WO2004005263A1

WO2004005263A1 - Method for producing 1-methylcyclopropylguanidine

Info

Publication number: WO2004005263A1
Application number: PCT/EP2003/007287
Authority: WO
Inventors: Thomas GÜTHNER; Doris Krammer
Original assignee: Degussa Ag
Priority date: 2002-07-09
Filing date: 2003-07-07
Publication date: 2004-01-15
Also published as: DE10230780A1; AU2003249978A1

Abstract

The invention relates a method for producing 1-methylcyclopropylguanidine of the salts thereof. The inventive method consists in reacting an amidine heterocyclic composition of a general formula (1) with 1-methylcyclopropylamine or the salt thereof in one or several solvents which are selected in the group of nitriles and/or esters at a temperature ranging from -20 to 150 °C. In the formula (1), U, V, and W represent methylcyclopropene independently on each other N or C-R2; R1 and R2 represent independently on each other H, alkyl C1-C4; and HX represent a monobasic or polybasic acid, organic or inorganic acid which value pKs=7. Said method makes it possible to produce a target high purity final product with a high performance using an economical and technically pefrormable process.

Description

Process for the preparation of 1-methylcyclopropylguanidine or its salts

description

The present invention relates to a process for the preparation of 1-methylcyclopropylguanidine or its salts, starting from a heterocyclic amidine compound and 1-methylcyclopropylamine (salts).

1-Methylcyclopropylguanidine or its salts are valuable intermediates in the production of active pharmaceutical ingredients (cf. WO 01/02410).

There are a number of tried and tested reagents for the preparation of N-substituted guanidines from the corresponding amines. Are suitable for. B. cyanamide (see US 2,425,341, US 3,383,408), O-methylisourea salts (see F. Cramer et. Al., Chem. Ber. 95, 1670 (1962)) or formamidine sulfonic acid (see K. Kim et. al., Tetrahedron Lett. 29, 3183 (1988)). A disadvantage of all these reagents is the fact that highly substituted and thus sterically hindered amines can be converted to the corresponding guanidines only with difficulty and in poor yield or not at all.

A certain improvement was achieved by using 1-amidinopyrazole hydrochloride as guanylation reagent, preferably in N, N-dimethylformamide as the solvent (SM Bernatowicz et. Al. J. Org. Chem. 57, 2497 (1992)). However, these authors also note that guanidine derivatives cannot be obtained from sterically hindered secondary amines. Using the example of the sterically hindered tert-butylguanidine, it has recently been shown that acceptable yields of up to 50% can only be achieved using complex solid-phase and Protection group technology can be obtained. However, an economical process for the production of highly substituted, sterically hindered guanidines, which could also be carried out on a larger scale and which would be applicable in particular to the conversion of 1-methylcyclopropylamine to the corresponding guanidine, was not available.

The present invention was therefore based on the object of developing a process for the preparation of 1-methylcyclopropylguanidine or its salts which does not have the disadvantages of the prior art mentioned, but rather enables the desired product in good yields and in a technically feasible and economical manner ,

This object has been achieved according to the invention in that a heterocyclic amidine compound of the general formula (I)

where U, V, W independently of one another N or CR ₂ ,

R ₁ and R ₂ independently of one another are H, C 1 -C 4 alkyl and HX are a mono- or polybasic, organic or inorganic acid with a pKa value of <7, with 1-methylcyclopropylamine or a salt thereof in one or more solvents selected from the group consisting of nitriles and esters in the temperature range from - 20 to 1 50 ° C.

Surprisingly, it has been shown that 1-methylcyclopropylamine or its salts can be prepared in good yields and high purity in this way. You can also use the Produce well crystallizing salts of 1-methylcyclopropylguanidine according to the process of the invention, which was likewise not predictable.

In the process according to the present invention, a heterocyclic amidine compound of the formula (I) is used as the reagent for introducing the guanidino group.

Ri

The radicals U, V and W can independently of one another have the meaning N (nitrogen atom) or CR ₂ (substituted carbon atom), where R and R ₂ independently of one another are H or C 1 -C ₄ -alkyl.

"C ^ C ^ alkyl" means a straight-chain or branched, optionally substituted hydrocarbon radical having one to four carbon atoms. In particular, "CC ₄ " alkyl represents methyl, ethyl, propyl, i-propyl, butyl or t-butyl groups.

