DD219767A5 - PROCESS FOR THE PREPARATION OF DIHYDROARYLOXYALKYLAMINO-1,2,4-TRIAZOL DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of Dihydroaryloxyalkylamino-1,2,4-triazole derivatives of general formula I, wherein R1 and R2 are identical or different and independently of one another for hydrogen, C1-5 alkyl, C2-5 alkenyl, aralkyl or C3-7 cycloalkyl or together with the nitrogen atom to which they are attached form a 5-10 membered, saturated or at least one double bond-containing heterocyclic ring and R3 is C1-4 alkyl or C1-4 hydroxyalkyl, and pharmaceutically acceptable acid addition salts from that. Formula I

Description

16 150 58

Process for the preparation of dihydroaryloxyalkylamino-1,2,4-triazole derivatives

Field of application of the invention:

The invention relates to a new and improved process for the preparation of dihydroaryloxyalkylamino-1,2,4-triazole derivatives.

In the true sense, the invention relates to a process for the llorotellung of compounds of general formula I, wherein

Rv and R _{2 are} identical or different and independently of each other hydrogen, C-,, _

Alkyl, C, alkenyl, aralkyl or

2-2

C, ₇ cycloalkyl, or together with the nitrogen atom to which they are attached form a 5-10 membered saturated barren at least one double bond-containing heterocyclic ring, and R ₃ is ^C l-4 ^A - ^{Ll <y 1} ° C _{2 4 is} hydroxyalkyl, and the pharmaceutically acceptable salts thereof.

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Character he istik of the known technical solutions; ^

The compounds uer general formula I are known and have valuable pharmaceutical properties © ,.

These compounds are potent Hg antagonists and inhibit histamine receptor-stimulated gastric acid secretion. The compounds of general formula I can be used due to their histam-Hp-blocking \ activity in the treatment of gastric ulcer.

The only known preparation process for the compounds of general formula I is described in European Patent No. 28,483. After ^; In this method, the desired compounds of general formula I are prepared by Birch reduction of an aryl ", oxyalkylamino-1,2,4-triazole derivative of general formula VI (wherein R-, R ₂ and R 1 are the above have il, meaning) The reduction is and sodium in _|;. liquid ammonia, resulting in the presence of alcohol durehge- ".

The disadvantage of this process is that in the reaction, in addition to the desired 2,5-dihydro-3-alkylaminomethyl-aryloxyalkylamino derivative of the general formula I, the isomeric S-alkylaminomethyl-ssdihydro derivative of the general formula VII (in which R ₂ and Rg have the above meaning) is formed. The isolation of the desired product in pure, isomer-free form requires complicated reaction steps and is associated with significant losses of the final product.

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Aim of the invention: ^

The aim of the invention is the development of an improved, economical, the disadvantages of the known method not having method for preparing the compounds of general formula I.

Explanation of the essence of the invention;

In the process of the present invention, the dihydroaryloxyalkylamino-1,2,4-triazole derivatives of general formula I and pharmaceutically acceptable salts thereof are prepared by reducing an aryloxyalkylarain of general formula II wherein R 1 and R p are as defined above, the Dihydroaryloxyalkyiamin thus obtained of the general formula III, wherein R, and K ^ have the above meaning, with a substituted hydrazine of the general formula V, wherein R ₁ and R _{2 have} the above meaning, reacted with N-Cyanoiminodithiocarbamainsäuredimethylester and the isothiourea derivative thus obtained of the general formula IV in which R 1 and R _{2 have} the above meaning, with a substituted hydrazine of the general formula V

''}) ι ic'i-'t '

where R 1 has the above meaning, if desired, a

thus obtained compound of general formula I converted into a pharmaceutically acceptable acid addition salt.

The aryloxyalkylamines of the general formula II used as starting material are known and can be prepared by the methods described in Belgian Pat. No. 875,846. The reduction can be carried out with metallic sodium in liquid ammonia, at a temperature between -85 ⁰ C and -33 ⁰ C. The amount of sodium used is 1.1-4.5 molar equivalents, advantageously 2.5 molar equivalents.

The dihydroaryloxyalkylamines of general formula III thus obtained are new compounds which are not described in the literature. Under the reducing conditions used, in addition to the compound of the general formula III, a small amount of the isomeric Dihydroaryloxyalkylaminderivates of the general formula VIII, wherein Ri and Rp have the above meaning formed »

If desired, the isomers of the general formulas III and VIII can be separated from one another by known methods (for example distillation) or converted directly into a mixture of the isothiourea of the general formula IV and the isomeric compound of the general formula IX in which R 1 and R _{2 have} the above meaning become.

