DE2333014A1 - NEW IMMONIUM SALTS, THE PROCESS FOR THEIR PRODUCTION AND THEIR APPLICATION IN ORGANIC SYNTHESIS - Google Patents

Description

Dr. F. Zumstein sen - D- ". B. Assmann Dr. R. Koenigsberger - Dipl.-Phys. R. Holzbauer - Dr. F. Zumsteln Jun.

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TELEPHONE: COLLECTIVE NO. 22 5341

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8 MUNICH 2,

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Zd J OU I

97 / n

Cas 1545 D

ROUSSEL-UCLAF, Paris / France

New immonium salts, process for their preparation and their application in organic synthesis

The present invention relates to new immonium salts, processes for their preparation and their application in organic synthesis.

It relates in particular to the immonium salts of the formula I.

! I

wherein

and Rp is an alkyl radical, one optionally through a halo genatom-substituted phenyl radical or a benzyl radical or

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-Z-

R ^, and R "together represent an alkylene radical, a group

- (CH ₂ J ₂ -O- (CH ₂ J ₂ - or a group - (CH ₂ ) -N- (CH ₂ J-

in which R _{5 is} an alkyl radical having 1 to 5 carbon atoms,

R ₃ and R. denote a hydrogen atom, an alkyl radical having 1 to 5 carbon atoms or a phenyl radical, or

R-. and R ₄ together represent an alkylene radical having 3 to 5 carbon atoms or a benzoalkylene radical having 7 to 10 carbon atoms,

X represents a halogen atom and

Y is a dialkylamino radical whose alkyl radicals are 1 to 5 carbon Atoms contain a morpholino, piperidino ,. or 1-pyrrolidinyl radical.

In general formula I, when R 1 or R 1 denotes an alkyl radical, it is preferably an alkyl radical having 1 to 5 carbon atoms and in particular a methyl or ethyl radical; when R ^ or Rp represent a phenyl radical substituted by a halogen atom, the halogen atom is preferably a chlorine atom; when R 1 and R ₂ together form an alkylene radical, the alkylene radical preferably contains 2 to 6 carbon atoms; when R ₃ and R ₄ denote an alkyl radical having 1 to 5 carbon atoms, it is preferably a methyl, ethyl, n-propyl, isopropyl, isobutyl or tert-butyl radical; when R ₃ and R ₄ together represent a benzoalkylene radical, the alkylene radical preferably contains 1 to 4 carbon atoms, the benzoalkylene radical in particular of the type

where η is an integer between 1 and 3 inclusive and preferably the number 1 or 2; Rr is preferential

3 09883 / U89

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wise a methyl radical; X can be a bromine atom or, preferably, a chlorine atom; when Y is the dialkylamino radical, is it is preferably the dimethyl or diethylamino radical.

The invention relates in particular to the compounds of the formula I described in Examples 1 to 9 below.

The invention also relates to a process for the preparation of the compounds of the formula I. This process is characterized in that a phosgeneimmonium salt of the formula II \

wherein R ₁ , R ~ and X have the above meaning with an enamine of the formula III

^E 4

wherein R-., R-. And Y have the above meaning, reacts.

The reaction of the compounds of the formula II with the enamines III is preferably carried out in the presence of an organic solvent, for example methylene chloride or chloroform. Components II and III are reacted in essentially equimolar amounts. The temperature at which the reaction can be carried out can vary between about -50 and +150 ° C. However, it is preferred to carry out the reaction between about 0 and 50 ^° C., and in particular at room temperature.

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The compounds of formula I can by evaporating the solvent or by precipitation, e.g., by adding ether in which they are insoluble, isolated.

A currently preferred embodiment of the method is described below in the experimental section.

The compounds of the formula II can be prepared by the method mentioned in the article by A. Senning in "Chem. Rev.", 65_, (1965), page 388 by the action of halogen X _? to the corresponding thiocarbamoyl halide of the formula

Nc

Rj ^X

wherein R ₁ , R- and X have the above meanings, are prepared.

In this way the N-methyl-N-benzyldichloromethylimmonium, the N-morpholinodichloromethylimmonium and the N'-methyl-N-piperazinodichloromethylimmonium chloride by the action of chlorine on the corresponding thiocarbamoyl chlorides using made of methylene chloride as a solvent.

