DD219185A5 - PROCESS FOR THE PREPARATION OF ALKYLENEDIAMINES - Google Patents

Abstract

The invention relates to a novel process for the preparation of alkylenediamines of the general formula (I), their racemates, all stereoisomers and physiologically acceptable acid addition salts. In the general formula (I), R 1 and R 2 independently of one another represent a lower alkyl group or a halogen atom, R 3 and R 4 independently of one another represent hydrogen or a lower alkyl group or, together with the adjacent nitrogen atom, an optionally still further heteroatom, for example a nitrogen -, sulfur or oxygen-containing heterocycle having 5 or 6 members, wherein the meaning of n is 0 or 1. The compounds are prepared according to the invention by reacting compounds of general formula (VI b) with amines of general formula HNR5R6.

Description

The invention relates to a novel process for the preparation of alkylenediamines, their racemates and stereoisomers, and physiologically acceptable acid addition salts. The compounds which can be prepared by the novel process correspond to the general formula (I),

independently of one another represent a lower alkyl group or a halogen atom, independently of one another represents hydrogen or a lower alkyl group and independently of one another represent hydrogen or a lower alkyl group or, together with the adjacent nitrogen atom, optionally an additional heteroatom, for example an embroidery. form a heterocycle having 5 or 6 members containing the substance, sulfur or oxygen, and the meaning is 0 or 1.

wherein R ¹ and and R ² R ³ and R ⁴ R ⁵ R ⁶

In the general formula (I), the lower alkyl groups mean straight or branched alkyl groups having 1-5 carbon atoms, the halogenating agents may be bromine, chlorine or fluorine atoms. Accordingly, in the general

R 12 and R 4 independently of one another represent a methyl, ethyl, n-propyl, isopropyl, butyl or amyl group, furthermore a fluoro, chloro or sorator. Accordingly, the substituted phenyl group in the general formula (I) may be 2,6-dimethylphenyl, 2,6-diethylphenyl, 2-ethyl-6 ^l -methylphenyl, 2-chloro-6-methylphenyl-T 2,5-dichlorophenyl group, etc. R and R independently of one another may be, for example, a hydrogen atom, a methyl, ethyl, n-propyl, iso. propyl. Butyl or amyl group stand. R and R independently of one another may be, for example, hydrogen, a methyl, ethyl, n-propyl, isopropyl, butyl or amyl group or, together with the adjacent nitrogen atom, for example a piperidin-1-yl, piperazine-1 - yl, 1,4-oxazin-4-yl or l, 4-thiazin-4-yl group.

the "known tecbniscliezi solutions "

The compounds which can be prepared by the novel process are distinguished by their antiarrhythmic action. They are described in GB-PS 2 098 599 A. According to this patent, the compounds are obtained, for example, by reacting compounds of general formula (II) wherein the meaning of R, R, R, R and η is the same as above and R is hydrogen, the acyl group of an aliphatic or aromatic Carboxylic acid or the sulfonyl group of a lower alkanesulfonic acid or aromatic sulfonic acid, while X represents a halogen atom or the alkanesulfonyloxy group of a lower alkanesulfonic acid, with compounds of general formula (III), wherein the meaning of R and R is the same as above.

When in the starting compound of general formula (II) R and R have different meanings, in the reaction - depending on the meaning of R, one or two (isomeric) products are formed, in case R is an acyl or Sulfonyl group is a single product, namely the protected on the phenyl group derivative of the diarain of the general formula (I). From this compound, the end product of general formula (I) is obtained by the deprotection carried out in a separate reaction step.

However, in the starting compound of the general formula (II), when R and R have different meanings and R is hydrogen, then the starting compound temporarily becomes the corresponding asymmetrically substituted aziridine derivative (n = O) or azetidine derivative (n = 1) Formula (IV) or its salt formed. Through the ring opening of this compound, which can take place in two directions, a mixture of two compounds is formed: one corresponds to the general formula (I), the other is isomeric with it and corresponds to the general formula (V).

For this reason, it is emphasized in the cited patent, one must proceed to the preparation of pure isomers of compounds (I) of compounds of general formula (II), which are protected on the aromatic ring adjacent nitrogen atom by an acyl or sulfonyl group. From these, the desired compound of general formula (I) can be prepared in two steps.

Object of the invention:

By contrast, a more favorable process for the preparation of alkylenediaraines is to be provided by the invention.