The reaction of the compound of the general formula III with the N-Cyanoiminodithiocarbaminsäuredimethylester can be carried out in the presence or absence of a solvent. The solvent used may advantageously be an inert protic or aprotic solvent. For this purpose, in particular C.. Alkenols, dimethylformamide, ethers, halogenated organic hydrocarbons, aromatic hydrocarbons or acetonitrile. The isopropanol has proved to be particularly advantageous as a solvent. The reaction can advantageously be carried out at a temperature between 20 C and 120 C. The N-cyanoiminodithxocarbamic acid dimethyl ester may preferably be used in a 1.0 molar equivalent amount.

If an isonating mixture of the compounds of the general formulas III and VIII with the N-cyanoimino

Dithiocarbaminsäuredimethylester, a mixture of isomeric isothiourea derivatives of the general formulas IV and IX is obtained, from which the desired isomer of the general formula IV is separated by crystallization.

The isothiourea derivatives of the general formulas IV are new compounds. The reaction of the compound of general formula IV with the substituted hydrazine of general formula V can be carried out in a protic or aprotic organic solvent (eg C, ₄ alkanols, ether or aromatic hydrocarbons) at a temperature of 20-120 ⁰ C. The solvent used may in particular be n-butanol. The compound of the general formula V can be used preferably in an amount of 1.0-1.5 molar equivalent.

The substituted hydrazines of the general formula V and the N-Cyanoiminodithiocarbaminsäuredimethylester used by the process according to the invention are known commercial products.

The compounds of general formula I thus obtained can be converted into their pharmaceutically suitable acid addition salts as desired. These salts can be formed with inorganic or organic acids (e.g., hydrochlorides, hydrobromides, sulfates, methanesulfonates, acetates, maleates, succinates, citrates, fartarates, benzoates, fumarates, etc.). The salts can be prepared by methods known in the art, e.g. by mixing the free base of general formula I with an equivalent amount of the corresponding acid in a suitable solvent.

According to the process of the invention, the compounds of the general formula I can be prepared in a greater purity than according to the known methods; the separation of the intermediates of general formulas VIII and IX - which lead to the undesired compounds of general formula VII - can be carried out in an economical manner in an early stage of the synthesis.

The term "CJ- ₁ -alkyl" is to be understood as meaning straight-chain or branched alkyl groups having 1-5 carbon atoms (eg methyl, ethyl, n-propyl, isopropyl, n-3-butyl, etc.). The term "C _2-5 alkenyl" refers to straight-chain or branched olefinically unsaturated aliphatic hydrocarbon groups containing 2-5 carbon atoms (eg, allyl, propenyl, outenyl, etc.). ^The term "aralkyl group" refers to C _{1 r} , Alkyl groups containing an optionally substituted phenyl or naphthyl group instead of a hydrogen atom (eg benzyl, phenethyl, etc.). The "C ₇ 'cycloalkyl group" may be a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group. The -NR ^ R ₂ heterocyclic group may be a pyrrolidino, piperidino, morpholino, perhydroazepinyl, piperazinyl, N-alkyl-piperazinyl, N-benzyl-piperazinyl or N-phenyl-piperazinyl group.

The term "C. Hydroxyalkyl group" means a 2-4 carbon atom-containing, straight-chain or branched, by an L-lydroxygruppe substituted alkyl group (for example hydroxymethyl, 2-hydroxyethyl, etc.).

Further details of the method according to the invention can be found in the examples below, without restricting the Schutzumfarig to these examples.

Exemplary embodiments: Example 1

Preparation of 3 ~ <(^ 5- (1-pyrrolidinylmethyl) -1,4-cyclohexadienyl / Oxy-1-propanamine

