FR2620444A1 - CYCLOHEXYL PHENYL KETONE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS SYNTHESIS INTERMEDIATES - Google Patents

Abstract

The invention relates to cyclohexyl phenyl ketone derivatives of the general formula: (CF DRAWING IN BOPI) in which R represents an alkyl radical having from 1 to 4 carbon atoms and R1 represents a hydrogen or halogen atom. The derivatives of the invention are useful as intermediates in particular for the final synthesis of derivatives of benzodiazepine-1,4, active on the central nervous system such as tetrazepam.

Description

The present invention relates, in general, to new

  cyclohexyl phenyl ketone derivatives, to their preparation process as well as

  that their use as intermediaries for the

  thesis. More specifically, the subject of the invention is the novel cyclohexyl phenyl ketone derivatives of general formula: R

NH

  l. In which R represents an alkyl radical having from 1 to 4 carbon atoms and R 1 represents a hydrogen or halogen atom, in particular an atom of

chlorine or bromine.

  The compounds of the invention have proved particularly useful as intermediates

  especially for the final synthesis of benzene derivatives

  zodiazepine-1,4, subject of US-A-3,268,586 and FR-A-1,455,048, in particular for the preparation of 1,4-benzodiazepine derivatives of general formula:

R O

C Ia N - C Ia CH

N. C = N

K2 R3

  in which R has the same meaning as above

  R 2 represents a halogen atom such as

  chlorine or bromine, preferably chlorine, and R3 represents

  a cyclohexyl or cyclohexen-1-yl radical.

  These benzodiazepine-1,4 derivatives are of undoubted interest because of their properties.

  sedatives on the central nervous system.

  Consequently, another object of the invention

  The invention relates to the cyclohexyl phenyl ketone derivatives of formula I as novel industrial products useful especially as intermediates for

  example for the final synthesis of derivatives of ben-

zodiazepine-1,4 of formula Ia.

  Among the compounds of formula Ia in question

  chloro-7 (1-cyclohexen-1-yl) -5-methyl-2-oxo-2,3-dihydro-1H-benzorf] 1,4-dazepine or "tetrazepam" has proved particularly useful because of its

  valuable muscle relaxant properties.

  Therefore, the cyclohexyl phenyl ketone derivatives of formula I which can give access to the

  tetrazepam are preferred compounds of

  vention, that is to say the derivatives of formula I in

  which R represents methyl and R1 represents hydrogen

drug or chlorine.

  US Pat. No. 3,268,586 discloses a process for preparing 1-alkyl-5-cycloalkyl-2-oxo

  1H-benzo-1,4-fldiazepine with the use of

  2-amino-phenyl cycloalkyl ketones or

  5-halogeno-2-amino phenyl cycloalkyl ketones.

  This process envisages, in particular, the introduction

  of the alkyl-1 radical after the formation of the benzo

  1,4-diazepine and this, by alkylation of a 7-halogeno-5-cycloalkyl-2-oxo-1H-benzoúf7diazepine-1,4. However, it is known that this operation is performed quite laboriously as a result of a partial alkylation only, which can be at the origin of operations

  delicate and expensive purifications.

  In addition, the 2-amino phenyl cycloalkyl ketones and halogen-5-amino-2-phenyl cycloalkyl keto intermediates themselves are produced with difficulty from a benzoxazin-4-one derivative and an organomagnesium derivative. For example, 2-amino-5-chlorophenyl cyclohexyl ketone is obtained in a yield of only 13Z from 2-methyl-6H-chloro-4H-benzoxazin-4-one and cyclohexylmagnesium bromide. It has now been discovered that the derivatives of

  cyclohexyl phenyl ketone of formula I, which furthermore

  they can not be obtained according to the method described in the above US Patent, allow to prepare benzodiazepine-1,4 derivatives of formula Ia with overall yields greater than those obtained according to

  the prior art while avoiding the inconveniences

  of the latter. In addition, it has been found that these

  cyclohexyl phenyl ketone derivatives of formula I can

  can be obtained in a remarkably advantageous way and with very high yields of

the order of 90Z.

  In the context of the present invention, it has been attempted to prepare the cyclohexyl phenyl ketone derivatives of formula I according to the methods described in US Pat.

Synthesis, 1980, pp. 505-536.

  This reference teaches the preparation of

  ration of 2-amino-benzophenone derivatives N-alkylated or otherwise by opening the isatoic anhydride N-alkylated or not with phenyllithium in tetrahydrofuran

  at a temperature of -35 to -40 ° C.

  Similarly, this reference describes the preparation

  indoloquinazolone from the acid

  5-chloro-N-methyl isatoic acid and indolyl bromide

  magnesium. However, the preparation of cyclohexyl-5-chloro-N-methylamino phenyl ketone of formula I

  by reaction between 1-methyl-5-chloro-isocyanate

  and cyclohexylmagnesium chloride at -75 ° C, according to the method described in

  Synhtesis above, has only provided a maximum of

  16% of the desired compound but also led to

  to obtain, at 64Z, an alcoholic derivative as a by-product, namely the

  5-chloro-N-methylamino-2-phenyl-di-cyclohexyl metha-

  nol. The replacement of the magnesian derivative by a

  lithian derivative did not bring any improvement

  that it has provided yields of desired compound and by-product quite similar to those mentioned above.

