CS253739B2 - Process for preparing derivatives of 3,5-diamino-1,2,4-triazole - Google Patents

Description

The present invention relates to a new improved process for the production of 3,5-diaminool, 2,4-triazole derivatives.

Accordingly, the present invention provides a process for the preparation of 3,5-dimethylamino-2,4-triazole derivatives of the general formula I

(I) in which

R ¹ and R either nezááisle thee always meant alk ^y nominal Sapin having 1-4 carbon atoms or and R ₂ together with the adjacent nitrogen atom form a ring pyrrolidňnový or piperidňnový and

R ³ represents a hydrogen atom or a C 1 -C 4 alkyl group, and the pharmaceutically acceptable acid addition salts thereof.

The compounds of formula (I) are known histamine R-receptors with a prolonged action. These compounds antagonize histamine-stimulated gastric acid secretion and can be used to treat ulcer disease.

Several methods for the preparation of compounds of formula (I) are known. Belgian patent specification 875 846 discloses the amine of formula (V).

In which:

R and R, as defined above, are reacted with a cyanimine derivative of the general formula VI ^R 5 (VI) III

NCN in which

R and R are alkylthio or alkoxy.

The isourea or isothiourea derivative of the general formula VII thus formed

(VII) wherein

R and R are as defined above, then treated with a substituted hydrazine of formula VIII

R - NH - N = Z (VIII) in which

R is as defined above and

Z represents two hydrogen atoms.

This reaction yields a mixture of isomeric compounds corresponding to formula I and formula IX above

in which

R, R and R are as defined above.

(IX)

The compound of formula I is isolated from this mixture by crystallization.

A serious disadvantage of this process is that the isomers of formulas I and IX differing in each other by the position of the substituent R were not formed until the last stage of the synthesis. For this reason, the desired isomer of formula (I) is obtained with large borates. Moreover, due to the fact that these losses occur at the very end of the long, multi-stage synthesis, the entire process becomes very expensive.

In order to eliminate the formation of isomeric compounds of formula (IX), according to a further procedure described in Belgian Patent Specification No. 875 846, the isothiourea of formula (VII) is reacted with a protected hydrazine derivative by the above formula (VIII) wherein R is as defined above and Z is a protecting group. .

The resulting cyanguanidine derivative of formula (X) thus formed

NCN ”3 in which

R, R ^, R Z and Z are as defined above, are cleaved off protected. and the resulting cyanoiguide derivative of the general Formula XI

NCN

in which

R ₂ , R ₂ and R 1 are as defined above, spontaneously cyclize to the compound of formula (I).

According to the Belgian patent specification, the key intermediate of formula (X) can also be prepared by reacting a potassium hydroxide derivative of formula (VII) with a cyanimine derivative of formula (V). The raised protected cyanoborane derivative of formula (XII).

NCN

N-N = Z (XII) wherein

R and R 'are as defined above and

Z is a protecting group, then condensed with an amine of the above formula (V) to give the desired intermediate (X).

A general disadvantage of the two processes described above is the use of a Z-protecting group, the presence of which is intended to eliminate the formation of the isomeric triazole derivative of formula (IX) in the cyclization step to form the tri (III). circle. Indeed, it is known that the analogous reaction of diethyl N-cyaniline-1-dithioareateate and N-meetlhydrazine leads to the formation of isomers of the type of compounds of formulas I and IX by J. Org. Chem. 39, 1522 (1974)].

According to another reaction described in Belgian Patent Specification No. 875,846, the derivative of the isothiolecins of formula XIII

(XIII) in which

R and Rg mail as defined above and

R 8 represents an alkyl group having 1 to 10 carbon atoms, reacted with an aminoguanicin, a semicarbazide or a thienyl group (XIV)

Y (XIV) wherein

Y is -NH-, oxygen or sulfur; and

Rg is as defined above,

The compound of formula XV thus obtained

(XV) wherein, R g, R g and Y are as defined above and

Q is -NH-, then cyclized to a derivative of formula I.