a) 19.8 g (0.425 mol) of ethanol are added to 19.9 g (0.085 mol) of 3- / ** (1-pyrrolidinylmethyl) phenoxy / 1-propanamine, whereupon 500 ml of gaseous ammonia are condensed in the solution become. The reaction mixture is cooled to -85 ° C. in an acetone-dry ice bath and 10.00 g (0.425 mole) of broken metallic sodium are added in portions such that the second and further portions are added only after complete decolorization of the solution. After addition of 1 g of sodium, the cooling bath is removed and the reaction is continued at -33 ° C. After addition of the last portion of sodium, the blue color of the reaction mixture remains for 2.5-3 hours. When the color finally disappears, the reaction mixture is boiled for 30 minutes. After addition of 29.7 g (0.555 mol) of ammonium chloride, the ammonia is evaporated and the residue taken up in 400 ml of diethyl ether. The inorganic salt is filtered off and washed six times with 100 ml of diethyl ether. The ethereal solutions are combined and evaporated under reduced pressure. The residue is subjected to fractional vacuum distillation. There are obtained 18.6 g of a product (boiling point: 162-168 ⁰ C 1 Hgmm), which consists of a 4: 1 mixture of the title compound and the 3 - </ 3 ~ (1-pyrrolidinylmethyl) -1,4 cyclohexadienyl / oxyV-1-propanamine. The isomeric

Mixture is under reduced pressure. (IHgram.) Subjected to a fractional distillation. The product obtained (F .: 166-168 ⁰ C) contains more than 90 % of the desired isomer. Yield 73.9 % ,.

b) The procedure is as in Example la) with the difference that one uses the metallic sodium in an amount of 4.4 g (0.19 mol). '

^c .

After repeated distillation, 15.1 g of the titled product are obtained, mp 165-167 ⁰ G. Yield 67.6%.

Example 2;

Preparation of N-cyano-N * H [3- ^ 5- (1-pyrrolidinylmethyl) -! ^ -cyclohexadieny ^ -oxy-propyl-carbam-imidothioic acid methyl ester. '

a) 9 g (0.038 mol) of prepared according to Example 1 3- " 1 ~ ( 1-pyrrolidnylmethyl) -l, 4-cyclohex.adinyl / -oxy) -1-propanamine be at room temperature in 10 ml 5.5 g (0.038 mol) of dimethyl N-cyanoiminodithiocarbamate are added to the resulting solution The reaction is started at room temperature to give mercaptan and after half an hour the reaction mixture is heated to boiling for one and a half hours and then evaporated under reduced pressure The resulting royal residue is dissolved in 40 ml of acetonitrile while warming, the solution is cooled, the precipitated crystals are filtered off and washed with acetonitrile to give 1.1 g of the title compound, mp 117-119 ° C After concentration of the mother liquor, an additional 11.5 g of the title compound are obtained,

Rf = 0.45 (on silica gel 60 plates, eluent: a 60: 20: 11: 6 mixture of ethyl acetate: pyridine: water: acetic acid).

b) The procedure is as in Example 2a, with the difference that the solvent used is 40 ml of di-n-propyl ether and the reaction mixture is heated to boiling for 5 hours. There are 11.4 g of a phenolic product, Rf = 0.44. (The mobile phase has the composition given in Example 2a). The product is identical to the compound obtained according to Example 2a. ,

c) The procedure is as in Example 2a, with the difference that the solvent used is chloroform and the reaction mixture is heated to boiling for 4.5 hours. Rf = 0.45 (using the eluent described in Example 2a). The product is identical to the compound obtained according to Example 2a.

d) The procedure is as in Example 2a, with the difference that 100 ml of benzene is used as the solvent and the reaction mixture is heated to boiling for 10 minutes. 11.3 g of a product identical to the compound prepared according to Example 2a are obtained. Rr = 0.45 (the tread has the composition given in Example 2a).

e) 'The procedure is as in Example 2a, with the difference that the solvent used is 40 ml of acetonitrile and the reaction mixture is heated to boiling for 4.5 hours. This gives 11.5 g of a product identical to the compound prepared according to Example 2a. Rf, = 0.44 (the eluent has the composition given in Example 2a). Yield: practically quantitative.

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fj 9 g (0.028 mol) of 3-10 g of (1-pyrrolidinylmethyl) -1,4-cyclohexadienyl / oxyA -1-propanamine are dissolved at room temperature in 10 ml of dimethylformamide. 5.5 g (0.038 mol) of N-Cyanoiminodithiocarbamxnsäuredurediraethylester are added to the resulting solution. The reaction mixture is allowed to stand at 120 ° C for 5 hours, cooled, poured into 100 ml of water and extracted four times with 30 ml of chloroform. The chloroform phases are combined, dried over anhydrous magnesium sulfate and filtered off, the solvent is distilled off under reduced pressure, the residue is dissolved in 35 ml of acetonitrile with heating, the resulting solution is cooled, the precipitated crystals are filtered off and washed with acetonitrile 0.8 g of the N-cyano-N'-3- / 3- (1-pyroolidinylmethyl) -1-cyclohexadeienylZ-oxy-1-propylcarbaminothioic acid methyl ester, mp: 11-18 ° C. After evaporation 9.2 g of a honey-like product are obtained from the mother liquor R 1 = 0.46 (the mobile phase has the composition given in Example 2a) The product is identical to the compound prepared according to Example 2a.