The following combinations are preferred: a) U = N, V = CR ₂ , W = CR ₂ , ie an optionally substituted pyrazole ring, b) U = CR ₂ , V = N, W = N, ie an optionally substituted 4H- 1, 2.4-

Triazole ring and c) U = N, V = CR ₂ , W = N, ie an optionally substituted 1 H-1, 2,4-

Triazole ring.

HX can be any mono- or polybasic inorganic or organic acid. In particular, HX has a pKs value of <7. B. HCl, HNO ₃ , H ₂ SO ₄ (preferably Vi equivalent), p- Toluene sulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid or acetic acid. In a preferred embodiment, HX contains the counter ion of the desired 1-methylcyclopropylguanidine salt to be synthesized. The embodiment with HX = HCl is particularly preferred.

Because of their good handling and technical availability, 1-amidinopyrazole-HX and 1-amidino-1, 2,4-triazole-HX, in particular the hydrochlorides, are particularly preferred.

1 - Methylcyclopropylamine or a salt thereof is used as a further starting material in the process according to the invention. Any salts formed from the amine and a suitable inorganic or organic acid can serve as the starting compound. Examples of salts are the corresponding hydrohalide, in particular hydrobromide and hydrochloride, sulfate, hydrogen sulfate, nitrate, p-toluenesulfonate, benzenesulfonate, trifluoromethanesulfonate, trifluoroacetate and acetate. Preferred is on the one hand the free base and on the other hand the amine salt corresponding to the desired guanidine salt. Free 1-methylcyclopropylamine and 1-methylcyclopropylamine hydrochloride are particularly preferred.

It is to be regarded as essential to the invention that the reaction of the heterocyclic amidine compound with methylcyclopropylamine (salts) is carried out in one or more solvents, selected from the group consisting of nitriles and esters. Surprisingly, it has been found that these solvents have a considerable positive effect on sales and yield and thus make the process technically feasible and economical.

Nitriles preferred as solvents are aliphatic, branched or unbranched carboxylic acid nitriles, in particular with 1 to 10 Carbon atoms, more preferably up to 8 carbon atoms, even more preferably up to 5 carbon atoms. According to the invention, nitriles with a boiling point between 30 and 180 ° C. (at 1,013 mbar) are particularly useful. Preferred nitriles are e.g. B. acetonitrile, propionitrile and butyronitrile.

Preferred esters are those which consist of an aliphatic, branched or unbranched, mono- or polybasic carboxylic acid residue and one or more aliphatic, branched or unbranched alcohol residues. The carboxylic acid residue preferably contains 1 to 10 carbon atoms, preferably up to 7, more preferably up to 5 carbon atoms. The carboxylic acid residue is particularly preferably derived from formic acid, acetic acid or propionic acid.

The alcohol radical preferably consists of 1 to 10 carbon atoms, more preferably up to 7 carbon atoms, particularly preferably up to 5 carbon atoms. In particular, the alcohol residue is derived from methanol, ethanol, n-propanol, i-propanol or n-butanol. The boiling point of the particularly preferred ester is between 30 and 180 ° C. Examples of suitable esters are e.g. B. methyl formate, ethyl formate, methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, dimethyl carbonate and diethyl carbonate. Acetonitrile and ethyl acetate are particularly preferably used as solvents.

The method according to the invention can optionally be carried out with the addition of an auxiliary base. In particular, in the event that a salt of 1-methylcyclopropylamine is used, the addition of an auxiliary base may be necessary in order to obtain a satisfactory yield.

In particular, amines, preferably alkylated amines, which are independently branched or unbranched alkyl radicals having 1 to 10 carbon atoms, preferably 2 to 7, preferably 3 to, are used as auxiliary bases Have 5 carbon atoms. Trialkylamines are particularly preferred, especially those with branched or unbranched

to watch . Triethylamine and diisopropylethylamine are particularly preferred.

Alkali metal alcoholates can be used as further auxiliary bases. Sodium or potassium are preferably used as alkali metals and branched or unbranched C ₁ -C ₄ alcoholates, for example C ₂ or C ₃ alcoholates, are used as alkoxides. Sodium methylate and sodium ethylate are particularly preferably used.

The alkali metal alcoholates can be used both in solid form and in solution, in particular in alcoholic solution.

The stoichiometric application factors can be varied within wide limits in the method according to the invention. Advantageously, the application factors are aligned with economic considerations.