In accordance with the further procedure described in the aforementioned Belgian patent, the isocyanate addition reaction of formula XVI is carried out.

(XVI) in which

R 8 and R ₃ are as defined above and

P is oxygen or sulfur, and a compound of formula XVI wherein Rg is as defined above and Y is -NH-, and the resulting compound of formula XV is then cyclized to the desired traazole derivative of formula I.

A general disadvantage of the above two processes is that the preparation of the reactants is rather complex, the last condensation step is very lengthy and energy intensive, and the yields are only moderate.

According to another reaction described in the aforementioned Belgian patent, the isothiomide of formula (XIII) is reacted with a protected hydrazine of formula (VI), followed by cleavage of the protecting group. The resulting aminogununidine derivative of formula XVII

NH

(XVII) ⁿ 3 in which

R g, R ₂ and Rg maai abovementioned meaning, are then reacted with carbamoylchoride to give the compound of formula I.

The disadvantage of this process is that in order to eliminate the formation of an undesired isomer of formula (IX), a protected hydrazine derivative of formula (VII) is used in which Z is a protecting group, the preparation of the reactants is somewhat complicated and the final condensation stage of the synthesis is lengthy and energy consuming. .

The other type of reaction described in Belgian patent specification 875 846 differs from the above reactions in that it uses an acid amide of the formula X obecnéhoH HI instead of the amino compound of the formula V

(XVHI) in which

R 8 and R ₂ are as defined above, or R ₅ or R _{5 is a} cyclic acetal of formula XIX

R ₆ 0

(XIX) & in which

R 8 represents an alkyl group or (R 8 O) ₂ CH- represents a cyclic acetal.

The last step of this synthesis is to build up a group of formulas (R (R, R, N-CH)) in the resulting intermediates of formulas (XX) and (XXI).

(XXI) in which:

R, R 2, R 3 and R 8 are as defined above in the synthesis of compounds of formula V.

this is accomplished by known methods used

In accordance with another method described in Belgian patent specification no.

875 846 is a key intermediate of general formula XXII

(XXII) in which

R ₃ is as defined above and

X is halogen, condensed with an amine of the formula ## STR2 ## in which

R 1 and I 2 are as defined above.

so,

According to European Patent Application No. 29,303, compounds of formula I are prepared by preparing an aldehyde of formula XXHI

(XXHI) in which

R 3, as defined above, undergoes, under reducing conditions, an amination reaction with an amine of the formula R ₁ R ₂

R 6a are as defined above.

In accordance with the further reaction described in the above-mentioned European patent application, the secondary amine of formula XXIV is used as the starting maer.

(XXIV) in which

_R2 and R3 dem maai general meanings indicated above, which either is subjected to condensation with reduutivní aldehyvzorce

R 2 CHO where ^R 1 'of the R 1 -CH 2 group formed by reduction from an aldehyde of the formula R 1 -CHO, has the meaning as or is alkylated with a compound of the formula

R? - CH 2 - X in which the moiety R-C 1 - is as defined above and

X represents a halogen atom to form a compound of formula I.

In the reactions of the following four types, the same reaction steps are used as in the methods described above, but the order of these reaction steps is different. It follows, however, that these four procedures are accompanied by the same disadvantages as the methods discussed above.

According to another process described in Belgian patent specification 875 846, a narrower subgroup of compounds of formula I is prepared by reacting a phenoxyacyl derivative of formula XXV

(XXV)

ve which R ₃ is as defined above, with an amine chloride of formula XXVI ©

(CH ₃ ) ₂ N = CH ₂ C1 (XXVI)

Thus, a compound of formula (I) is obtained in which both R and R ₂ are methyl. The disadvantage of this procedure is that it is only suitable for the preparation of a narrow group of desired compounds. Moreover, the preparation of the compound of formula XXVI and the reaction itself are complicated and laborious.

