DD284225A5 - PROCESS FOR THE PREPARATION OF 1,3-BIS- (1'-AZOLYL) -PROPAN-2-OLENE AND THEIR SALTS - Google Patents

Abstract

The invention relates to a process for the preparation of * and their salts. The * are indicated by the general formula I. The aim of the invention is the provision of potentially medically and agriculturally useful agents or intermediates. The process is characterized in that 1,3-dichloro-propan-2-ol, 1,3-dibromopropan-2-ol, * (epichlorohydrin) or * (epibromohydrin) are conveniently treated with azoles II, wherein X is CH or N , YH or lower alkyl and ZH or alkali metal (in particular sodium), and the resulting azole bases are subsequently converted into salts which are tolerable for higher plants and warm flowers. Formula {* salts, 1,3-dichloropropan-2-ol, 1,3-dibromopropan-2-ol, * * imidazoles, * medical and agricultural agents, intermediates}

Description

Field of application of the invention The invention relates to the preparation of 1,3-bis (1'-azolyl) -propan-2-ols I of the general formula

-N- c; -! - cn - c:! - l - κ> Γ

I OM '

Y Y

with X = CH or N and Y = H or lower alkyl, and their plant physiologically and pharmacologically acceptable salts. Such compounds have as potential pesticides and pharmaceuticals or as starting materials for such importance.

Characteristic of the known state of the art

In the since 1970 extraordinarily increased number of known in the world literature 1-substituted imidazoles and 1,2,4-triazoles, it must be considered surprising that compounds of type I and their salts have remained unknown. Only a few representatives with nitro groups in the heterocyclic nucleus have been described (Tulecki, J., and L. Zaprutko, Acta Polon, Pharm. 61 [3], 281 [1984]). However, such compounds or their derivatives are not used for purposes that are the subject of the present application. On the other hand, those described in British Patent Application 2078719 A of 13.1.82 (ICI), European Applications 0044605 of 27.1.82 (ICI) and 0096569 of 6.6.83 (Pfizer) as well as in US Pat

DDK application 202565, 21.9.83 (Pfizer) disclosed 1,3-bis- (1'-triazolyl) -2-aryl-2-propanols (type fluconazole) multi-step syntheses, partly using expensive, technically difficult to handle chemicals. In addition, the substances described there z.T. proved teratogenic.

Object of the invention

The aim of the invention is to find processes for the preparation of 1,3-bis (1'-azolyl) -propan-2-ols and their salts, which or their derivatives can be used as medically or agriculturally useful agents.

Explanation of the essence of the invention The object of the invention is particularly rational, technologically easy to carry out on a larger scale Synthasewege on the basis of cheap available raw materials to imagine. According to the invention the object is achieved in that as starting materials in addition to azoles of the general formula II,

in which X, Y and Z are the meanings mentioned in the claims of the invention haβη ha.Den, 1,3-dihalopropan-2-ols or 1-halo · 2,3-epoxypropanes are used. Here are the industrially easy and cheap available connections

VS-dichloropropane-Z-ol (α, γ-dichlorohydrin) and 1-chloro-2,3-epoxy propane (epichlorohydrin) are preferred. Starting from the 1,3-Dihalogonpropan-2-ol you can carry out the reaction so that per mole of halo alcohol from the outset

at least 2 moles of the azole. However, it is also possible initially to replace only one halogen atom with an azolyl radical and then to convert the compounds III or IV formed in situ into a type I compound with a second mole of azole, thereby

Compounds with different Azolylresten in the molecule are accessible. Likewise, one can proceed when using 1 -halogen-2,3-epoxypropanen. Compounds of type IV proved

especially in the imidazole series (X = CH, Y = H, CH ₃ ) as unstable with a strong tendency to strongly exothermic running

Separation. Their isolation and characterization was therefore omitted. Rather, they became equal in situ

corresponding I processed (Example 8). The procedure is suitable for representing asymmetric I with different X and Y in one molecule.