The NjN-dimethyldichloromethylammonium chloride was prepared by the action of chlorine on tetramethylthiuram disulfide as described by A. Senning in the above-mentioned article and by Viehe and Janousek in "Angewandte Chemie" (International Edition), 10 , (1971), pp. 573-574.

The enamines of the formula III are obtained by the action of the secondary amines of the formula YH, where Y has the above meaning on the carbonylated derivatives of the formula

T ²

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where R ^. and R. have the above meaning, according to the for the production of enamines conventional processes.

The compounds of the formula I are valuable intermediates for organic synthesis, especially for production of heterocyclic compounds, and the present invention further relates to the use of the compounds of the formula I in organic synthesis.

A first use of the compounds of the formula I, which forms an object of the present invention, relates to the process for the preparation of pyrazoles of the formula

^R \ / 2 N

R ₃ -C ^R 4 ^c

^R 7

IVa IVb

wherein R ₁ , R-, R-. and R ₄ are as defined above and R _{7 is} a hydrogen atom, an alkyl radical having 1 to 5 carbon atoms or a phenyl radical which is essentially characterized in that a compound of the formula I is mixed with a hydrazine of the formula VI

R ₇ NH-NH ₂ VI.

or one of the salts of this hydrazine, in which R _{7 has} the above meaning, and, if R _{7 is} not hydrogen, if desired separates the two isomers obtained.

According to a currently preferred embodiment, the hydrazine R ₇ -NH-NHp or one of its salts, such as the hydrochloride, is gradually added to a solution of the compound of the formula I, the solvent being, for example, methylene chloride or chloroform. The compounds of the formula I and the hydrazine are

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those used in essentially equiir.olar amounts. The reaction is carried out at a temperature between 0 and 100.degree. C. and preferably between 20 and 80.degree. By adding a Mineral base, such as an aqueous solution of an alkali metal hydroxide, the pyrazole salt obtained is in the free, not pyrazole present in the salt form is converted. Then isolated the pyrazole by the usual methods, such as by evaporation of the solvent or by extraction with subsequent Evaporation of the solvent.

When R _{7 represents} a hydrogen atom, the product obtained is a mixture of the tautomeric forms IVa and IVb. If R _{7 is} not hydrogen, the isomers IVa and IVb can optionally be separated, for example by chromatography.

The compounds of formula IVa or IVb have interesting pharmacological properties, especially analgesic and anti-inflammatory properties, and they can be used as Medicines, especially in the treatment of complaints of an inflammatory nature, such as sciatica, rheumatism, arthrosis or muscle or joint pain, toothache, and migraines, - some of these compounds are already in place as analgesic and anti-inflammatory agents in the GB-PS 1 145 544 described.

A second. Use of the compounds of formula I, which also The subject of the present invention relates to a Process for the preparation of pyrimidines of the formula

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wherein R., R ~, R ₃ and R ₄ are as defined above and R _{6 is} a hydrogen atom, an alkyl radical having 1 to 5 carbon atoms or an aryl radical having 6 to 10 carbon atoms, which is characterized in that a compound of the formula I with an amidine of the formula VII

^H 2 ^H \

C R ,. VII

wherein R, - has the above meaning, reacts.

In a currently preferred embodiment, the reaction effected by gradually adding the compound of formula I to a solution of the amidine of formula VII. The solvent is e.g. methylene chloride. The reaction can also be performed without Solvent by heating the mixture of the two reactants causes v / ground. It is preferable to work in the presence of a tertiary base, such as triethylamine. The reaction is preferably carried out at a temperature between 50 and 150.degree. One can, for example, at the reflux temperature of methylene chloride work. After the reaction has ended, the reaction mixture is prepared by adding a mineral base, e.g. by adding neutralized with an aqueous sodium or potassium hydroxide solution. Subsequently, the pyrimidine formed according to the usual Methods isolated.

The pyrimidines of the formula V have interesting biological properties and in particular fungicidal properties, they are used in agriculture to combat plant diseases, that can be traced back to mushrooms, make valuable. The use of certain pyrimidines of formula V as fungicides Agent is described, for example, in FR-PS 1 583 150.