  However, surprisingly

  ante, it is possible to prepare the cyclohexyl phenyl ketone derivatives of formula I, in particular cyclohexyl N-methylamino-2 phenyl ketone and cyclohexyl chloro-N-methylamino-2-phenyl ketone, according to an industrial process providing significant yields from an N-alkyl-isatoic anhydride

  using an organomanganese or organococcal derivative

  prate. However, this reaction proved to be totally

  inefficiently when the isatoic derivative is the same isatoic anhydride. As a result, the process

  of the invention could not be used for the prepa-

  ration of the amino-2 cycloalkyl phenyl ketones of the patent

  US-A-3,268,586 and their halo-5 derivatives.

  Thus, the process of the invention for the preparation of the compounds of formula I consists of reacting an isatoic anhydride derivative of general formula: R

N O

  ! C / R1, wherein R and R1 have the same meaning as

  previously, with an organometallic derivative of

General mule:

IM

  in which M represents a radical -MnX or -Cu-MgX I S-R4 in which X represents a halogen atom such as chlorine or bromine and R4 represents an aryl group such as, for example, phenyl, and then hydrolyzing the

  complex obtained to obtain the desired compound.

  The compounds of formula III in which M represents a radical. -MnX are favorite products. The reaction can be carried out according to

  conventional modes of implementation of organic derivatives

  metal, namely in an anhydrous ether such as tetrahydrofuran, dibutyl ether or dioxane and at a temperature for example between -10 ° C and

Room temperature.

  Similarly, the hydrolysis of the complex can be carried out according to known procedures, for example at

  medium of an aqueous solution of ammonium chloride.

  The use of organomanganese or gold

  ganocuprates. according to the invention, instead of the

  corresponding lithians or organomagnesium compounds makes it possible to obtain a significant increase in the yields of the compound of formula I. For example, in the case of cyclohexyl-5-chloro-N-methylamino phenyl ketone, the yields are increased from 16Z to 90Z using the

method of the invention.

  The compounds of formula II are products

  known having been described in Synthesis 1980 cited above.

  or that can be prepared by the method that

is described there.

  As for the manganous derivatives of formula III, these can be obtained by transmetallation, that is to say by exchange reaction of the lithian or magnesium derivative of general formula:

-M 'IV

  in which M 'represents a lithium atom or an -MgX radical in which X has the same meaning as above, by means of a manganese salt such as a halide, for example chloride, bromide or iodide. Preferably, manganese chloride is used because of its commercial accessibility and

its low cost.

  As for the organocuprates of formula III, these can be obtained according to the method described in synthesis, 1974, p. 662, involving, for example, the following reactions: R4-SH + n-C4H9> R4-SL1 R4-S-Li + CuX> R4-S-Cu R4-S-Cu + MgX> C-MgX

S-R4

  X having the same meaning as before.

  The method of the invention can be implemented according to different procedures. For example, in the case where the use of a manganous derivative of formula III is envisaged, one of the following implementations may be used: addition of the magnesium derivative of formula IV to a suspension of salt of manganese in an ether and then, after formation of the manganous derivative, addition of the compound of formula II to the clear solution obtained, - addition of the magnesium derivative of formula IV to a solution of lithium manganeseesalt salt 1: 2 in an ether, by example a solution of manganese chloride lithium chloride 1: 2 and then add the

  compound of formula II to the manganese derivative solution.

  nous. Manganese salt forms a suspension in

  ether such as tetrahydrofuran. The salt of

  In this case, thium has the effect of homogenizing the medium until a solution is obtained. The magnesium derivative of formula IV is added to a mixture of compound of formula II and of manganese salt in an ether. The addition will be however

  in such a way that the reaction medium does not

  no magnesian derivative of formula IV in excess.

  As mentioned above, the cyclohexyl phenyl ketone derivatives of the invention can give

  access to benzodiazepine-1,4 derivatives of formula la.

  Consequently, another object of the invention

  The invention relates to the preparation of the compounds of the formula Ia by carrying out a process according to which: A. In order to obtain a compound of the formula Ia in which R is the cyclohexyl radical a) a compound of the formula I below is reacted. above - when R 1 represents hydrogen, with an acetyl halide of general formula

X-CH V

  where X and X ', which are the same or different,

  each represents a halogen atom, for example a chlorine or bromine atom, the reaction taking place in a suitable solvent for example an aromatic hydrocarbon such as benzene, toluene or xylene, and at a temperature between ambient temperature and the reflux temperature, to obtain an acetyl halide derivative of general formula R0

N-C-CH 2 X

  VI C = O in which R and X have the same meaning as

  previously, acetyl halide derivatives of

  mule VI which is subsequently treated with a halogen such as chlorine or bromine in a suitable solvent such as N-Ndimethylformamide, dichloromethane or dichloroethane and at a temperature of

  between room temperature and temperature

  reflux, which provides a 2-amino-5-halo-phenyl cyclohexyl ketonic derivative of formula

gene-

rale: R 0 t He

-N-C-CH 2 X

l

/ -C = O VII

  in which R, R2 and X have the same meaning as above, or when R1 represents a halogen atom, with an acetyl halide of formula V, the reaction having

  in a suitable solvent, for example a hydro-

  aromatic carbide such as benzene, toluene or

  a xylene and at a temperature between

  ambient temperature and the reflux temperature, to obtain a corresponding amino-2-halogeno-phenylcyclohexyl ketone derivative of formula VII, b) the compound of formula VII is cyclized at room temperature and in a suitable solvent such as

  alcohol, for example, ethanol, by means of

  methylenetetramine and in the presence of ammonium carbonate

  monium or an acid such as formic acid, which provides the desired benzoEfldiazepine-1,4 derivative of formula Ia wherein R3 represents the cyclohexyl group and B. To obtain a comoose of formula Ia wherein R represents the radical cvclohexen-1 vle

  c) the benzo derivative [fidelity

  zebra-1,4 of formula Ia wherein R3 represents the cyclohexyl radical, at room temperature and in a suitable organic sovant, for example dichloromethane or dichloroethane, with an N-halogenated derivative, in particular an N-halogenated derivative of a carboxylic or sulphonic imide, especially the