Example 3

5 - - Preparation of 1-Methyl-N - ^ 3 ~ / _ £ 5- (l-pyrrolidinylmethyl) -l, 4-cyclohexadienyl7-oxy7 ~ ^rt P> pyl] K · IiI-1,2,4-triazole 3 "5-diamine"

a) 9g (0.027 mol) of the prepared according to Example 2a to 2f N-cyano-N '-3 - <(/ ~ 5- (1-pyrrolidinylmethyl) -1, 4-cyclohexadienyl / -oxy) -propylcarbamimiothioäuremethylesters be at room temperature in 200 ml of n-butanol dissolved. To the solution is added 1.24 g (0.027 mol) of methylhydrazine. The reaction starts immediately under mercaptan

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development. The reaction mixture is boiled for 20 minutes and held at this temperature for 20 hours. The solvent is distilled off under reduced pressure. The honey-like residue is poured into a mixture of 20 ml of cyclohexane and 5 ml of acetonitrile. The mixture is cooled, the precipitated crystals are filtered off and washed with acetonitrile. There are obtained 7.5 g of the title compound, yield 83.8 %, mp.: 81-84 ⁰ C. The crude product is recrystallized from 60 ml of an ethyl acetate: cyclohexane mixture (1: 4). There are obtained 6.8 g of the title compound, yield 76 %. F.: 36-87 ° C.

b) The procedure is as in paragraph a, with the difference that the solvent used is di-n-propyl ether. After recrystallization, 5.4 g (60.3 %) of the title compound are obtained. The product is identical to the compound prepared according to Example 3a. Mp: 85-87 ⁰ C.

c) The procedure is as in Example 3a with the difference that the solvent used is benzene. Recrystallization gives 5.1 g of the title compound. Yield 57 %. F .: 85-88 ⁰ C. The product is identical with the compound prepared according to Example 3a.

d) The procedure is as in Seispiel 3a, with the difference that 1.86 g (0.041 mol) of methylhydrazine used. After recrystallization 6.6 g of the title compound are obtained, yield 73.9%, m.p .: 85-87 ⁰ C. The product is idenstisch with the prepared compound.

F .: 85-87 ⁰ C. The product is according to Example 3a

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Example 4. , ...-.

Preparation of 3 - ^^ "5- (1-piperidinylmethyl) -1,4-cyclohexadienyl / oxyX-1-propanamine

4.62 g (0.1 mol) of ethanol are added to 5.97 g (0.02 mol) of ΊΊ- ( 3- 3- (1-piperidinylmethyl) -1 -phenoxy-1-propanamine and are taken in the solution thus obtained 200 ml of ammonia is condensed. the mixture is cooled in an acetone -Trockeneis.Bad to -75 ^P C, and 2.41 g (0.105 mol) of sodium are broken metallic added in portions such that the second and further portions only be added when the color of the solution has completely disappeared.

After addition of about 0.5 g of sodium, the blue color of the reaction mixture is maintained for 2.5-3 hours. After final decolorization of the solution, the reaction mixture is heated to boiling for 30 minutes and 6.89 g (0.13 mol) of ammonium chloride are added. The ammonia is evaporated, the residue is taken up in 200 ml of diethyl ether, the inorganic salt is filtered off and washed six times with 50 ml of ether each time. The ethereal solutions are combined and the solvent is removed under reduced pressure. The oily residue _x is subjected to a fractional vacuum distillation. There are obtained 4.85 g of a product (boiling point: 13O-135 ° C / O, 3 Hgmtn), which from a 4: 1 mixture of the title compound and the isomeric 3 - <^ "* 3- (l The mixture of isomers is subjected to repeated fractional distillation at 0.3 Hgmm The fraction boiling at 133-135 ° C contains more than 90 % of that mentioned in the title Pre-binding Yield 78.0 %.