In accordance with another method described in Belgian Pat. No. 875,846 to arninoguaaňdin formula XIV, in which R ₃ has the abovementioned meaning and Y represents NH, is reacted with karOaτnoylchloridei XXVII

(XXVII) in which

Rg and Rg shows, all suitable protecting groups thus formed 3,9-d Lam] ^ c ^ - ^: ln 2 _/ 2,4-tri- ^ zole derivative of formula XXXIII

(XXXIII) in which

^R 3 ^{and R 8,} as defined above, are reacted with an aldehyde of formula XXIX

(XXIX) in which

R 8 and R ₂ are as defined above, the obtained Seciff base of formula XXX

(XXX) in which

R 8, R 2 ', R ₃ ' R 8 and R 8, as defined above, are reduced, and the resulting product is then deprotected.

In accordance with the modification of this procedure, the aminotriazole of formula XXVIII above is reacted with an actiolated acid derivative of formula XXXI

(XXXI) in which

Rg and R ₂ are as hereinbefore defined and

A represents a halogen atom, a hydroxyl group, an alkoxy group or an acyloxy group, and the acid amide thus formed of formula XXXXI

(XXXII) in which

R, R ₂ , R 1, R g and R g as defined above are reduced to the desired compound of formula (I).

According to a further mooification of the above process, the aminothiazole of formula XXXIII is reacted with an actiolated ester of formula XXXXII

(XXXXII) in which

R and R ₂ have the above meanings and

B is methyl or ethyl, to give the desired product of formula (I).

The above-described methods are accompanied by the disadvantages that the traazole ring is built by the complicated pathways discussed above, while other problems and inconveniences entail the need for appropriate selection and cleavage of protecting groups in terms of R _g and R _g .

SUMMARY OF THE INVENTION It is an object of the present invention to provide the above-mentioned shortcomings of the known processes and to provide an economical and easy-to-implement process for the preparation of the compounds of formula (I).

Accordingly, the invention provides a process for the preparation of compounds of the above general formula (I) wherein:

R 1 and R ₂ either independently represent an alkyl group having 1 to 4 carbon atoms or R ₁ and R ₂ together with the adjacent nitrogen atom to which they are attached form a new ring and

R 3 represents a hydrogen atom or a C 2 -C 4 alkyl group, and pharmaceutically acceptable acid addition salts thereof, characterized in that the hydroxy compound of formula II

(II) in which it has the meaning given above, is converted to a halogen-derivative of the formula III

(III) wherein

R ₃ is as defined above and

X represents a halogen atom, and this halogenated derivative is reacted with an alkali alkaline earth metal salt of a phenolic derivative of the formula IV

in which

R 1 and R ₂ are as defined above, whereupon the optionally obtained compound of formula (I) is converted to its pharmaceutically acceptable acid addition salt.

The hydroxy compound of the formula II is converted to the halogenated compound of the formula III by methods known per se. Preferably, the compound of formula (II) is reacted with a suitable halogenating agent, in particular a thionyl halide, in particular thionyl chloride, in an inert solvent. The excess thionyl halide may advantageously act as a reaction medium. However, an aromatic hydrocarbon such as benzene, toluene or xylene may also be used as the reaction medium. The reaction may be carried out at room temperature or with heating (for example at a temperature of 20 to 80 ° C).

The halogenated derivative of the formula III is then reacted with an alkali metal (for example potassium, sodium or lithium) or an alkaline earth metal (for example calcium or magnesium) salt of the phenolic compound of formula IV. This reaction may be carried out in a dipolar aprotic solvent, for example dimethylformamide.

The alkali metal or alkaline earth metal salt of a phenolic compound of formula IV may be prepared in a reaction mixture by reacting a phenolic derivative of formula IV in a dipolar aprotic solvent (e.g. dimethylformamide) with a hydride or alkoxide of the appropriate alkali or alkaline earth metal, e.g. calcium hydride or potassium t-butoxide.

The compound of formula (I) thus produced can be isolated by methods known per se.