Suitable reaction conditions are all known per se methods of alkylation of imidazoles and

1,2,4-triazoles in the 1-position with alkyl halides or the addition of imidazoles and 1,2,4-triazoles to oxiranes in question. It has also proved to be favorable for the synthesis of the compounds according to the invention, the azoles Il (Z = H) before Umsei * with the 1,3-dihalopropan-2-ol or 1-halo-2,3-epoxypropane by conversion into their alkali salts (in particular

Z = Na). When using 1-halo-2,3-epoxypropanen it is sufficient, only one of the necessary To transform Azolmoleküle in the alkali salt, since the other also without activation with sufficient Reaction rate added to the oxirane ring. The conversion of the azoles into alkali metal salts can be carried out in the manner known from the literature

by means of alkali metal hydroxides ^ -alcoholates, -hydrides or -amides. The alkylation of the invention

Imidazoles / triazoles II (Z = H) can also be used in the presence of organic or inorganic acid scavengers such as trialkylamines or

Anhydrous alkali metal carbonates (preferably potash) happen. The alkylating agents can be activated with catalytic amounts of an alkali metal iodide.

The solvents used are alcohols, aliphatic nitriles (for example acetonitrile) or ketones (for example acetone or ethyl methyl ketone), Hexamethylphosphorsäuretriamid or dialkylamides of lower carboxylic acids in question. Preferred solvent is Dimethylformamide (DMF). The reactions are carried out at temperatures zwischf η room temperature and 155 ⁰ C. Preferred for the alkylation of Il (Z = Na) is the temperature range between 50 ui, d 100 ⁰ C. The process variant with Il (Z = H), the z. B. with the use of Alkali metal carbonate is required, tempera tures between 90 and 13O ⁰ C and a prolonged reaction time. As free bases, the I are water-soluble compounds. They are first honey-like and not indigestible distillable.

The purification can be carried out by Umkriatallisation (eg, I, X = N, Y = H) or column chromatography. It is generally possible to crystallize them in the form of salts. While the hydrochlorides and tartrates are very hygroscopic, the nitrates, oxalates, maleates, methanesulfonates, 5-sulfosalicylates and naphthalene-1,5-disulfonates are well handled. The dinitrates are preferred. The use of dibasic carboxylic acids produces acidic salts. The salts described are water-soluble. The structures of all compounds were confirmed by elemental analysis, IR, NMR, and mass spectra.

embodiments example 1

1,3-BiS- (1'-imidazolyl) -propan-2-ol

7.44 g (0.31 mol) of sodium hydride and 150 ml of dry dimethylformamide are added and the mixture is stirred and cooled with ice

20.4 g (0.30 mol) of imidazole. The batch is gassed with dry nitrogen. After the imidazole under

Dissolved hydrogen evolution, 17.42g (0.135 mol) of 1,3-dichloropropan-2-ol are added dropwise. Cool when the Temperature exceeds 30 ° C. Without further cooling, the mixture is allowed to stand overnight and then heated

2 hours on the boiling water bath to make the precipitated salt easier to filter. After sucking off the same, the solvent i. Distilled off V. and the remaining honey dissolved by boiling in 50 ml of isopropanol.

Column chromatography on silica gel (elution with methylene chloride / 10% methanol) allows the free base to crystallize

to be brought. Mp. 106-108 ⁰ C (acetonitrile / ethyl acetate).

Preparation of dinitrate: Substituting the isopropanolic solution of the base with conc. ENT ₃ , the salt initially oily, but soon solidifies. Yield: 33.4 g (84% of theory, based on 1,3-dichloropropan-2-ol used in the above batch). The substance is for reactions

clean enough. It can be recrystallized from methyl glycol or glacial acetic acid. The melting range is then between 151 and 154 ⁰ C, whereby the salt decomposes with evolution of gas.

Preparation of the acid oxalate (C ₈ H ₁₂ N ₄ O- 2C ₂ H ₂ O ₄ ): The salt precipitates in 81% yield upon the reaction of the isopropanolic solution of the base with an isopropanolic solution

of oxalic acid. It can be recrystallized from DMF / 1-butanol. Mp 177.5-80.5 ⁰ C (Zers.)