Explanation of the essence of the invention:

It has now been found that the compounds of the general formula (I) in a pure state, free of the isomer of the general formula (V), can be prepared more simply and in a single step "if, as starting compound, analogues of the compounds (II) used together in which together represent a single group, namely a divalent sulfone group (= SO ₂ ), for the protecting group R and the leaving group X. This means that for the preparation of compounds of the general formula (I) from the cyclic sohfelsäurehalbesterhalbamiden

or 1,2,3-oxathiazine

2,2-dioxyd derivatives) of the general formula (VIb) in which R, R, R, R and η have the same meaning as above. Substituting the compounds of general formula (VIb) at high temperatures, for example 80-15Ö ° G, with the amines of general formula (III), the compounds of general formula ( ¹ I) arise directly. However, if the compound (VIb) is reacted at room temperature with the amines (III), the compounds of the general formula (VII) which can be referred to as the internal salts of the corresponding N-sulfonic acids (I) are formed first. From these, the compound (I) is released by treatment with an acid. If desired, the compounds of the general formula (VII) can also be isolated in crystalline form.

The invention accordingly provides a process for the preparation of alkylenediamines of the general formula (I) in which the meaning of R-R and η is the same as above, their racemates and stereoisomers and physiologically acceptable acid addition salts. The process is characterized in that compounds of general formula (VIb) wherein the meaning of R-R and η is the same as above, at temperatures between 20 and 150 C with amines of general formula (III), wherein the meaning of R and R is the same as above, and the resulting compound of the general formula (I) - optionally after treatment with an acid - isolated from the mixture, desired, and possibly the isomers separated from one another and / or if desired from the Compounds of the general formula (I) which are obtained as base form acid addition salts and / or, if desired, liberate the base from the resulting salt of the compound of the general formula (I). '

According to a preferred embodiment of the process according to the invention, the compound of the general formula (VIb) is dissolved at temperatures between 80 and 150 ° C. in a solvent, for example a lower alcohol, such as methanol or ethanol, or an aromatic hydrocarbon, for example benzene or toluene, in mixtures of the listed solvents or without solvent with 3-15 times the equivalent amount of the amine of general formula (III) is reacted ·

According to another embodiment of the process according to the invention, the compound of the general formula (VIb) is reacted at room temperature, preferably in a lower alkanol, in particular methanol or ethanol, with 3-15 times the equivalent amount of the amine of general formula (VIb).

 - 6 -

reacted my formula (III) and the reaction mixture then at 2O-15O ° C with an acid, suitably a mineral acid, for example hydrochloric acid or sulfuric acid treated.

The compounds of general formula (VIb) used as starting materials in the process according to the invention are new compounds. A single compound of similar structure is known from the literature: that of Y. Noda et al. from series O-sulfuric acid ester in dimethylformamide using dicyclohexyl-carbodiimide 4-carboxy-l, 2 ^ 3-oxathiazolidine-2,2-dioxyd.

The compounds of the general formula (VIb) required as starting materials of the process according to the invention can be prepared, for example, by reacting the corresponding compounds of the general formula (VIa), (VIa: m = 1, VIb: m = 2), where the meaning from R -

4

R and η are the same as above, in a suitable solvent, for example water, acetic acid, dioxane or mixtures thereof, at 0 ° C with an oxidizing agent, for example potassium permanganate or a peroxide such as hydrogen peroxide, oxidized. The compounds of general formula (VIa) are also new. However, the preparation of similar compounds is known (IA.Deyrup and CLMoyer, O. Org. Chem. 34, 175/1969 /; F. Wudl and BlK.Lee, D. Am. Chem. Soc. 95, 6349/1973 /; T. Nishiyama and F. Yamada, Bull. Chem. Soc. Oapan 44 , 3073/1971 /). According to the first two references, the corresponding 1,2,3-oxathiazolidin-2-oxyde are prepared by reacting the corresponding amino alcohols with thionyl chloride, while the Japanese authors made the same compounds by reacting N-sulfinylanilines with epoxides. As noted by the noted authors, the sulfur atom is in

2-position, further the carbon atoms in 4- and / or 5-position (6-position) Asymraetriezentren, and accordingly, the oxygen atom attached to the sulfur atom in the 2-position and in the A and / or 5-position (6 Position) in relation to each other in the cis or trans position. The compounds of the general formula (VIa) can be prepared, for example, from the aminoalcohols of the general formula (VIII) by the methods already known per se. The compounds of the general formula (VIII) are known or can be prepared by methods known from the literature (see GB-A-2 098 599 A, published in German published patent application).