  N-chlorosuccinimide, to obtain a halogen derivative

  no-1 cyclohexyl) -5-oxo-2,3-dihydro-1H-benzofurazione

pine-1,4 of general formula: R

N - C '

VIII

2 Y

  in which R and R 2 have the same meaning as above and Y represents a halogen atom, for example a chlorine or bromine atom, and

  d) the (halo-1-cyclohexyl) derivative is

  hexyl) -5-oxo-2,3-dihydro-1H-benzotfdiazepine-1,4 of formula VIII to the action of lithium carbonate in 1 1

  presence of a lithium halide such as chlorine

  or the bromide, the reaction taking place in a suitable solvent such as N, N-dimethylformamide and at a temperature between 50.degree. C. and 120.degree. C., which provides the desired 1,4-benzoZf2diazepine derivative of formula Ia in which R3 represents the grouping

cyclohexen-1-yl.

  According to another particularly advantageous variant, it is also possible to prepare the compounds of formula Ia in which R3 represents the radical

  cyclohexen-1-yl from the 2-amino-halo derivatives

  5-phenyl cyclohexyl ketone compounds of formula VII, themselves obtained from the cyclohexyl phenyl ketone derivatives of formula I, by means of a process according to which: a) the 2-amino-5-halogeno phenyl cyclohexyl ketone derivative in question is treated; formula VII, with a halogen such as chlorine or bromine

  in a suitable solvent such as N, N-dimethylfor-

  mamide, dichloromethane or dichloroethane and at a temperature between room temperature and reflux temperature, which provides a 1-halogeno cyclohexyl ketone derivative of general formula: R 0 g II

N-C-CH 2 X

  Where R, R2, X and Y have the same meaning as above,

  b) the halogeno-1-cyclopropyl derivative is

  hexyl ketone of formula IX with the action of a basic agent such as an alkali metal carbonate by

  example, lithium carbonate, possibly in the form of

  a lithium halide such as chloride or bromide or an alkali metal bicarbonate such as sodium bicarbonate or an amine such as, for example, diethylamine or triethylamine, the reaction taking place in a suitable solvent such as N, N-dimethylformamide and at a temperature of

  between 50 ° C and 120 ° C, which provides a cyclo-

  hexenyl ketone of the general formula: R 0 I il

/ 5-N-C-CH2X

-C = O X

  R in which R, R2 and X have the same meaning as above, and

  c) finally cyclizes the cyclohexane derivative

  xenyl ketone of formula X at room temperature and in a suitable solvent such as an alcohol for example ethanol, with hexamethylenetetramine and in the presence of ammonium carbonate or an acid such as formic acid, which provides the desired derivative of formula Ia wherein R3 represents the grouping

cyclohexen-1-yl.

  This variant is of interest

  ticuller with respect to the above process according to which the derivatives of formula Ia in which R3 represents

  the cyclohexen-1-yl radical are obtained through

  intermediates of formula VIII derivatives.

  In the context of this process, using derivatives of formula VIII, the reaction of the cyclohexen-1-yl ring is carried out on a benzodiazepine compound, namely a 7-halo-5-cyclohexyl-2-oxo-2,3-dihydro-1H- 1,4-benzoifdiazepine of formula Ia by halogenation using an N-halogenated derivative and then by dehydrohalogenation by means of the couple

  lithium carbonate / lithium halide.

  In this case, the use of a halogenating agent, as in the above variant, would have led to parasitic halogenation in position 3 of the

  compounds of formula VIII and on the other hand dehydro-

  halogenation of the same compound of formula VIII with a

  base other than the lithium carbonate / halo

  lithium genius would cause the formation of a

  mixture of ethylenic isomers as described in

FR-A-1 455 048.

  The cyclohexyl phenyl ketone derivatives of the invention have an undeniable advantage over the 2-amino phenyl cycloalkyl ketones and 5-halogeno-2-amino cycloalkyl ketones of US-A-3.

268,586.

  Indeed, the introduction of the N-alkyl radical is carried out at the level of the starting isatoic derivative, the presence of this N-alkyl radical being, moreover, necessary during the implementation of the process of the invention for the production of the compounds of formula I. In fact, the process of the invention was found to be incapable of producing the non-alkylated analogs of the compounds of formula I, ie 2-amino phenyl cycloalkyl ketones and halogen-5 2-amino cycloalkyl

ketones of the US patent in question.

  In addition, the N-alkylation of the compounds

  no-2 phenyl cycloalkyl ketones and halo-5 amines

  no-2 cycloalkyl ketones of US-A-3,268,586 using for example an alkyl halide appear-trait more expensive than the method of preparation of the compounds of the invention given: - it would put in already prepared compounds, ie 2-amino-phenyl cycloalkyl ketones and their halo-5 derivatives, would very likely require prior protection of the nitrogen with a labile group (formylation, sulphonylation) in order to to avoid

dlalkylation.

