DE2826452A1 - METHOD FOR PRODUCING SUBSTITUTED GUANIDINES - Google Patents

Description

PATtf iMTAN WALTE

A. GRUNECKER

DIPL KMG.

H. KINKELDEY

URGENT

W. STOCKMAlR

OR-ING - A »E (CAl-TC-CH

K. SCHUMANN

DR REa NAT. · DIPL-PHYS

P. H. JAKOB

CHPL-ING

G. BEZOLD

DR Fitft NAT. - DIPL-CHEAA

Aktieselskabet Gea 89, Holger Danskesvej DK-2000 Copenhagen

8 MUNICH 22

MAXIMILIANSTRASSE 43

June 16, 197Ö

P 12 876

Process for the production of substituted guanidines

The invention relates to a new process for the preparation of mono-, di- and trisubstituted guanidines of the general Formula:

R ¹ -NH-C-NH-ft

(D

wherein the substituents R ¹ , R and R ^ each represent hydrogen, an alkyl group including cycloalkyl having 1 to 6 carbon atoms, or a phenylalkyl group having not more than carbon atoms in the alkyl part, with the proviso that

3
at least one of the substituents R, R and R- ^ is different

Has meaning as hydrogen.

809882/0768

? 8? 6452

In particular the compounds of formula I in which one

12 3
the substituents R, R and R ^ stand for a benzyl group or an ethyl ethyl group, are already known and they are used therapeutically because they selectively dampen the sympathetic nervous system and have little or no effect on the parasympathetic or central nervous system (cf. e.g. G3-PS 973 382).

According to this patent, these compounds can be prepared in such a way that ammonia or an ammonia derivative or a salt thereof is reacted with an S-substituted isothiourea or a salt thereof. The implementation can for example according to the following equation:

R ² NH ₂ > _ ₊ . ^ C-NHR ² + RSH

1 2

In this scheme, R and R have the above meanings, while R represents an alkyl group, generally methyl, and X represents an anion.

The putrid smelling mercaptans formed during this process must be completely removed. This can prove difficult. In each case is a separate one Cleaning process necessary.

In the process of the invention, compounds of the above Formula I prepared in a simple manner and with good yields from substituted thiourea compounds, without how in the known process - putrid smelling mercaptans are formed.

809882/0768

R ¹ -NH ι R ³ -NH R ¹ -NH R ³ -N

According to the invention, an N- or N, N'-substituted one is thus used Thiourea or isothiourea or a salt thereof is oxidized to form the corresponding formamidine sulfonic acid. This is then reacted with ammonia or an amine to give the desired compound of the formula I. This will be in the following Reaction schemes illustrated, where R, R and R ^ the Have the meanings given above.

R ¹ -NH-.
S + 3 H ₂ O ₂ ^ C-SO ₃ H + 3 H ₂ O

R ² -W

R ¹ -NH. ·

-SO ₃ H + R ² NH ₂ "^ C-NH-R ² + H ₂ SO ₃

R ³ -IT

12 * 5

Depending on the selection of the substituents R, R and R ^ yields the method mono-, di- or trisubstituted guanidines.

As shown in the reaction schemes, hydrogen peroxide is that preferred oxidizing agent as it forms water through the reaction. However, other peroxides can also be used.

The invention is illustrated in the examples.

example 1

A. N-Benzyl-N'-methylformamidine sulfonic acid

^{45 g (0.25 mol) of N-benzyl-N 1} -methylthiourea were added in small portions over a period of 2 hours to a mixture of 100 g of 34.6% strength hydrogen peroxide (1 KdL) and 200 ml of water. Since the. Reaction was exothermic, the temperature of the reaction mixture was kept below 18 ° C by the reaction

8098 8 2/0768

vessel was cooled in a mixture of ice and water.

After the addition of the thiourea derivative, the reaction mixture was allowed to stand for 2 hours without cooling. In this way this slowly reached room temperature.

It was then cooled again in ice water, as a result of which the compound given in the title was precipitated in the form of white crystals. The crystals were filtered off and washed with a small volume of cold water and finally with ether. The yield was 44 g (0.19 mol), which corresponds to 76% of the theoretical yield. The compound had a melting point of 120 to 125 ^° C. with decomposition.