In the process according to the invention, the compounds of the general formula (I) are generally obtained in the form of the base. The salts of the compounds of the general formula (I) are conveniently prepared by dissolving the base in a suitable solvent, for example methanol, isopropanol, diethyl ether or mixtures thereof and adding the solution of the corresponding acid prepared with a suitable solvent to the solution. The salt is isolated either directly by filtration or optionally by partially or completely distilling off the solvent.

The compounds of general formula (I) are liberated from their salts by dissolving the salt in question in a solvent, for example water, methanol, ethanol or mixtures thereof, rendering the solution alkaline, for example with caustic soda or ammonia, and shaking out the liberated base separated with chloroform or benzene.

Those compounds of the general formula (Ί) in which R or R have a meaning other than hydrogen contain an asymmetric carbon atom and can consequently be present as two optically active antipodes or as a racemate. The optical isomers of these compounds are conveniently separated from each other by dissolving the racemic compound, for example, in methanol, ethanol, ethyl acetate, acetone or other solvent, and containing 0.5-1.0 times the equimolar amount of an optically active acid, for example d-tartaric acid, 0,0-dibenzoyl-d-tartaric acid, Q, or-dibenzoyl-d-tartaric acid dimethylhalbaraid, thiazolidine-4-carboxylic acid or any other common optically active acid and thus reacting either the product depending on the acid used the salt of one optical isomer is obtained in pure form or by repeated recrystallization, while the other isomer is obtained by working up the mother liquors. Oe according to the amount of acid used, the second isomer precipitates as the base or in the form of the corresponding salt. The pure isomers can then be liberated from the resulting salts in the manner described above. If desired, acid addition salts can be formed from the optically active bases with physiologically tolerated acids.

If, in the compounds of the general formula (I), both R and R have a meaning other than hydrogen, the compounds can be obtained as geras of the diastereomers. The diastereomers can be separated from one another in the manner known per se.

Export Examples: '

The method according to the invention is explained in more detail below with reference to examples, but is not limited thereto.

Example 1 (method a)

l- (2,6-dimethylphenylamino) -2-dimethylamino propane

0.5 g (2.07 mmol) of 3- (2,6-dimethylphenyl) -5-methyl-1,2,3-oxathiazolidine-2,2-dioxyd and 5 ml (0.8 g = 17.7 mmol Dimethylamine-containing) ethanolic dimethylamine solution are heated in a steel bomb tube for 3 hours on an oil bath of temperature 120-125 ° C. After cooling, the mixture is poured into 30 ml of water and shaken with 3x10 ral of chloroform. The combined organic phases are washed with 3 × 10% water, dried over magnesium sulfate and evaporated under reduced pressure. This gives 0.40 g (93%) of the title compound

 Sp. : 105 ° C / 53 Pa

The starting compound 3- (2,6-dimethylphenyl) -5-methyl-1,2,3-oxathiazolidine-2,2-dioxyd can be prepared, for example, in the following manner.

Step a)

To a solution of. 18 g (100 x mmol) of l- (2,6-0imethylphenylamino) -2-propanol in 300 ml of anhydrous pyridine are placed on an ice bath at 0-5 ⁰ C was added dropwise 11 ml (18.1 g, 150 mmol) of thionyl chloride. Then, the G _e is stirred mixture for one hour on the ice bath and for one hour at room temperature. The mixture is poured into 1000 ml of ice water. The failed one

- 10 -

Precipitate is filtered off, washed with water and then dried. In this meadow, 16.7 g (74 %) of 3- (2,6-dimethylphenyl) -5-methyl-l, 2,3-oxathiazolidin-2-oxide in the form of a crystalline, hellsandfarbenen substance in which the ratio of the -S-O group in the 2-position and the methyl group in the 5-position, cis isomer to the trans isomer according to the

H-NMR spectroscopic examination is about 4: 6. The urakristallisierte from isopropanol product melts at 87-90 ⁰ C and has a ice: trans ratio of 3: 1.