  The following nonlimiting examples illustrate

  trent the preparation of the compounds of formula I.

EXAMPLE 1

  Preparation of cyclohexyl (5-chloro-N-methylaminophenyl) ketone a) Chloro-5-N-methylisatoic anhydride In a 500 ml three-necked flask equipped with a mechanical stirrer, a condenser, a thermomete- be and one. 200 ml of N, N-dimethylformamide and 35.4 g (0.2 mole) of N-methylsatoic anhydride are introduced into the gas introduction system. The mixture is heated to -50 ° C. and 37.5 g of chlorine are added over one hour, while maintaining the temperature of the reaction medium at 45.degree. To 50.degree. The medium is left stirring for 30 minutes at this temperature and then

  poured with stirring into a mixture of 200 ml of

  and 200 ml of water cooled to 0 ° C so as to precipitate the desired compound which is filtered and then dried.

  In this way, 35 g of anhy-

  5-chloro-N-methylisatoic acid, which represents a

yield of 82Z.

M.p .: 200'C.

  (b) Cyclohexyl (5-chloro-N-methylamino-2-phenyl)

nyl) ketone

  In a 500 ml flask equipped with a

  To a refrigerant, a thermometer and a refrigeration system, 300 ml of anhydrous tetrahydrofuran and 29.7 g (0.236 moles) of anhydrous manganese chloride are introduced. A suspension is obtained which is cooled to -10 ° C. 136 g are then added

  (0.2 mole) of a 21Z solution of cyclohexyl chloride

  hexylmagnesium in tetrahydrofuran while

  holding the temperature of the medium at -10'C. At the end of

  addition of the magnesium derivative, the reaction medium

  at -10 ° C for 30 minutes and then warmed to 0 ° C before adding, in 15 minutes, 38.1 g (0.18

  mole) of 5-chloro-N-methylisatoic anhydride. We are

  The mixture is stirred at 0 ° C. for 1 hour and then poured into 700 ml of ice water. The medium is acidified with hydrochloric acid to pH = 4 and then the tetrahydrofuran is distilled off and the aqueous phases are extracted with 3 times 250 ml of toluene. The toluene phases are pooled, dried and concentrated to give 44.1 g of a light brown oil which can be purified by passage over

silica column.

  In this way, cyclohexyl-

  (5-chloro-N-methylamino-2-phenyl) ketone.

  Yield: 89.2Z R.M.N. Spectrum (CDCl3):

  9-8.7 ppm (m, 1H); 7.7-7.6 ppm (D, 1H); 7,4-

  7.1 ppm (m, 1H); 6.6-6.5 ppm (d, 1H); 3.5-2.9 ppm (m, 1H)

  : CH-C = O); 2.8-2.7 ppm (d, 3H); 2-1 ppm (m, 10H).

EXAMPLE 2

  Preparation of Cyclohexyl (5-chloro-N-methylamino-2-yl-1-ketone)

  In a 100 ml flask equipped with a stirring agent

  refrigerant, a thermometer and a refrigeration system, 1.73 g (0.01

  mole) of cuprous thiophenate in 50 ml of tetrahydro-

  drofuranne. With the medium under an inert atmosphere, it was cooled to 10 ° C. and 6.5 ml (approximately 0.01 mole) of a solution of approximately 1.55 M cyclohexylmagnesium chloride in tetrahydrofuran was added thereto. The temperature of the medium is allowed to rise to + 10 ° C.

  obtain a homogeneous solution of green color. We are

  This solution is cooled to 0 ° C. and 2 g (0.0095 mole) of 5-chloro-N-methylisatoic anhydride are added. The reaction medium is left stirring for one hour at room temperature and the product is isolated.

  desired as described in Example 1.

  From this amnium, cyclohexyl (5-chloro-N-methylamino-2-phenyl) ketone is obtained in the form of

  gross which represents a return of 98X. By step

  on a silica column, the compound is isolated

question in pure form.

Yield: 90 '.

  R.M.N .: spectrum identical to that obtained at

Example 1

EXAMPLE 3

  Preparation of cyclohexyl (N-methylamino-2-dhenyl)

ketone

  In a 500 ml flask equipped with a stirring

  a refrigerant, a thermometer and a system

  refrigeration system, 200 ml of tetra--

  anhydrous hydrofuran and 18.4 g (0.146 mol) of chlorine

  anhydrous manganese content. We cool to 0 ° C the sus-

  obtained pension and then 109.3 g (0.13 mol) is added

  of a 17% solution of cyrohexyl magnesium chloride

  in tetrahydrofuran by keeping the temperature

* middle erection at O'C. At the end of the addition of the derivative

  magnesian, the temperature of the medium is

  place at 0'C for 2 hours. We then introduce in 20

  minutes, 19.5 g (0.11 mole) of N-methylisocyanate

  toique. The medium is kept under stirring and at 0OC

  for one hour then poured into 250 ml of water.