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- Λ.3 -

example b

Preparation of N-cyano-3-x (1-5-piperidinylmethyl} -l, 4-cyclohexadienyl-7-oxy) -propyl-carbamidothioic acid methyl ester

3.0 g of the pure (1-piperidinylmethyl) -1-cyclohexadienylamine prepared according to Example 4 are dissolved in 30 ml of diethyl ether and 1.75 g (0.012 mole) of N-cyanoiminodithiocarbamate are added with methylmercaptan development. The reaction mixture is heated to boiling for 2 hours and then concentrated. The white solid residue is suspended in a small amount of ether and filtered off. There are obtained 3.9 g of the title compound. Yield 93.3%. .Z F-90-95 ⁰ C. After recrystallization from isopropanol the product melted at 95-97 ⁰ C.

Example 6

5 - - ·

Preparation of 1-methyl-N - <{3 ~ Z ^ 5- (l-piperidinylmethyl) -l, 4 x 'cyclohexadienyl7-oxγ7-pfopyl y ~ IH-1,2,4-triazole-3,5-diamine

1.74 g (Ü, 10 moles) of the N-cyano-N'-3 / 5- (1-piperidinylmethyl) -1,4-cyclohexadienyl / oxypropyl-carbamidothioic acid methyl ester prepared according to Example 5 are prepared in Butanol dissolved, whereupon the solution 0.62 g) ü, 054 mol) of methylhydrazine are added. The reaction begins immediately with mercaptan development. After 20 minutes, the reaction mixture is heated to boiling and held at this temperature for 20 minutes. The Reaktionsgemiech is cooled, the solvent below

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removed ent reduced pressure and the residue dissolved in a small amount of a 4: 1 cyclohexane-ethyl acetate mixture. The solution is cooled, the precipitated crystals are filtered. There are obtained 1.5 g of the titled compound, yield 86.2 %, F .: 1OO-1O3 ° C "After recrystallization from a 4: 1 cyclohexane-ethyl acetate mixture, the product melts at 10.5-106 ⁰ C.

-15 ~

NCN

SCH,

Rj-NH-NH ₂

[Y)

NCN

[IX)

SCH.

η "..ι-- C I-.

Claims (7)

Pat e η t η s ρ s r e before: I.! A process for the preparation of Dihydroaryloxyalkylaraino-1,2, '4-triazole derivatives of general formula I, wherein R ₁ and R ₂ are identical or different and are independently hydrogen, C ^l _1- C'Alkyl, '' C _2-5 alkenyl, aralkyl ^or? C ₇ -, cycloalkyl or together with the nitrogen atom to which they are attached form a 5-10 membered saturated or at least one double bond-containing heterocyclic ring and R- ,. C,. Is alkyl or C-, _4- hydroxyalkyl, and the pharmaceutically acceptable acid addition salts thereof, characterized in that an aryloxyalkylamine of the general formula II in which R- and Fi _{2 have} the above meaning, reduces the Dihydroaryloxyalkylamin thus obtained of the general formula III, wherein R ^ and R "the above Having reacted with N-Cyanoiminodithiocarbaminsäuredimethylester and the resulting isothiourea derivative of the general formula IV, - wherein R ^ and R _{2 have} the above meaning, with a substituted hydrazine of the general formula V, wherein R, has the above meaning, and if desired, converting a compound of the general formula I thus obtained into a pharmaceutically suitable acid addition salt. ,,; . ''..' 2. The method according to claim 1, characterized in that the aryloxyalkylamine of the general formula II is reduced with metallic sodium in liquid ammonia. , '' '' ". , '- ..', '": - ie - 3. The method according to claim 2, characterized in that one uses the metallic sodium in an amount of 1.1-4.5, 'preferably 2.5 molar equivalents. 4. The method according to any one of claims 2 and 3, characterized in that one carries out the reduction at a temperature between · -85 ⁰ C and -33 ⁰ C. 5. The method according to claim 1, characterized in that the reaction of the compound of general formula III with the N-Cyanoiminodithiocarbaminsäuredimethylester / in a protic or aprotic solvent, preferably in isopropanol. 6. The method according to claim 1, characterized in that reacting the compound of general formula IV with 1.0 to 1.5 molar equivalents of the hydrazine derivative of the general formula V. 7. The method according to claim 6, characterized in that one carries out the reaction in a protic or n aprotic organic solvent - advantageously in n-butanol. - For this 2 formula sheets -