The use of 0.8 to 4 mol of the heterocyclic amidine compound of the formula (I) per 1 mol of 1-methylcyclopropylamine or its salts is preferred, 0.9 to 3 mol are more preferred and 1.0 to 2 are particularly preferred To watch 0 moles.

The stoichiometric proportion of the auxiliary base to be used may be 0.1 to 4 moles per mole of 1-methylcyclopropylamine or its salts, but should preferably not exceed the stoichiometric use factor of the heterocyclic amidine compound of the formula (I).

The reaction temperature is - 20 to 150 ° C; the reaction preferably takes place at 0 ° C. to 100 ° C., more preferably at ambient temperature or 20 to 80 ° C. The reaction mixture obtained can, for. B. be concentrated by distillation. To complete the precipitation, the mixture is then cooled to temperatures between - 50 and + 50 ° C, preferably - 20 to + 20 ° C, more preferably 0 ° C to ambient temperature. The 1-methylcyclopropylguanidine or its salts are preferably isolated by filtration using customary technical devices, e.g. B. by centrifuges, pressure filters or filter presses.

The filter cake obtained is washed with one or more solvents selected from the group consisting of nitriles and esters as defined above. Here, the washing solvent can be the same or different from the solvent used for the reaction, and it can be preferred to use the same solvent. The filter cake obtained is dried in a conventional manner. In this way, pure 1-methylcyclopropylguanidine or its salts are obtained in high yield and high purity.

With the aid of the method according to the invention, well crystallizing salts of 1-methylcyclopropylguanidine are also prepared, such as, B. the hydrochloride, nitrate, sulfate, p-toluenesulfonate, benzenesulfonate, trifluoromethanesulfonate and acetate.

The following examples are intended to explain the process according to the invention.

Examples

Example 1 :

321 g (3.0 mol) of 1-methylcyclopropylamine hydrochloride and 531.4 g (3.6 mol) of 1-amidino-1, 2,4-triazole hydrochloride were placed in 1800 ml of acetonitrile. At 50 ° C in the course of 3.5 hours, 648 g (3.6 mol) of a 30% sodium methylate solution was added dropwise. The mixture was then stirred at 60 ° C for 6 hours. The precipitated sodium chloride was filtered off from the suspension obtained and washed with 150 g of acetonitrile.

1,200 ml of methanol and acetonitrile were distilled off from the solution obtained, cooled to −10 ° C. for crystallization and suction filtered. The filter cake was washed with 300 ml of ethyl acetate and then dried in vacuo.

31 1.5 g of 1-methylcyclopropylguanidine hydrochloride with a content> 98% were obtained. The yield was 69.4%.

Example 2:

107.6 g (1.0 mol) of 1-methylcyclopropylamine hydrochloride and 177.1 g (1.2 mol) of 1-amidino-1,2,4-triazole hydrochloride were placed in 600 ml of ethyl acetate. 216 g (1.2 mol) of a 30% sodium methylate solution were added dropwise at 53 ° C. in the course of 3 hours. The mixture was then stirred at 60 ° C for 7 hours. The precipitated sodium chloride was filtered off from the suspension obtained at 40 ° C. and washed with 100 ml of ethyl acetate.

About 500 ml of methanol and ethyl acetate were distilled off from the solution obtained, cooled to 10 ° C. for crystallization and suction filtered. The filter cake was slurried with 200 ml of ethyl acetate, suction filtered again and then dried in vacuo.

97.2 g of pure 1-methylcyclopropylguanidine hydrochloride were obtained. The yield was 65%. Example 3:

36.9 g (0.25 mol) of 1-amidino-1, 2,4-triazole hydrochloride were placed in 150 ml of acetonitrile. 17.9 g (0.25 mol) of 1-methylcyclopropylamine were added dropwise at 50 ° C. in the course of 2.5 hours. The mixture was then stirred at 60 ° C for 7 hours.

The reaction mixture was crystallized at 10 ° C. and suction filtered. The filter cake was washed twice with 20 ml of ethyl acetate and then dried in vacuo.

31.9 g of 1-methylcyclopropylguanidine hydrochloride with a content of 98% were obtained. The yield was 85%.