  Acidified with hydrochloric acid to pH = 3, the tetrahydrofuran is distilled and extracted

  the aqueous phases with 3 times 200 ml of diisopropyl ether

  propyl. The organic phases are combined, dried over sodium sulphate and evaporated, yielding 22.9 g of an oil. By passing 4.3 g of this crude product over a silica column, 3.9 g are obtained.

  of cyclohexyl (N-methylamino-2-phenyl) ketone

tallise. Yield: 87Z

P.F .: 47C

Spectrum R.M.N. (CDCl3):

  7.8-6.3 ppm (m, 5H); 3.5-2.9 ppm (m, 1H: CH-

  C = O); 2.8-2.7 ppm (s, 3H); 2-1 ppm (m, 10H).

  The non-limiting examples below

  lustrate the preparation of the compounds of formula Ia from cyclohexyl phenyl ketone derivatives of formula I.

EXAMPLE 1

  Preparation of 7-chloro (cyclohexen-1-yl) -5-methyl-1-oxo-2,3-dihydro-1H-benzyl-1,4-diazepine-a) 2-chloro-N- (2-cyclohexylcarbonylphenyl) -N-methylacetamide

  In a 250 ml flask equipped with a stirring

  of a thermometer, a refrigerant and a system

  heating-cooling system, 18.45

  g (0.085 mol) of cyclohexyl (N-methylamino-2-phenyl) -

  ketone and 130 ml of toluene. The reaction medium is

  under an inert atmosphere and with stirring then

  9.6 g (0.085 mol) of chlorine are added over 5 minutes.

  chloride of chloroacetyl. The toluene is refluxed for one hour, concentrated in a rotary evaporator and the residue is taken up in a mixture of 35 ml of toluene.

  ml of isopropyl ether and 35 ml of dry ethanol.

  With stirring, the suspension obtained is cooled to -10 ° C., the precipitate is filtered off and rinsed with 2 times 10 ml of diisopropyl ether. After drying, 18.65 g of 2-chloro-N- (2-cyclohexylcarbonyl) are obtained.

phenyl) N-methyl acetamide.

Yield: 67Z

P.F.:68'C

  Spectrum R.M.N. (CDCl3): 7.8-7.1 ppm (m, 4H); 3.8 ppm (s, 2H); 3.15 ppm

(S, 3H); 2-1 ppm (m, 1OH).

  b) 2-Chloro-N- (4-chloro-2-cyclohexylcarbonylphenyl) N-methylacetamide

  In a 100 ml flask equipped with a stirring

  14.7 g (0.05 mole) of 2-chloro-N (2-cyclohexylcarbonylphenyl) N-methylacetamide and 13.4 g of a refrigerant, a thermometer and a cooling system are introduced. ml of a solution

  of chlorine (0.01 mole) in N, N-dimethylformamide.

  The medium is heated to 60.degree.

  26.8 ml of the chlorine solution (0.02 mole) in N, N-dimethylformamide. At the end of the addition of the chlorine,

  the medium is left for one hour at 60.degree.

  center under vacuum while chasing N, N-dimethylformamide.

  The residue is taken up in an acetone / water mixture

  obtained which provides 9lg of precipitate containing essen-

the desired compound.

  In this way, we obtain chloro-2

  N- (4-chloro-cyclohexylcarbonyl-2-phenyl) N-methyl acetoacetate

  tamide which can be purified by passage on a column

of silica.

Yield: about 50Z

M.p .: 98 ° C

  Spectrum R.M.N. (CDCl 3): 7.7 at -7 ppm (m, 3H); 3.5 ppm (d, 2H); 3.2 to 2.6 ppm (m, 4H); 2 to 1 ppm (m, 10H).

  (c) 2-Chloro-N-4-chloro-chloro-1-cyclohexyl

  xyl) 2-carbonylphenyl-N-methylacetamide

  In a 500 ml flask equipped with a stirring

  a thermometer and a heating system-

  24.2 g (0.065 mole) of

  2-chloro-N- (4-chloro-2-cyclohexylcarbonylphenyl) -

  N-methylacetamide, 18.5 g of a solution of chlorine (0.26 mole) in N, N-dimethylformamide and 250 ml of N, N-dimethylformamide. The homogeneous medium is heated at 60 ° C. for 90 minutes and, after evaporation of the N, N-dimethylformamide under reduced pressure, the residue is taken up in the form of a thick oil in 150 ml of water and 300 ml of dichloromethane. The organic phase is dried over sodium sulphate and evaporated, which gives 26.5 g of a yellow powder whose purity, determined by chromatography in phase

  liquid by external calibration, is 70Z.

  In this way, 2-chloro-N-echloro-4 (1-chloro-cyclohexyl) 2-carbonylphenyl-N-methylacetamide is obtained which can be purified by passage through a silica column.

Yield: 77.5Z

M.p .: 112'C

  Spectrum R.M.N. (CDCl3): 7.9-7.2 ppm (m, 3H); 4.15-3.9 ppm (2s, 2H);

  3.4-3.1 ppm (2s, 3H); 2.4-1.4 ppm (m, 10H).

  d) 2-Chloro-N- [4-chloro (cyclohexen-1-yl)]

  2-carbonylphenyl N-methylacetamide.

  In a 250 ml flask equipped with stirring

  of a thermometer, a refrigerant and a system

  heating-cooling system, 11.6 g

  (0.032 mol) of 2-chloro-4-chloro-chloro-1-chloro

  hexyl) 2-carbonylphenyl] N-methylacetamide, 140 ml of dry N, N-dimethylformamide and 6.56 g (0.089 mol) of lithium carbonate with 0.615 g (0.0125 mol) of

  lithium chloride. The whole is heated to 80 ° C.