In the above formulas V and VII, when R ^ is an alkyl radical, it is preferably the methyl,

Ethyl or propyl radical; when R, - is an aryl radical, acts it is preferably the phenyl or naphthyl radical.

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In the above formulas IV and VI, when R ₇ denotes an alkyl radical, it is preferably a methyl, ethyl, isopropyl, η-butyl or tert-butyl radical.

The following examples are intended to explain the invention further without, however, restricting it.

Examples of the preparation of the compounds of the formula I.

In the following examples 1 to 9, the compounds of formula I were obtained by the following general procedure ..

The phosgene - immonium salt of the formula II is suspended in methylene chloride or chloroform. It is added dropwise with stirring at room temperature a stoichiometric amount of the enamine of Formula III, dissolved in methylene chloride or chloroform, added. Stirring is then continued until all of the phosgene immonium salt is present has reacted, i.e. until the reaction mixture has changed into a solution.

Then 2/3 of the solvent is evaporated and an excess of ether is added to prevent the precipitation of the salt of the Formula I effect. The precipitate formed is separated off, washed with pentane and then under reduced pressure dried.

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At-' ; game no.

Output products

Phosgene immonium salt enamine of the formula II Formula III

Reaction solution agent

Product received
of formula I.

UV spectrum ^X max. ^{In nm}

CH ₃ CH ₃

Cl

- (CH ₂ J ₄ -

CH ₂ Cl ₂

^CH

Ii

Cl

\ J

389

-ΓΟΟ (D

(-CH ₂ )

Cl

"(CH ₂ J ₄ -

CHCl

CH CII

365

CH ₃ CH

Cl

"(CH ₂ ) 3-

^CH 2 ^C1

N © Cl

370

Example no.

Output products

Phosgene immonium salt enamine der of Formula II Formula III

R, R-

R ₃ R ₄

Reaction solvent

Obtained product of formula I.

UV spectrum

λ in nm

Max.

(O OO GO

CH ₃ , CH ₂ C ₆ H ₅

Cl

- (CH ₂ ) 3-

^CH 3 \ / ^CH 2- ^C 6 ^H 5 V

CH ₂ Cl ₂

Cl

372

CH ₃ ^; CH ₃

Cl

-C = C- (CH ₂ ) HC CH

C-CH H

CH ₂ Cl ₂

CH.

Cl

vJ

387

•• ■ -6

CH ₃ CH ₃

Cl

C ₆ H ₅ H

CHa / CH

CH ₂ C1

Cl

^C 6 ^H 5

366

Example no.

Au sq anq products

Phosgene immonium salt enamine of the formula. II formula III

R, R,

^R 3 ^R 4

Reaction solution smitbel

Product received
of formula I.

OV spectrum ^{max.xn ηπΊ}

Cl

/ - ^

CKCl.

Cl

378

CIU CH.

Cl

CH.

H '-C-CH.

CH.

CH ₂ Cl ₂

Il

^H 3 ^C N

363

CH "CH.

Cl

-CH ₀ -C = C-

V \

HC · 'CH

C-CH H CH

he

Cl

404

The products of the formula I obtained in Examples 1 to 9 were also obtained by Urr, v. ^; Treatment in β-oxoamides is characterized by hydrolysis according to the general procedure below.

1 g of a compound of the formula I is dissolved in 100 ecm of methylene chloride or chloroform. An excess of an aqueous saturated sodium bicarbonate solution is added and the mixture is stirred 1/4 hour. The ß-oxoamide obtained is extracted with the aid of Chloroform or methylene chloride, removes the solvent by evaporation and purifies the residue by distillation under reduced pressure. The following table shows the properties of some of the ß-oxoamides obtained in this way.