Example 4:

26.8 g (0.25 mol) of 1-methylcyclopropylamine hydrochloride and 58.6 g (0.4 mol) of 1-amidinopyrazole hydrochloride were placed in 150 ml of acetonitrile. 30.3 g (0.3 mol) of triethylamine were added dropwise at 50 ° C. in the course of 2 hours. The mixture was then stirred at 60 ° C for 9 hours. The precipitated triethylammonium chloride was filtered off from the suspension obtained and washed with a little acetonitrile.

The mixture was concentrated in vacuo and crystallized at 10 ° C. The precipitated product was filtered off, washed with 50 ml of acetonitrile and dried.

29.5 g of pure 1-methylcyclopropylguanidine hydrochloride were obtained. The yield was 79%. Example 5 (not according to the invention):

26.8 g (0.25 mol) of 1-methylcyclopropylamine hydrochloride and 40.3 g (0.275 mol) of 1-amidinopyrazole hydrochloride were placed in 150 ml of N, N-dimethylformamide. 25.3 g (0.25 mol) of triethylamine were added dropwise at 50 ° C. in the course of 2 hours. The mixture was then stirred at 60 ° C for 6 hours. The precipitated triethylammonium chloride was filtered off from the suspension obtained and washed with a little N, N-dimethylformamide.

The mixture was evaporated in vacuo to give a non-crystallizing oil. After adding 500 ml of diethyl ether, the oil crystallized over the course of 3 days. After suction and drying, 17.3 g of a yellow-brown, sticky product were obtained. The 1-methylcyclopropylguanidine hydrochloride content was only about 80%.

Claims

Expectations

1 . Process for the preparation of 1-methylcyclopropylguanidine or its salts, characterized in that a heterocyclic amidine compound of the general formula (I)

Ri

where U, V, W independently of one another N or CR ₂ ,

R _T and R ₂ independently of one another H, C ₁ -C ₄ alkyl and

HX is a single or polybasic, organic or inorganic acid with a pKa value of

<7 mean, with 1-methylcyclopropylamine or a salt thereof in one or more solvents, selected from the group consisting of nitriles and esters, in the temperature range from -20 to 150 ° C.

2. The method according to claim 1, characterized in that the heterocyclic radical in formula (I) is an optionally substituted pyrazole ring (U = N, V = CR ₂ , W = CR ₂ ), 4H-1, 2,4-triazole ring ( U = C-

R _{2 represents} V = N, W = N) or 1 H-1, 2,4-triazole ring (U = N, V = CR ₂ , W = N).

3. The method according to claim 1 or 2, characterized in that HX in formula (I) HCl, HNO ₃ , H ₂ SO ₄ (preferably V2 equivalent), p-

Toluenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid or acetic acid.

4. The method according to any one of claims 1 to 3, characterized in that the corresponding hydrochloride is used as 1-methylcyclopropylamine salt.

5. The method according to any one of claims 1 to 4, characterized in that when using a 1 - methylcyclopropylamine salt as the starting compound, an auxiliary base is additionally used.

6. The method according to claim 5, characterized in that a trialkylamine with branched or unbranched C ^ C _B alkyl radicals is used as the auxiliary base.

7. The method according to claim 6, characterized in that triethylamine or diisopropylethylamine is used as trialkylamine.

8. The method according to claim 5, characterized in that an alkali metal alcoholate having 1 to 4 carbon atoms is used as the auxiliary base.

9. The method according to claim 8, characterized in that sodium alkoxide or sodium ethoxide is used as the alkali metal alkoxide.

10. The method according to any one of claims 1 to 9, characterized in that 0.8 to 4.0 mol, in particular 1.0 to 2.0 mol, of the heterocyclic amidine compound is used per mol of 1-methylcyclopropylamine or its salts.

1 1. Method according to one of claims 1 to 10, characterized in that the stoichiometric proportion of the auxiliary base 0, 1 is up to 4.0 moles per mole of 1-methylcyclopropylamine or the salts thereof.

12. The method according to any one of claims 1 to 1 1, characterized in that the reaction in an aliphatic nitrile with a boiling point between 30 and 180 ° C (at 1,013 mbar), in particular acetonitrile, propionitrile or butyronitrile.

13. The method according to any one of claims 1 to 1 1, characterized in that the reaction in an ester with a

Boiling point between 30 and 180 ° C, in particular methyl formate, ethyl formate, methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, dimethyl carbonate or diethyl carbonate is carried out.

14. The method according to any one of claims 1 to 13, characterized in that the reaction temperature is between 20 and 80 ° C.