  After 2 hours 30 minutes, the N, N-dimethylformate is evaporated

  mide under reduced pressure and the residue is taken up

  obtained in 150 ml of water and 200 ml of dichloromethane.

  After drying the organic phase, the solvent is evaporated, which gives 11.36 g of a yellow powder

  containing 87% of the desired product determined by chroma-

  In this way, 2-chloro-N- (4-chloro-1-cyclohexen-1-yl) 2-carbonylphenylmethylacetamide is obtained, which can be purified by chromatography.

on a silica column.

Yield: 94Z

M.p .: 113'C

Spectrum R.M.N. (CDCl3):

  7.6-7.25 ppm (m, 3H); 6.6 ppm (m, 1H); 4,1-

  3.85 ppm (2s, 2H); 3.35-3.1 ppm (2s, 3H); 2.6-1.5 ppm (2m, 8H). e) Chloro-7 (cyclohexen-1-yl) -5-methyl-1-oxo-2,3-dihydro-1H-benzyl-1,4-diazepine-1,4

  In a 25-ml balloon, protected from light

  first, a solution of 1 g (0.00309 mole) of 2-chloro-4-chloro (1-cyclohexenyl) carbonyl-2 is introduced.

  phenyl N-methyl acetamide in 10 ml of ethanol

  degassing and then 0.993 g (0.0071 mole) of hexamethylenetetramine and 0.978 g (0.010 mole) of ammonium carbonate were added. The mixture is heated at reflux

  for 2 hours, it is cooled to room temperature

  biante then poured into 5 ml of water, 1.5 ml

  of acetic acid and 20 ml of dichloromethane.

  After decantation, the organic phase is washed

  10 ml of water, dried over sodium sulphate and concentrated in vacuo to afford 0.930 g of a yellow-orange powder, the title of which, by calibrated liquid chromatography

external, is 65Z.

  By rapid passage over a silica column, chloro-7 (cyclohexen-1-yl) -5-methyl-1-oxo-2 is obtained.

  2,3-dihydro-1H-benzyl-1,4-diazepine.

P.F .: 140'C

  Spectrum R.M.N. (CDCl3): 7.6-7.1 ppm (m, 3H); 6.1-5.9 ppm (m, 1H); 4.75 ppm and 4.55 ppm (d, 1H): 3.7 and 3.5 ppm (d, 1H); 3.3 ppm

(S, 3H); 2.4-1.5 ppm (m, 8H).

EXAMPLE II

  Preparation of 7-chloro-7-cyclohexyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo-4-diazidine-a (a) 2-chloro-N- (4-chloro-2-cyclohexylcarbonylphenyl) N-methylacetamide

  In a one-liter flask equipped with a stirring

  of a thermometer, a refrigerant and a cooling heating system, we introduce

  50.3 g (0.2 mol) of cyclohexyl (5-chloro-N-methylamine)

  no-2 phenyl) ketone and 450 ml toluene. The reaction medium is placed under an inert atmosphere and, with stirring, 23.7 g (0.21 mol) of chloroacetyl chloride are added over about 15 minutes. The toluene is refluxed for one hour, concentrated to dryness and then the residue is taken up in a mixture consisting of 1 ml of diisopropyl ether and 100 ml of absolute ethanol.

  With stirring, the mixture is cooled to -10.degree.

  pension obtained, the precipitate is filtered and rinsed

  with 50 ml of a mixture 1: 1 diisopropyl ether / -

  ethanol. After drying, 57.6 g of 2-chloro-N- (4-chloro-cyclohexyl-2-carbonylphenyl) -N-methylacetamide (purity: 96.) are obtained which can be purified by

passage on a silica column.

M.p .: 98 ° C

  Spectrum R.M.N. (CDCl3): 7.7-7 ppm (m, 3H); 3.5 ppm (d, 2H); 3,2 to

  2.6 ppm (m, 4H); 2 to 1 ppm (m, 10H) ..

  b) 7-Chloro-5-cyclohexyl-1-methyl-2-oxo-2,3-dihydro-1H-benzotriziazepine1,4

  In a one-liter flask equipped with a stirring

  of a refrigerant, a thermometer and a cooling heating system, we introduce

  16.4 g (0.05 mole) of 2-chloro-N- (4-chloro-cyclohexyl)

  2-hexylcarbonylphenyl) N-methylacetamide, 14.7 g (0.105 mol) of hexamethylenetetramine and 328 ml of methanol. The reaction medium is stirred and added

  28.5 ml of water and 1.4 ml of hydrochloric acid

  center. Refluxed for 20 hours and then concentrated in vacuo. The residue is taken up in 250 ml

  of water and extracted with 3 times 250 ml the dichloro-

  methane. We combine the organic phases, we dry them

  and concentrated with a rotary evaporator.

  In this way, we obtain 14.6 g of chlorine

  5-cyclohexyl-1-methyl-2-oxo-2,3-dihydro-1H-ben-

  1,4-diazepine-1,4, as a crystalline solid,

  83X titration in liquid chromatography with

external correspondence.

  Yield: 82Z By passage over a silica column, it is possible to

purify this compound.

M.p .: 150'C

  Spectrum R.M.N. (CDCl3): 7.6-7.1 ppm (m, 3H); 4.9 ppm (d, 1H); 3.6 ppm (d, 1H); 3.3 ppm (s, 3H); 2.5-2.9 ppm (m, 1H); 2.2-0.8 ppm (m, 1OH).