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Hydrolysis of the
Connection d.
Formula I, be
wrote in Receive formula series ß-oxoamide Example no. ^CH 3 \; / ^CH 3
N
\ properties 1 f3
0
cc Bp = 110-120 ° C / 0.2 mm Hg
IR spectrum: V at 1710,
¹ ^ max. _ΛΓ λ ^ -1
1640 cm ^x 2 ^CH 3 / ^CH 3
^. N Kp .. "= # 120 ° C / O, 0.5 mm Hg
IR spectrum: \> at
2930, 2850, 2790, 1710 and
1640 cm 5 ^CH 3 / ^CH 3
N
⁶ ^ CfT Bp = 160-170 ° C / 0.5 mm Hg
IR spectrum: V- '1710,
^r max. ' * - i
1640 cm 6th 0
cc IR spectrum: V at 2940,
Max. . '
2740, 1730 'and 1640 cm " ¹ 7th Bp = 130 ° C / O.05 mm Hg
IR spectrum: V at 2940,
Max"'
2860, 1710 and 1640 cm " ¹

3883/1 Λ 8 9

Example 10

Use of the compounds of formula I for the preparation of Pyrazoles of the formula IV. Example of the reaction with methylhydrazine

0.030 mol of the compound obtained in Example 1 is dissolved in 100 ecm chloroform. 0.032 mol is added dropwise with stirring Methylhydrazine, dissolved in 50 ecm of chloroform, is added and the mixture is then heated under reflux (about 70 ° C.) for 14 hours. Man neutralizes the hydrochloric acid formed by adding an aqueous concentrated potassium hydroxide solution and then extracted with chloroform. The chloroform is evaporated, and the residue is distilled under reduced pressure. The product passing over at 80 to 85 ° C (0.02 mm Hg) is collected on. A mixture of the compounds of the formulas is obtained

CH \ /,

/ 3 _CH

and

CX »H

Isomer A Isomer B

which, if desired, are separated by chromatography. The mixture consists of 90 % isomer A and IO % of isomer B.

The two isomers were identified by comparison with a sample of isomer B prepared in a different manner.

The two isomers A and B are iron in the NMR spectrum (in CDCl ..) the following values:

Isomer A; _c f = 1.75 (4H, m); 2.45 (4H, m); 2.78 (6H, s);

3.55 (3H, s)

Isomer B: <j = 1.70 (4H, m); 2.5 (4H, m); 2.65 (6H, s);

3.5 (3H, s)

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Example 11

Verv; endunq of the compounds of the formula I for the preparation of pyrazoles of the formula IV. Example of the reaction with hydrazine

9.34 g of the compound of the formula I obtained in Example 1 are dissolved in 50 ml of methylene chloride and added then gradually a solution of 2.33 g of hydrazine dihydrochloride in 100 ecm of methylene chloride is added. It is heated under for 5 hours Reflux, cools to 0 C and then 15 ecm of an aqueous concentrated potassium hydroxide solution are added. The organic Phase is dried over potassium carbonate and the solvent is removed by evaporation. The residue is obtained by distillation cleaned. The product of the formula is isolated

Kp. = 17O ° C (0.04 mm Hg)

NMR Spectrum: O = 9.3 (IH, br); 2.85 (6H, s); 2.6 to 1.4 (8H)

Example 12

Use of the compounds of the formula I for the preparation of pyrazoles of the formula IV. Example of the reaction with phenylhydrazine

By proceeding as in Example 11, starting from the compound of Example 1 and from pheny / hydrazine, the mixture is obtained the connections of the formulas

CH

CH

\ / ^CH =

3, N

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Examples of the use of the compounds of the formula I for the preparation of pyrimidines of the formula V

In the following Examples 13 and 14, the compounds of Formula V were obtained by the following general procedure.

The chosen amidine and the triethylamine are in 100 ecm methylene chloride brought in. The solution is added dropwise the selected compound of the formula I in 50 ecm of methylene chloride. The mixture is stirred under reflux for 24 hours and neutralized then the reaction mixture by adding a Potassium hydroxide solution. The aqueous phase is saturated with potassium carbonate and then extracted with methylene chloride. The methylene chloride is then removed by evaporation, and the pyrimidine of the formula V is isolated by distillation under reduced pressure.

Example 13 The respondents are the following:

Compound of the formula I, obtained in Example 1: 2.7 g of benzamidine: 1.04 g
Triethylamine: 2.5 ecm

The pyrimidine obtained boils at 150 ° C. (0.3 mm Hg). It is recrystallized from a water / ethanol mixture (l / l).