Preparation of the acid maleate (CgH ₁₂ N ₄ O 2C ₄ H ₄ O ₄ ): Upon addition of an isopropanolic solution of the base with an isopropanolic solution of maleic acid. Mp. 112 to 114.5 ⁰ C (isopropanol) Preparation of methanesulfonate (C ₉ H) ₂ N ₄ O ₂ CH ₄ O ₃ S): The salt precipitates in the cold, after an isopropanolic solution of the base with a sufficient amount Methanesulfonic added and boiled. Mp 126-130 ° C (dec.), From isopropanol Preparation of the naphthalene-1,5-disulphonic acid salt (CgH ₁₂ N ₄ O.Ci ₀ H ₈ O ₆ S ₂ .H ₂ O): The salt precipitates in high yield, if, isopropanolic solutions of base and naphthalene-1,5-disulfonic acid

together there.

Mp. 261-263 ⁰ C (from 90% ethanol / 10% water) Preparation of the 5-sulfosalicylic acid salt (C ₉ H ₁₂ N ₄ O 2 C ₇ HtO ₈ S): The salt initially precipitates from a compound of ethanolic solutions of the base and 5-sulfosalicylic acid, but solidifies

when standing in the refrigerator after occasional rubbing with the glass rod.

Mp 172-173.5 ⁰ C

Example 2

1,3-bis (1'-imidazolyl) -propan-2-ol (as dinitrate)

20.4 g (0.3 mol) of imidazole are added to a resolution of 6.9 g of sodium in 150 ml of methanol and boiled Vj Std. At reflux.

Then, the methanol is distilled off. Dia last traces are after the addition of 100ml toluene and further distillation

dragged out to dryness. The solid residue is dissolved in warm 150 ml DMF and within 15 minutes to the cooled solution 17,41 g (0.135 mol) of 1,3-dichloropropan-2-ol to. The temperature rises to 84 ° C. The approach is still 3 hours.

stirred on the boiling water bath. After cooling, the precipitated sodium chloride is sucked off and distributed

Solvent i.v. After addition of 100 ml of isopropanol and boiling, the dinitrate is precipitated by means of 65% nitric acid.

Output: 34.14g (85.9%)

Using 29.43 g (0.135 mol) of 1,3-dibromopropan-2-ol (α, γ-dibromohydrin) instead of the dichloro prebaking

29.5g (68%) of the product. The resulting sodium bromide remains dissolved in the DMF and can only after the addition of the

Isopropanols are separated. Example 3

1,3-bis- (1'-imidazolyl) -propan-2-ol (as dinitrate)

As described in Example 2, a solution of 0.3 mol of imidazole sodium in 150 ml of DMF har is added and 20.4 g of this are added

(0.3 mol) imidazole in 150 ml UMF. Upon dropwise addition of 12.95 g (0.14 mol) of epichloro.ydrin or 19.2 g (0.14 mol) of epibromohydrin within 15 minutes in each case half of this mixture, the temperature rises to about 75-8O ⁰ C. Man stirring 5 Std. At 8O ⁰ C. If epichlorohydrin is used, the precipitated sodium chloride is filtered off with suction after cooling.

The solvent is i.v. distilled off and the oily residue by boiling with 100 ml of isopropanol in solution

brought. If epibromohydrin has been used, the precipitated sodium bromide must be sucked off after cooling.

Subsequently, each with about 25ml conc. Nitric acid adjusted to pH 2. Leave in the fridge overnight

crystallize and wash after aspiration, the white salt with a little isopropanol and then with ether.

Yield: 39.8 g (89.4% of theory) using epichlorohydrin; 41.9 g (94.1% of theory) when using epibromohydrin The melting range of the crude products is between 137 and 149 ⁰ C with decomposition. By recrystallization according to Example 1

he is to bring to 148-154 "C.

Example 4

1,3-bis | 1 '- (1'.2', 4'-triazolyl) l-propan-2-ol

The procedure is as in Example 2 and uses instead of imidazole 20.7 g (0.3 mol) of 1,2,4-triazole. The alkylation of Triazole sodium occurs with 18.06 g (0.14 mol) of 1,3-dichloropropan-2-ol. After the addition, it is stirred for 10 h. at 80 ° C and works

As in Example 2 on.