EXAMPLE III

  Preparation of 7-chloro (cyclohexen-1-yl) -5 methyl

  1H-benzyl-1,4-dihydro-1,2-dihydro-1,2-dihydro-1,4-difluoroacetamidine N-4-bromo-N- (4-chloro-2-cyclohexylcarbonylphenyl) N-methylacetamide

  In a 250 ml flask equipped with a refrigerator

  From a thermometer, a stirrer and a heating system, 82 ml of toluene and 13.8 g (0.055 mole) of cyclohexyl (5-chloro-N-methylamino-phenyl) ketone are introduced. Then add in 10

  minutes, 5.2 ml (0.06 moles) of bromoacetyl bromide.

  The temperature of the medium increases from 20 to 35 ° C. After stirring for 15 minutes, the medium is poured into 100 ml of a saturated solution of sodium bicarbonate and then

  we decant. The toluene solution is dried over sodium

  sodium fate and concentrated under reduced pressure

  which provides 23.4 g of a yellow powder. After-

  on a silica column, the bromo-2-N

  (4-chloro-2-cyclohexylcarbonylphenyl) N-methylacetate

mide with a yield of 90Z.

M.p .: 100'C

  Spectrum R.M.N. (CDCl 3: 7.75-7.3 ppm (m, 3H), 3.95 and 2.65 ppm (d, s, 2H), 3, 45 and 3.15 ppm (2s, 3H); , 7 ppm (m, 1H);

2-1.1 ppm (m, 10H).

  b) 2-Bromo-4-t-chloro (1-bromo-cyclohexyl) -

  2-carbonylphenyl-N-methylacetamide

  In a 100 ml flask equipped with a stirring

  refrigerant, a thermometer and a cooling heating system, 48 ml of dry dichloroethane and 11.9 g (0.032 mol) of

  2-bromo-N- (4-chloro-2-cyclohexylcarbonylphenyl) N-methyl-

  thyl acetamide. 1.76 ml (0.035 moles) of bromine are added and the mixture is refluxed for about 5 minutes until the medium is decolourised. After cooling, the medium is poured into 50 ml of a saturated aqueous solution of sodium bicarbonate and then decanted. The organic phase is dried over sodium sulphate and evaporated under reduced pressure, which gives 14.67 g of a thick yellow paste. After passing on a column of

  silica, 2-bromo-N-Echloro-4 (bromo-1-cyclohexyl) is isolated

  hexyl) 2-carbonylphenyl N-methylacetamide in pure form. Yield: 85Z

P.F. = <50'C

Spectrum R.M.N. (Cdc13):

  8.2-7 ppm (2m, 3H); 3.80 and 3.65 ppm (d, s, -

  2H); 3.35 and 3.05 ppm (2s, 3H); 2.5-1 ppm (m, 10H).

  (c) 2-Bromo-N-4-chloro (1-cyclohexen-1-yl) -carbonyl-phenyl) -N-methylacetamide In a 25 ml flask, 5 ml of anhydrous N, N-dimethylformamide, 0.450 g (0.00099 mol) of 2-bromo-N-Echloro4 (1-bromo-cyclohexyl) -2-carbonylphenyl-N-methylacetamide, 0.214 g (0.0029 mol) of lithium carbonate and 0.020 g (0.0005 mol) of lithium chloride. The medium is heated to 60 ° C.

  yellow for 30 minutes and then cooled

  said at room temperature. It is then poured into 20

  ml of water and 25 ml of dichloromethane and decanted.

  The organic phase is dried over sodium sulphate and then concentrated under reduced pressure, which gives 0.340 g of a yellow powder. By passage over a silica column, 2-bromo-N-Echloro4 (cyclohexen-1) is obtained.

  yl) pure 2-carbonylphenyl-N-methylacetamide.

  Yield: 88 / NMR Spectrum (CDCl3): 7.6-7.2 ppm (m, 3H); 6.55 ppm (m, 1H); 3.85

  ppm (s, 2H); 3.1 ppm (s, 3H); 2.5-1.5 ppm (2m, 8H).

  d) Chloro-7 (cyclohexen-1-yl) -5-methyl-2-oxo-2,3-dihydro-1Hbenzolfydiazine-1,4 This compound was obtained from 2-bromo-4-chloro (cyclohexen-1-yl) carbonyl -2 phenyl N methyl

  acetamide, according to the method of Example Ie.

Claims (11)