Example 14 The respondents are the following:

Compound of the formula I, obtained in Example 5: 0.7 g of benzamidine: 0.52 g
Triethylamine: 1.5 ecm

The pyrimidine obtained boils at 160 ° C (0.04 mm Hg). It will recrystallized from benzene.

The results of Examples 13 and 14 are summarized in the following table:

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(O CD OO CO

-ΤΟ UO

at
game
No. Starting products Amidine Obtained pyrimidine formula properties 13th link
the formula
I received
in example
No. Benzamidine CH \
^
α IR spectrum: V = 2940, 2860,
1590, -1550 and 1400 cm " ¹
Γ = OO L.
Mass spectrum: 253 (M)
- 14th I. Benzamidine
V. pJ
T ι * I.
IR spectrum .: V * 2940, 2860,
1600 and 1550 'cm " ¹ ■
Mass spectrum: 301 (M) V / ^CH 3
* CH ^ CH
^L 6 ^H 5

Claims (7)

Patent claims 1.) Immonium salts of the formula I R. and R _{2 represent} an alkyl radical, a phenyl radical optionally substituted by a halogen atom or a benzyl radical, or R ₁ and Rp together represent an alkylene radical, a radical - (CH ₂ ) ₂ -0- (CH ₂ ) ₂ ~ or a radical - (CH ₂ ) ₂ ~ M- (CH ₃ ) ₂ ~ form, where R _{5 is} an alkyl radical having 1 to 5 carbon atoms, R-. and R. denotes a hydrogen atom, an alkyl radical having 1 to 5 carbon atoms or a phenyl radical or R ₃ and R together "denote an alkylene radical with 3 to 5 carbon atoms or a benzoalkylene radical with 7 to 10 carbon atoms, X represents a halogen atom and Y denotes a dialkylamino radical, its alkyl radicals Contain 1 to 5 carbon atoms, a morpholino, Means piperidino or 1-pyrrolidinyl radical. 2.) Compounds according to claim 1, characterized in that X is a chlorine atom. 309883 / U89 233301A 3.) Compound according to claim 1 according to one of the following formulas: a) ^CH 3 / ^CH 3 N ^ Cl Il b) CH. N ■ Cl c) d) CH ₃ . / CH ₃ Il C. Cl / ^ ² Il egg Cl 309883 / U89 - ΙΦ- CH N ^
Il t
Cl Cl ^ CH ₃ ⁵ C CH ₃ , C] Il
C.
f ^ / ^C 6 ^H 5 \ L. y
H 1 Cl ^ Cl N ^CH 3 Cl ΓΗ CH ₃ and me- Cl 309883/1 23330H - 2i - 4.) Process for the preparation of the compounds according to claim 1, characterized in that a phosgene immonium salt is used Formula II Φΐ χ θ (II) wherein R ₁ , R ₂ and X have the above meaning with an enamine of the formula III (III) • wherein R ^, R. and Y have the above meaning, converts. 5.) Use of the compounds according to claim 1 for the preparation of pyrazoles of the formula N I R_ C N 3 Il j or R c N (IVa) (IVb) wherein R ₁ , R ~, R- and R, have the above meaning and R _{7 is} a hydrogen atom, an alkyl radical having 1 to 5 carbon atoms or a phenyl radical, characterized in that a compound of the formula I with a hydrazine of the formula VI R ₇ NH NH ₂ (VI) in which R _{7 has} the above meaning or reacts with a salt of this hydrazine and, if R _{7 is} not a hydrogen atom, if desired separates the two isomers obtained. "S883 / U89 - 2JL - 6.) Use of the compounds according to claim 1 for the produc- tion of pyrimidines of the formula V I (V) C N St. wherein R, R ", R ₃ and R _{4 have} the above meanings and Rg is a hydrogen atom, an alkyl radical with 1 to 5 carbon atoms or an aryl radical with 6 to 10 carbon atoms, characterized in that a compound of the formula I with an amidine of formula VII (VII) CR ₆ in which Rg has the above meaning. 7th 309883 / U89