric acid, followed by stirring in ice water under cooling for 2-3 h.

The product is filtered and washed with water and air dried. The yield is about 59 g (= 90% of theory) of colorless 3-hydroxy-9-morpholino-1,2,5-adiadiazole with a concentration of about 92-99% (HPLC. Contains inorganic salts.). After recrystallization from ethanol, the concentration is> 98%.

Mp 192-199 ° C. 1 H-NMR (CD 2 SO): 63.2-9.0 (m, 8H).

EXAMPLE 6.

26 71933 Preparation of RS-3-Morpholino-4- (3 * tert-butylamino-2 * -hydroxy-propoxy) -1,2,5-tladlazolyl-benzo-11-L-v11 n Acid O-monoester And liquid chromatography Resolution R, S-3-Morpholino-4- (3'-tert-butylamino-2'-hydroxy-propoxy) -1,2,5-tolylazole dlbent soyl-11-L-VIII acid monoester1 is prepared as described in Example 2 / but using d1acetyl-L-tartaric anhydride instead of d 1 benzoyl-L-tartaric anhydride (prepared by J. Am. Chem. Soc. 5J ^: 2605 (1933), where D-tartaric acid is replaced L-vI InIhapol1 a). The yield is 312 g (= 100% of theory) of pure product.

1 H-NMR (CDCl 3): δ 1.1-1.5 (2s, 9H), 62.8-4.0 (m, 10H), 64.2-5.0 (s, 2H), 65.0-5.9 (m, 3H), 67-0-8.3 ( m, 10H) 13 C-NMR ((CD 3) 2 SO + (CD 3) 2 CO): see Table 1.

1R (KBr-tab count): 3410, 3050, 3025, 2960, 2840, 1760, 1720, 1640, 1600, 1560, 1530, 1500, 1445, 1380, 1370, 1310, 1290, 1255, 1170, 1110, 1065, 1020, 1000, 950.

Φ 27 71 933

Liquid chromatographic resolution.

10 g of the above prepared R, S-3-morpholino-4- (3'-tert-butylamino-2 * -hydroxypropoxy) -1,2,5-thiol-d i benzoloyl The acid O-monoester is dissolved in 20 ml of eluent (80% methanol and 20% water, relative to 2% HAc. PH 3.7 of the solution (NH 4 OH)). The solution is dissolved in InjI and run on the above eluent using a Waters * In Prep PAK-500 / C ^ g column at a flow rate of 2 l / ml, whereby the S-enantiomer is separated off as the latter. After evaporation of the solvent, pure S-3-morpholino-4- (3, -tert-butylamino-2'-hydroxypropoxy) -1,2,5-tladlatol-1-benzoyl IL-1'-Acid O-monoester is obtained. .

Mp 92-93 ° C.

20 ° C

| aj = + k.0 ° (c = 1 g / 10 ml HAc)

D

1 H-NMR (CDCl 3): δ JM.4 (s, 9H), δ 2.8-3.9 (m, 9H), δ 4.7 (m, 2H), δ5.2 (s, 1H), δ 5.5 (q, 2H), δ 7.2-8.2 (m, 10H), S 9.0 (s, 1H9.

1 H-NMR ((CD 3) 2 SO + (CD 3) 2 CO): see Table 1.

IR (KBr tablet 1): Identical to the corresponding racemic substance.

The 5-ester is hydrolyzed as described in Example 3 to give 4.A g (= 91% of theory) of S-timolol base with an optical purity of> 99.5% (HPLC).

Claims (2)

1. L-tartaric acid O-monoesters of 3-morpholino-4- (3'-tert.-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole, wherein the formula is 0 O-CH -CH-CH, -NH-C (CH_). R 2 R 5 in which and R 2 - are the same or different and represent a straight or branched alkanoyl group having 1 to 5 carbon atoms in the alkyl group, a benzoyl or a p-methylbenzoyl group. A process for the preparation of S (-) - 3-morpholino-4- (3'-tert.-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole of formula C '); N 0 -CH-C-CH -NH-C (CHJ_ i-rt, v characterized in that a racemic compound of the formula CD H O-CH.-C-CH .- 'NH-CtCH h II c = 0 RS-IL-XIX n NIH - C - ° R |, R50 C - H COOH 11