B. N-Benzyl-N ', N'-dimethylg ^ tanidinium.iodide

4.56 g (0.020 Hol) N-benzyl-N'-methylformamidine sulfonic acid, a 24? & Lge solution of 15 ml methylamine in water and 50 ml Water were mixed. The mixture was refluxed for 6 hours. Excess methylamine was removed by suction in vacuo removed. Thereafter, the volume of the reaction mixture was 50 ml. The mixture was made up with concentrated hydrochloric acid Acidified pH between 1 and 2. Then 10 ml of a Saturated aqueous solution of NaI and 5 g of solid NaCl were added. The mixture was then left stirring overnight, producing an off-white precipitate of the title said compound was obtained. The precipitate was filtered off and recrystallized from ethanol, yielding 3.5 g (0.01148 moles), which is 57.4 µS of the theoretical yield is equivalent to. The melting point was 192 to 194 ° C.

Example 2 N-Benzyl-N ', N' -dimethylguanldinium.iodide

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A mixture of 3.0 g (0.0197 mol) of NjN ^ dimethylformamidinesulfonic acid (prepared from N, N'-dimethylthiourea in a manner similar to that described in Step A of Example 1), 10 ml (0.092 mol) of benzylamine and 60 ml of water was mixed and refluxed for 3 1/2 hours. Concentrated hydrochloric acid was added to a pH between 1 and 2. Then 10 ml of a saturated aqueous solution of NaI were added. After standing for a short time, an almost white precipitate _{t was} formed.

The reaction mixture was cooled in a mixture of ice and water for about 2 hours. After that, the precipitate was made consisted of the compound indicated in the title, filtered off and recrystallized from ethanol. The yield was 4.7 g (0.0154 Mol) (78%) and the melting point 192 to 194 ° C.

Example 5 N-Benzyl-N '-N "-dimethylguanidinium iodide

A mixture of 12 g of NyN'-dimethylformamidine sulfonic acid, 20 ml Benzylamine and 120 ml of water were stirred at room temperature overnight. The mixture was then treated with hydrochloric acid acidified to pH 1 and mixed with a saturated aqueous solution of sodium iodide. After stirring for one hour and The precipitate, consisting of the compound mentioned in the title, was filtered off and first with water and cooling then washed with ether. Finally it was dried at 30 ° C. The melting point was 195 ° C and the yield was 19 g (7996).

Example 4 N, N ^t , N "-Trimethylanidinium.1odide

809882/0768

15.2 g (0.10 mol) of Ν, Ν'-dimethylformamidine sulfonic acid and 75 ml of a 24% strength aqueous methylamine solution were dissolved in 250 ml of water. The mixture was refluxed for 3 hours. Excess methylamine was suctioned off in vacuo. Concentrated hydrochloric acid was then added to pH 1-2. A saturated aqueous sodium iodide solution was then added, as a result of which a large precipitate of the compound named in the title was obtained. The precipitate was filtered off and recrystallized from water. White shiny needles were obtained. The yield was 18.0 g (0.0786 mol, 78.6%). The melting point was above 320 ^° C.

Example 5

N »N '-Dirne thyl-N" - (3 , 4-methylenedioxybenzyl) guanidinium _t iodide

4.56 g (0.030 mol) of NjN'-dimethylforinamidine sulfonic acid and 18.1 g (0.12 mol) of 3,4-methylenedioxybenzylamine were dissolved in 60 ml of water and the solution was refluxed for 41/2 hours. The reaction mixture was then concentrated to a volume of 40 ml. Concentrated hydrochloric acid was then added to pH 1-3. Then 25 ml of a saturated aqueous sodium odide solution were added. A white crystalline precipitate of the compound named in the title formed. This was filtered off and washed with water. The yield was 8.4 g (0.0241 mol), which corresponds to 80.3% of the theoretical yield. The melting point was 211.0 to 212.0 ⁰ C.