The corresponding salt may be prepared in a manner known per se by reacting the compound of formula I thus obtained in an organic solvent with a suitable inorganic or organic acid, for example hydrochloric acid, hydrobromic acid, sulfuric acid, mmesic acid, fumaric acid, lactic acid and the like.

The starting materials of formulas II and IV are known and readily available.

The compounds of formula (III) are novel and have not been described so far

The term alkyl in this case refers to straight or branched chain saturated C 1 -C 4 hydrocarbyl groups, such as methyl, ethyl, n-propyl, and the like.

R 1 and R ₂ preferably represent methyl groups or together with the nitrogen atom form a pyrrolidano or piperidine group. R 1 is preferably a methyl group.

Ccording to Method ^{P Y is N,} is to increase climbing ST ^ ^h o ^{d p} ro ^p Nu ^at pH rave l-methyl-N--Zj-Q-PR p ^ i ^ - ^] -). MTI ^]]. (R) -oxy] -piperidin-4H-1,2,4-triazole-3,5-diamine and its salts.

The advantages of the method according to the invention can be summarized as follows:

a) The process is easy to implement, even on an industrial scale.

b) No special apparatus or equipment is required to implement this method.

c) Starting materials are readily available, even in large quantities.

d) Since there is no formation of isomeric compounds of formula (IX) and the synthesis of the desired compounds of formula (I) is not carried out in several steps but by reaction of filamentous intermediates of about the same size, the overall yield of the process is much higher than known methods.

The invention is illustrated by the following examples, which, however, are intended to limit the scope of the invention in any direction.

Peak: la č l

N ⁵ - (3 ^- H ^l or ^{of about FEP]) -} H ^- L, 2.4 ^"tčiavol-, 3, u n ^{of ICAM-hy u u} rvihlori

5 g (0.032 mol) of N ⁵ - (3-hydroxypoyl) -1H-1,2,4-trisyl-3,5-diamine is dissolved in 15 ml of zinc and the solution ^r is stirred at ¹⁰ ° with stirring C ^{gives 4.2} g ( ^{P of 35} mil) of i-oneyl-lorium. The reaction mixture was allowed to slowly warm to room místnoosi and then a further 0.5 ^d ioy it blends. The precipitated crystals are filtered off and washed with benzene. 6.3 g (yield: 92.8%) of the title compound are obtained in the form of a strong hygroscopic white crystalline substance which liquefies in air. Temperature T ^{ck (s} měřfn in kčpiUře) ^P ro ^d uktu ^{or tup 130} C ^{from 131} ° C.

Peak a d 2

N, ^N - (l · ^^^^] ^) - ^first-1,2,4 -triene ^{as in} VA ^{-3, 5} - ^{hy d} ičmin- Droo ^ch ori ^d

The procedure described in Example 1 was repeated except that benzene was replaced, but the reaction was carried out with 10.6 ml (0.15 mil) of thionyl chloride, which also served as the reaction medium. 6.8 g (94.4% yield) of the desired compound is obtained. The product is identical to the compound prepared in case 1.

Example 3

Pim ^ -f ^{(3-chloropropyl)} -1H-l, ^2, 4-triazole-3,5-diamine hydrochloride

It operates in an analogous manner as in example 2, as starting Zt St maaetřál ^p oužijt ^8, 6 ^{g (0,} 0 ⁵ mil) ir.e ^ ^^ N ^ ^{- (3} - ^{h OPL} ydrOxyppo ΗΠί- ^-1 ^^ The reaction mixture is heated to 60 DEG C. and kept at this temperature for ¹⁵ minutes to give 10.7 ^g (yield ^94.7 ) of the desired product, m.p. rozklrdu at ^{17 0-172} ° C.

Example 4 ^{1 <-} methyl ^5- N ^{Y 1} / Q ^{3 - [(1-p ip} ti7 ^iri ^ ny ¹⁾ mυ ^e l ^l ^ w ^ C ^ oyJ- ^- n) ^C ^] ^ ^y - ^- H - ^{- 2 3-triazole, 5 "d} iamin

To a solution of an oily suspension of 1.0 g (0 .033 mol) of 80% t natriumhydri.ru 20 ml of anhydrous rimetyioorrnamiru pommlu We added 5.7 g (0.03 mole) of 3- ^(1-p iperirinylmet ^yl) ftnolu and the mixture was stirred at room temperature for 0.5 h.