The free base occasionally crystallizes from the isopropanolic solution. It can be made by recrystallization from ethanol or

purified by column chromatography on silica gel with methylene chloride / Mathanol (90/10) as eluent.

Mp 127.5-129 ⁰ C

Preparation of dinitrate: Is the isopropanolic solution of the mixture with conc. Nitric acid brought to pH 2, the salt turns white. Yield .; 40.0 g (89.2% of theory, based on 1,3-dichloropropan-2-ol). The substance melts with decomposition between 166 and 174 ⁰ C and

is clean enough for realizations. After recrystallization from ethyl glycol, the salt melts with decomposition between 176 to

Preparation of the acidic oxalate (C ₇ Hi ₀ NeO.2C ₂ H ₂ O ₄ ): The salt falls when mixing isopropanolic solutions of base and oxalic acid. Recrystallization from methanol.

Fp.168-174 ° C (dec.)

Preparation of the acid maleate (C ₇ Hi ₀ NgO.2C ₄ H ₄ O ₄ ): From the isopropanolic solutions of base and maleic acid. Fp.124-127 ° C (isopropanol) Preparation of Methanesulfonate (C ₇ Hi ₀ N ₆ O 2CH ₄ O ₃ S): When adding methanesulfonic acid to the isopropanolic solution of the base. Mp. 172-177 ⁰ C (dec.), Isopropanol Preparation of the 5-sulfosalicylic acid salt (C ₇ H ₁₀ N ₆ O 2 C ₇ H ₆ O ₆ S): Upon addition of an isopropanolic solution of 5-sulfonic salicylic acid to the isopropanolic solution of the base. Mp. 186-19O ⁰ C (Zers.), From ethanol Example 5

1,3-bis (1 '- (1', 2 ', 4'-triazolyl)] - propan-2-ol (as dinitrate)

3.45 g (0.16 gramotom) of sodium are dissolved in 75 ml of methanol, and 20.7 g (0.3 mol) of 1,2,4-triazole are introduced into this solution. After Vastündigem boiling at reflux, the methanol is distilled off and drags the last residues with 50ml

Toluen out. Add 150 ml of dry DMF to the dry residue and dissolve by heating gently. Starting at Room temperature are added dropwise within 15 min 18.5 g (0.135 mol) of epibromohydrin, the temperature to about 65-70 ° C.

increases. It is stirred for 4 hours. at 8O ⁰ C and distilled off the solvent IV. Under reflux, the residue is then dissolved in 100 ml of isopropanol. After standing overnight, the precipitated sodium bromide is filtered off with suction and the dinitrate is precipitated with 65% nitric acid. If the free base already crystallizes out at room temperature before filtering off the sodium bromide, the sodium bromide must be filtered off with suction while warm.

Y. almost quantitative.

Fp.166-174 ° C (dec.)

Example β

1,3-bis- [1 '- (1', 2 ', 4'-triazotyl)) - propan-2-ol (as dinitrate)

A mixture of 20.7 g (0.3 mol) of 1,2,4-triazole, 17.41 g (0.135 mol) of 1,3-dichloropropan-2-ol, 1 g of sodium iodide, 42 g of anhydrous Potassium carbonate and 200 ml of dry DMF are stirred at 125 ^° C. for 30 hours. Then it is sucked off from the inorganic salt,

Wash the same with 30 ml of DMF and distil the solvent from the filtrate i.V. from. The residue is 100ml

Isopropanol boiled and the resulting solution stored overnight in the refrigerator. It gets smaller again Suction amounts of precipitated inorganic material and then the dinitrate by means of conc. nitric acid

precipitated.

Yield: 39.0 g (90.1% of the theoretical)

The crude product is immediately useful for further reactions. Example 7

1-imidazolyl-3- | V- (1'.2 ', 4'-triazolyl) -1-propan-2-ol (as dinitrate)

9.52 g (0.14 mol) of imidazole are dissolved in 75 mL of dry DMF under nitrogen and ice cooling in a slurry of 3.48 g (0.145 mol) of sodium hydride. To this solution is added dropwise 19.35g (0.15 mol) of 1,3-dichloropropan-2-ol and stirred for 2 hrs. At 80 "C.