Example 6 N- (2-chlorobenzyl) -N * _t N "-dimethylguanidinium.iodide

4.56 g (0.030 mol) Ν, Ν'-dimethylformamidine sulfonic acid and

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"17.0 g (0.12 mol) of 2-chlorobenzylamine were in 60 ml of water dissolved and the solution was refluxed for 5 1/2 hours. The solution was adjusted to pH with concentrated hydrochloric acid acidified from 1 to 3. Then 25 ml of a saturated aqueous sodium iodide solution was added. This parted off a yellow oily substance. The reaction mixture was stirred overnight, whereby the deposited oil became semi-crystalline. The mother liquor was decanted off and the residue was washed repeatedly with ether. In this way he became complete crystalline. The substance was recrystallized from water and the solution was purified with activated charcoal. The in The title compound was separated off again as an oil, which, however, quickly became crystalline on scratching. The yield of the cream colored compound was 6.7 g (0.0197 moles, 65.7? 0 and the melting point was 157.5 to 158.5 ° C.

Example 7 N, N ^t -Dimethyl-N "- (4-methoxybenzyl) -guanidinium .-) odide

The procedure of Example 6 was repeated using 16.44 i (0.12 mol) of 4-methoxybenzylamine instead of 2-chlorobenzylamine were used. The compound named in the title, which was also first separated off as an oil, was finally obtained as a white substance with a yield of 5.8 g (0.0173 mol, 57.7%) and a melting point of 162.0 to 162.5 ° C won.

Example 8 N-Cyclohexyl-N ', Η "- dimethylguanidiniuinnodid

4.56 g (0.030 mol) of N, N ^f -dimethylformamidine sulfonic acid and 12.0 g (0.12 mol) of cyclohexylamine were dissolved in 60 ml of water. The mixture was stirred overnight and evaporated

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concentrated to a volume of about 30 ml. The reaction mixture was then acidified to pH 2 with hydrochloric acid. Then 10 ml of a saturated aqueous sodium iodide solution was added. An oily substance separated out and quickly crystallized when scratched. The solid substance was filtered off and recrystallized from water. The white solid, consisting of the compound referred to is Tital, was obtained in a yield of 3.70 g (0.0125 mol, 41.7 #) and obtained a melting point of 195.5 to 196.0 ⁰ C.

Herein the terms "alkyl group" are intended to be inclusive of "cycloalkyl group" and "phenylalkyl group" denote the corresponding substituted or unsubstituted groups.

809882/0783

Claims (4)

Claims 1. Process for the preparation of substituted guanidi the general formula: R ¹ - NH - C - NH - R ² (I) Il 12 ^ where each of the substituents R, R and R "^ are hydrogen, an alkyl group including a cycloalkyl group having 1 to 6 carbon atoms; or a phenylalkyl group having 1 to 3 Carbon atoms in the alkyl part, at least one 12 ^ the substituents R, R and R do not have the meaning hydrogen, or a salt of the substituted guanidines mentioned, characterized in that a thiourea or an isothiourea which is substituted by two of the substituents R, R and R ^ N, N'-substituted , or a salt thereof is oxidized to the corresponding formamidinesulfonic acid and that the formamidinesulfonic acid is oxidized with an amine of the third of the substituents R,. R and Vr reacts to form a compound of the formula I or a salt thereof. 2. The method according to claim 1, characterized in that that one for the preparation of a salt of a substituted guanidine with the above general formula I a thiourea or an isothio 12 " ³ S urea, which is substituted with two of the substituents R, R and R ^ Ν, Ν ¹ -substituted, oxidizes to the corresponding formamidinesulfonic acid, that the latter is oxidized with the amine of the third of the sub- 12 "" 5
substituents R, R and R are converted to the corresponding compound of the formula I and that the compound of the formula I is reacted with a sodium salt under acidic conditions in order to form the desired salt of the substituted guanidine of the general formula I. 809882/0768 ORIGINAL INSPECTED 3. The method according to claim 1 or 2, characterized in that one avoids the oxidation of the thiourea or isothiourea hydrogen peroxide. 4. The method according to claim 3, characterized in that the N, N'-dimethyl thiourea is oxidized with hydroperoxide and that the resulting NjN'-dimethylformamidine sulfonic acid is reacted with benzylamine. 809882/0768