In another Bani ce st to a solution of 8.1 g (0.036 mml) of 1-mmtyl-N ⁵ - (3-chloropropyl ^py l) -1H-1,2,4-triazd ^{riamin-1,5-l-y} in drocCloriri 15 ml of anhydrous dimethyl Crmamide with stirring at. 3.04 g (0.03 mil) of ethyl acetate was added at room temperature, the precipitated triethylamine hydrochloride was filtered off and washed with a small amount of anhydrous dimethylformamide. We thus obtained solution under stirring at ROOM ^ i přír the above připaavnéému dίmet ^y lComarmdOovémi oxide solution. The reaction mixture was stirred at room temperature for 72 hours, then 30 ml of boiling water was added and the resulting mixture was extracted three times with 20 ml of chloroform each. The combined organic phases are extracted three times with 20 ml of water each time, the chloroform mixture is dried over anhydrous magnesium sulphate and the chloroform is removed in vacuo. The brown oily residue (9.6 g) slowly crystallized on standing and recrystallized with 1: 4 ethyl acetate: cyclohexane. ZIS ^{Ka 5} 6 ^g (5 eq howl ^ ^ ^{4%) of} the reference linear regression ^é ^ III ¹ of te ^ o ^ = 93 and ⁹⁴ ° C.

Scheming ad 5 l-Methyl-S - ^ - ^ S ^ d-pi-petiHny ^ mm ^ l] ^{ířenoxy], 2,} 4-trilzol ^{-3,5 "d} iamin fumarate

The oily crude product prepared in Example 4 was dissolved in 30 ml of ethanol ^and treated with ^p s ev ^il rpm ^{with 50} ° ^{C in 3.5} řičlá ⁽⁰ ° ³ mo ^ei ^ ^alkyl is n ^{y p} terme of its extended-Stone st reaction was cooled and allowed to stand overnight in a refrigerator. the precipitated crystals were filtered and washed with a small AC mnnCžtaím ethanol. We obtained 7.8 g (yield 56.4%) of the desired compound ^No. enyne ^y of ^th the temperature between approximately ^142-145 ° C.

Example 6 ³ - ³ - ^{- (1} ppei..jL ^{-piperazine-l-n)} m ^{tty] l} eachother] Pio У ^{c il} - ¹ H- ^1,2, 4-triazole ^3,5 - ^d iamin

A similar procedure as in Example 4, Item Down ZT with 10.2 g (0.045 mol) of 1-IneVyl-N ⁵ - ^{(3-chloro and} ro ^py l) - ^1H - ^1,2,4 '-trilzcl ^{- 3.4} - ^{r-h yd} ilmin ROC ^Cl patterning by ^{chromatography. From} iS ^{ka 5.3 g} (yield 51.4%) of the desired compound. The product is identical to the compound floated according to case 4.

EXAMPLE 7 ^1-N 1meVyl ^- - / ^3--3-1 -pi ^{overloading R} IN ^yl) mmtyl] ^{l lp} TNOC io ^il y ^p - ¹ H- ^1,2, 4-triazole ^-3,5-d iamin

It works similar procedure as in Example 4, · Zt as starting maattiál 'will kill 6.8 g (0.03 mol) of 1-γ1 Ν ^^ ⁵ 1- (3-chlcrprciyl) -1H-1,2, ⁴ -trilec1,5-dilmine hydrochloride. 4.9 g (yield 47.6%) of the desired compound are obtained. The product is identical to the compound prepared according to Case 4. _ t ·

Example 8

1-methyl-N ⁵ - [3- [3 - [(1-piperidinyl) methyl] phenoxy] propyl] -1 H -1,2,4-triazole-3,5-diamine

The procedure is analogous to Example 4 except that 1.4 g (0.033 mol) of calcium hydride is used instead of sodium hydride. 5.1 g (yield 49.5%) of the desired compound are obtained. The product is identical to the compound prepared as in Example 4.