The compound can also be prepared by means of a variant of the process described, in which, instead of pyridine, 1,2-dichloroethane is used as the solvent and triethylamine as acid binder. The thus prepared 3- (2,6-dimethylphenyl) -5-methyl-l, 2,3-oxathiazolidin-2-oxide melts after recrystallization from isopropanol at 100-104 ⁰ C, its cis: trans ratio is 8 : 2nd

Step b) / '. '..,

To a solution of 13.5 g (60 mmol) of 3- (2,6-Dxmethylphehyl) -5-methyl-l, 2,3-oxathiazolidin-2-oxide in 300 ml of acetic acid is at 20-22 ⁰ C with temporary Ice water cooling, a solution of 23.6 g (150 mmol) of potassium permanganate in 300 ml of water was added dropwise over about 15 minutes. Then the mixture is stirred at room temperature for one hour and then treated with 120 ml of 10% aqueous sodium hydrogen sulfite solution. The mixture is stirred for a further half hour on the ice bath, then the precipitate is filtered off, washed with water and finally dried. This gives 6.15 g (42 %) of 3- (2,6-dimethylphenyl) -5-methyll, i2,3-oxathiazolidin-2,2-dioxyd in the form of a crystalline

- 11 -

Substance that melts after recrystallization from isopropanol at 116.5-118.5 ⁰ C. , ,

The oxidation can also be carried out in Oioxan as solvent with 30% aqueous hydrogen peroxide as oxidizing agent. In this procedure, however, the yield is only 9 % *

Method b)

0.5 g (2.07 mmol) of 3- (2,6-dimethylphenyl) -5-methyl-l, 2,3-oxathiazolidin-2,2-dioxide are dissolved in 10 ml of ethanol with 1.6 ml of an aqueous Oimethylarainlösung with a Concentration of 59 g / 100 ml according to the method a) implemented. This gives the title compound in a yield of 55%.

Method c)

A mixture of 2.0 g (8.3 mmol) of 3- (276-dimethylphenyl) -5-methyl-1,2,3-oxathiazolidine-2,2-dioxyd and 25 ml of ethanolic dimethylamine solution having a concentration of 15, 4 g / 100 ml (corresponding to 85 mmol dimethylamine) is stirred at room temperature for 8 hours »and then allowed to stand overnight. The following day, the solvent and the excess amine are distilled off under reduced pressure. The viscous residue is dissolved in 15 ml of water. To the solution, 15 ml of concentrated hydrochloric acid and the mixture is kept for one hour at 60-65 ⁰ C. After cooling, the resulting yellow solution is diluted with 30 ml water, then in an ice bath with about 20 ml of 1ON sodium hydroxide to a pH Value of 10 made alkaline and shaken with 3x20 ml of 1,2-dichloroethane. The combined organic phases are washed with 3x10 ml of water, dried over anhydrous sodium sulfate and concentrated under reduced pressure

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freed from the solvent. There are obtained 1.66 g (97 %) of the title compound in the form of a pale yellow oil »

The viscous oil obtained after distilling off the ethanol and the excess amine can also be dissolved in 15 ml of concentrated hydrochloric acid. The solution is allowed to stand at room temperature for 24 hours and, after dilution with water, the product is extracted as described.

Preparation of the hydrochloride.

1.66 g of the base obtained are dissolved in 5 ml of ethanolic hydrochloric acid (12 g of HCl / 100 ml of solution). The solution is diluted with 15 ml of ethyl acetate with stirring and then stirred for one hour at room temperature and for one hour on the ice bath. The precipitated crystalline product is filtered off, washed with ethyl acetate and dried at room temperature. 2.11 g (91 %) of the oihydrochloride of the title compound is isolated. Melting point (in a closed tube): 195-197 ° C.

Examples 2-10

According to the manner described in Example 1, from the corresponding compounds of the general formula (VIb) and the corresponding amines of the general formula (III) the alkylene diamines of the general formula (I) which are compiled in the following table are prepared.

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Example meth, no.

Sp. C / Pa mp.

ο 'Yield

2 B CH ₃ CH ₃ H CH ₃ H CH ₂ CH ₃ 0 92/27 38 3 4 A A CH ₃ CH ₃ CH ₃ CH ₃ Ή B CH ₃ CH ₃ C ₂ H ₅ C -NR ⁵ R ⁶ α 1. Oxazin-4-yl 2 ^H 5 4- CH ₃ 0 0 99-100 / 27 71-73 57 96 5 A CH ₃ CH ₃ H CH ₃ -NR ⁵ R ⁶ = piperazin-1-yl CH ₃ 0 170-173 / 80 71 6 A CH ₃ Cl H CH ₃ CH ₃ CH ₃ 0 108-110 / 53 62 7 A C ₂ H ₅ ^C 2 ^H 5 H CH ₃ CH ₃ CH ₃ 0 110-114 / 80 56 8th A Cl Cl H CH ₃ CH ₃ 0 120-128 / 40 48 9 A CH ₃ CH ₃ CH ₃ H CH ₃ 0 130-132 / 93 65 10 A CH ₃ CH ₃ B CH ₃ CH ₃ 1 110-112 / 67 44

I-

The compounds used in Examples 2-10 _ö the general formula (VIb) are conveniently prepared in the following two steps.