Then added dropwise a solution of 0.14 mol of 1,2,4-triazole sodium in 75 ml of dry DMF and heated again for 2 hours under Stirring to 8O ⁰ C. After standing overnight, the salt is sucked off (15.75 g = 0.272 mol) and works as in the

previous examples. The product crystallizes as dinitrate.

Yield: 27.2 g (61% of theory)

Mp 159.5-163.5 ° C (dec.), From methyl glycol Example 8

1 -imidazolyl-3-H '- (1', 2 ', 4'-triazolyl)] - propan-2-ol (as dinitrate)

A 500 ml three-necked flask is charged with 185 g (2.0 mol) of epichlorohydrin and 13.8 g (0.2 mol) of 1,2,4-triazole. You give

with stirring within 1.5h. 11.3 g of finely powdered caustic potash and then heated for a further 2 hours on a water bath at 40 ^° C. After cooling, the phases are separated and the epichlorohydrin is distilled from the organic phase at a maximum of 45 ^° C.

Internal temperature from. The remaining oil is immediately dissolved in 50 ml of dry DMF, since it is rapidly submerged in free form Darkening and increase in viscosity decomposes.

This solution is then added dropwise to a solution of 0.21 mol of imidazole Natrlum in 75 ml of dry DMF, keeping the temperature by cooling below 3O ⁰ C. After standing overnight, the mixture is heated for a further 2 hours to 8O ⁰ C and then worked up as in the previous examples

 Aurb.:35,0g(55%d.Th.) Mp.159-163 ° C (decomp.), From methylglycol

Example 9

1,3-bis (2'-methylimidazolyl) -propan-2-ol (as dinitrate)

The procedure is as in Example 1 angegebon using 24.6 g (0.3 mol) of 2-methylimidazole. The dinitrate first falls out of the

isopropanolic solution of the base as honey, but crystallizes overnight when standing in the refrigerator.

Yield: 38.4g (82.2% of the theoretical)

The recrystallization succeeds from methyl or ethyl glycol.

Mp 157-161 ° C (decomp.)

Claims (4)

A process for the preparation of 1,3-bis- (1'-azolyl) -propan-2-ols of general formula I, wherein X is optionally the CH group or nitrogen and Y is hydrogen or lower alkyl, characterized in that either 1,3-dihalopropan-2-ols, !. \ ί - ( ¹ M ,. - CiI - C !! .. - H ^r !. ι \ υϋ where the term "halogen" means chlorine or bromine, but preferably chlorine, as starting materials and these under suitable reaction conditions with two equivalents of the azoles II, in which X and Y have the abovementioned meanings and Z is hydrogen or alkali metal (preferably sodium) or that one carries out the alkylation of two equivalents of types II using one equivalent of 1-halo-2,3-epoxypropane III, with Hai = chlorine or bromine, and on both Where appropriate, then converted into well-crystallized, plant-physiologically and pharmacologically acceptable salts of inorganic or organic acids due to the resulting bases. 2. A process for the preparation of the types I according to claim 1, characterized in that one brings the 1,3-dihalopropanols instead of 2 equivalents Il first with only one equivalent of the reaction and II, the intermediate IV, in which X and Y are those mentioned above Have meaning, without isolation with a further equivalent Il implements, whereby I can be prepared with both sides different groups X and Y. _..., . _{z IV} ^N - I oi-i 3. A process for the preparation of the types I according to Ar-Pruch 1, characterized in that 1-halo-2,3-epoxypropanes III, with Hai = chlorine the bromine, in the presence of an alkaline condensing agent, first with an equiva 3nt of the azole II (Z = H) to form compounds of type V and then optionally without isolation then with a further molecule N (Z = H or alkali metal) into diel, whereby also I with in each case two 'different Azolresten can be produced. Ν == - M - CII ₉ - CM - Ci -! _ _V Y 0 4. The method according to claim 1, characterized in that is used to obtain well crystallizing, non-hygroscopic salts of the compounds I preferably nitric acid, organic sulfonic acid-methanesulfonic acid, sulfosalicylic acid or naphthalene-1,5-disulfonic acid or organic dicarboxylic acids such as oxalic acid or maleic acid.