Example 9

1-methyl-N ⁵ - [3- [3-E (1-pyrrolidinyl) methyl] phenoxy] propyl 1 H -1,2,4-triazole-3,5-diamine

The procedure is analogous to Example 4 except that 5.3 g (0.03 mol) of 3- (1-pyrrolidinylmethyl) phenol is used as the starting material of formula IV. 4.9 g (49.4% yield) of the title compound of melting point 94-95 ° C are obtained.

Example 10

1-methyl-N ⁵ - [3- [3- [1 H -pyrrolidinyl) methyl] phenoxy] propyl] -1 H -1,2,4-triazole-3,5-diamine fumarate

The procedure was as in Example 5 except that the compound of Example 9 was used as the starting material. 7.2 g (yield: 53.7%) of the desired product were obtained, m.p. 140-142 ° C.

Example 11

1-methyl-N ⁵ - [3- [3- (dimethylamino) methyl] phenoxy] propyl] -1 H -1,2,4-triazole-3,5-diamine

The procedure is analogous to Example 4 except that 4.5 g (0.03 mol) of 3-dimethylaminomethylphenol is used as starting material. 4.1 g (44.9% yield) of the desired product are obtained, m.p. 95-96 ° C.

Example 12

N ⁵ - [3- [3-Q (1-piperidinyl) methyl] phenoxy] propyl] -1H-1,2,4-triazole-3,5-diamine

The procedure is analogous to Example 4 except that 7.6 g (0.036 mol) of N - (3-chloropropyl) -1H-1,2,4-triazole-3,5-diamine hydrochloride is used as starting material. 4.7 g (yield 47.4%) of the desired product of melting point 100 DEG-101 DEG C. is obtained.

Example 13

N ⁵ - / 3 * [3- [dimethylamino) methyl] phenoxy] propyl] -1H-1,2,4-triazole-3,5-diamine

The procedure is analogous to Example 4 except that 4.5 g (0.03 mol) of 3-dimethylaminomethylphenol and 7.6 g (0.036) of N ⁵ - (3-chloropropyl) -1H-1 are used as starting materials. 2,4-triazole-3,5-diamine hydrochloride.

4.2 g (48.2% yield) of the desired product with a melting point of 91-93 ° C are obtained.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of 3,5-diamino-1,2,4-triazole derivatives of the general formula I in which and R ₂ are each independently C 1 -C 4 alkyl or R 1 and R ₂ together with an adjacent atom the nitrogen to which they are attached form a pyrrolidine ring and ^R ₃ represents a hydrogen atom or a C 1 -C 4 alkyl group, and pharmaceutically acceptable acid addition salts thereof, characterized in that the hydroxy compound of formula II H (II) nh ₂ in which ^R ₃ is as defined above, is converted to a halogen derivative of the general formula III (III) nh ₂ .hx in which ^R ₃ is as defined above, and X is a halogen atom, and the halogenated derivative is then reacted with an alkali metal or alkaline earth metal salt of a phenolic derivative of the formula IV in which (IV) is as defined, and then the compound of the formula I thus obtained R | and ^r ₂ have from above optionally converted to their pharmaceutically acceptable acid addition salt. 2. The method of item¹for the preparation of 1-methyl-3-dimethylaminomethyl) phenoxypropyl] -1H-1,2,4-triazole-3,5-diamine, characterized in that it is converted to 1-methyl-N - (3-hydroxyproppl) -1,2 4-triazole-4'-diamine acts t^hion^yl^hallogeneide and thus obtained^1-have^y1-N5-⁽3^-hand¹ogenprop^p(l) The 1,2,2-triazole-3,5-diaminohydrohalide is reacted under basic conditions with an alkali metal or alkaline earth metal salt of 3-dimethylaminomethylphenol.