&. "

Step a)

The procedure described in Example 1 in the preparation of the starting compounds under point a) manner and provides by reacting the correspondingly substituted amino alcohols of general formula (VIII) in pyridine with thionyl chloride in the following table combined l, 2,3-oxathiazolidin-2 Oxides or 1,2,3-Qxathiazin-2-oxide ago.

R ¹ R ² R ³ R ⁴ η Mp. ⁰ C Rx yield trans; ice % relationship CH ₃ Cl H CH ₃  0 oil ^: 0.75 75 2: 8 C ₂ H ₅ C ₂ H ₅ H CH ₃ O ⁺ ) 0, 85 80 ⁺⁺ ) ^L 1: 2- Cl Cl H CH ₃ Ό 61-63 0.7 87 ⁺⁺ ) 1: 9 CH ₃ ^C M ₃ " CH ₃ Ή, O 57-59 0.8 69 2: 8 CH ₃ CH ₃ H CH ₃ 1 67-69 0.85 61 45:55

*) Boiling point 120 ° C / 40 Pa

with 2 equivalents of thionyl chloride

+++) silica gel G thin layer, benzene: ethyl acetate = 3: 1

The amino alcohols of the general formula (VIII) required for the preparation of these compounds are prepared by the method described in GB-A-2 098 599 A. Of these, the following compounds are new:

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_i l- (2-Chloro-6-methylphenylamino) -2-propanol, mp .: 122 ° C / 27 Pa l- (276-0iäthylphenylamino) -2-propanol, mp .: 148-l52 ° C / 27 Pa 2 - (2,6-dimethylphenylamino) -l-propanol / column: 126 ° C / 133 Pa. l- (2,5-Diraethylphenylamino) -3-butanol hydrochloride, Schrap .: 198-200 ⁰ C.

Step b)

The reaction is carried out according to the procedure described in Example 1 in the preparation of the starting compounds under point b), and by reacting the above compounds of general formula (VIa) with acetic acid aqueous potassium permanganate solution, the 1,2,3-oxathiazolidine summarized in the following table 2,2-dioxyde or l, 2,3-oxathiazine-2 _# 2-dioxyd, forth.

R ¹ R ² R ³ R ⁴ η Mp. ° C Yield % CHj Cl H CH ₃ 0 84-86 33 C ₂ H ₅ C ₂ H ₅ H CHj 0 70-72 15 \ Cl egg. H CHj 0 133-135 38 CH ₃ CH ₃ CH ₃ H 0 152-153 34 CHj CH ₃ H CH ₃ 1 160-163 38

τ 16 -

NH-CH- (CH ₂ ) _n -CH- N

(I)

N is CH- (CH ₂ ) _n -CH-X

R R '

(I)

, R '

(JLL.

(CHA

(IZ)

NH CH- (CH ₂ ) _n -

R ⁴ ·

CH-

iu

(CHJ ₁

l's

(O) S

Ό '

(3ZIb)

CH- (CH ₂ J _n -CH-

NH '

(M)

• R ^£

CH- (CH ₂ ) r-CH-OH

Claims (1)

claim 1. A process for the preparation of alkylenediamines of the general formula (I), wherein 12 4 ¹ R and R independently for lower one 'Alkyl group or a halogen atom, R and R independently of one another are hydrogen or a lower alkyl group and 5 6 R and R independently of one another represent hydrogen -. · Or a lower alkyl group or together with the adjacent nitrogen atom, form an optionally still another heteroatom, for example a nitrogen, sulfur or oxygen-containing heterocycle having 5 or 6 members, and the meaning of
^: η 'is 0 or 1, and their racemates, all stereoisomers of further physiologically acceptable acid addition salts, characterized in that compounds of general formula (VIb), wherein the meaning of R-R and η is the same as above, at temperatures between 20 and 150 C with amines of the general Formula (III), wherein the meaning of R and R is the same as above, and the resulting compound of general formula (I) - optionally isolated after treatment with an acid from the mixture, desired and possibly the isomers separated from one another and / or, if desired, from the compounds of the general formula (I) which are obtained as the base, acid addition salts are formed and / or, if desired, the base of the compound of the general formula (I) is liberated from the resulting salt. · ·, ... · - 2 sheets formulas.-  '' '' '' - 17 -