  1. Cyclohexyl phenyl ketone derivatives of the general formula: R   R 1 -NH wherein R represents an alkyl radical having 1 to 4 carbon atoms and R 1 represents an atom hydrogen or halogen.   Cyclohexyl phenyl ketone derivatives according to claim 1, wherein R1 represents a hydrogen atom or chlorine atom.   3. Cyclohexyl (5-chloro-N-methylamino-2-phenyl) ketone.   4. Cyclohexyl (N-methylamino-2-phenyl) -   ketone. 5. Process for the preparation of cyclohexyl phenyl ketone derivatives according to claim 1, characterized in that an isatoic anhydride derivative of general formula R is reacted. N I0   R1 in which R and R1 have the same meaning as   in claim 1 with an organometallic derivative   of the general formula: III in which M represents a radical -MnX or -Cu-MgX I S-R4   in which X represents a halogen atom and R4   represents an aryl group, and then hydrolyzes the.   complex obtained to obtain the desired compound.   6. Process according to claim 5,   characterized in that M represents a -MnCl radical.   7. Process for the preparation of 1,4-benzo [1,4-diazepine derivatives of the general formula: R 0   ## STR1 ## where R is an alkyl radical having   1 to 4 carbon atoms, R2 represents a halogen atom,   and R represents a cyclohexyl or cyclohexen-1-yl radical, characterized in that: A. to obtain a compound of formula Ia wherein R3 represents the cyclohexyl radical, a) a cyclohexyl phenyl ketone derivative is reacted according to claim 1 when R1 represents hydrogen, with an acetyl halide of general formula where X-CH 2-C-X 'V   where X and X ', which are the same or different,   each represents a halogen atom, the reaction taking place in a suitable solvent and at a temperature between room temperature and   the reflux temperature, to obtain a derivative of   acetyleneacetide of the general formula: RO 0 gl "-N-C-CH2X   -Cj = o v I in which R and X have the same meaning as   previously, acetyl halide derivatives of   mule VI, which is subsequently treated by means of a   halogen in a suitable solvent and at a temperature   between room temperature and   reflux temperature, which provides a friendly derivative   no-2 halogeno-phenylcyclohexyl ketone of the general formula: R O 305-N-C-CH X 310_ C-O VII   Wherein R 1, R 2 and X have the same meaning as above, or - when R 1 represents a halogen atom, with an acetyl halide of formula V, the reaction taking place in a suitable solvent and at a temperature of   between room temperature and temperature   reflux, to obtain a 2-amino-2-amino derivative   corresponding 5-phenenocyclohexyl ketone of formula VII, b) the compound of formula VII is cyclized at room temperature and in a solvent suitable for   hexamethylenetetramine and in the presence of   ammonium bonate or an acid, which provides the desired 1,4-benzoifl diazepine derivative of formula Ia wherein R3 represents the cyclohexyl group and B. to obtain a compound of formula Ia wherein R3 represents the radical cyclohexen-1 yl   c) reacting the benzo / f / diol derivative   1,4-zebra of formula la wherein R 3 represents the cyclohexyl radical, at room temperature and in a suitable organic sovant with an N-halogenated derivative, in particular an N-halogenated derivative of a carboxylic or sulfonic imide to obtain a halogeno (cyclohexyl) -5-oxo-2-dihydro-2,3H-benzof.7diazepine-1,4 derivative of the general formula: R f__C0 NC CH2 N VIII c4 R2 Y   in which R and R 2 have the same meaning as above and Y represents a halogen atom, and   d) the (halo-1-cyclohexyl) derivative is   hexyl) -5-oxo-2,3-dihydro-1H-benzoúf.diazepine-1,4 of formula VIII to the action of lithium carbonate in the presence of a lithium halide, the reaction taking place in a suitable solvent and at a temperature of between 50.degree. C. and 120.degree. C., which provides the desired 1,4-benzotriziazepine derivative of formula Ia in   which R3 represents the cyclohexen-1-yl group.   8. Process for the preparation of benzorf] diazepine-1,4 derivatives of the general formula R N-C CH2 / 2 C = N R2 I   in which R represents a lower alkyl radical having from 1 to 4 carbon atoms and R 2 represents a halogen atom, characterized in that: a) a cyclohexyl phenyl ketone derivative is reacted according to claim 1: when R 1 represents hydrogen, with an acetyl halide of the general formula: X-CH 2-C-X 'V 2V   wherein X and X ', which are the same or different   each represents a halogen atom, the reaction taking place in a suitable solvent and at a temperature between room temperature and reflux temperature, to obtain an acetyl halide derivative of the general formula: RO wherein R and X have the same meaning as above, derived from acetyl halide which is subsequently treated with a halogen such as chlorine. or brominated in a suitable solvent and at a temperature between room temperature and reflux temperature, which provides a 2-amino-5-halo phenyl cyclohexyl ketone derivative of general formula: RO y Il N-C-CH 2 X / \ / C = O R2 VII   Wherein R, R and X have the same meaning as above, or when R 1 represents a halogen atom, with an acetyl halide of formula V, the reaction taking place in a suitable solvent and at a temperature   between room temperature and temperature   reflux, to obtain a 2-amino-halogen derivative   corresponding geno-5-phenyl cyclohexyl ketones of formula VII, b) treating the 2-amino-5-halogeno phenyl cyclohexyl ketone derivative of formula VII with a   halogen in a suitable solvent and at a temperature of   between room temperature and temperature.   reflux temperature, which provides a halogen derivative   geno-1 cyclohexyl ketone of the general formula: R 0 C = R lx R2 IX   in which R, R2, X and Y have the same meaning as above,   c) the halo-1-cyclopropyl derivative is   hexyl ketone of formula IX with the action of an agent   the reaction taking place in an approved solvent.   and at a temperature between 50 ° C and * C, which provides a cyclohexenyl ketone derivative of the general formula: RO I i1 -N-C-CH 2 X -C = O X R22   in which R, R2 and X have the same meaning as above, and   d) the cyclohexane derivative is finally   xenyl ketone of formula X at room temperature and   in a suitable solvent, using hexamethylene   tetramine and in the presence of ammonium carbonate or   of an acid, which provides the desired compound.   9. Process according to claim 7 or 8, characterized in that X represents chlorine or bromine.   10. The method of claim 8, wherein   in that the basic agent is a carbonate of   alkali metal, optionally in the presence of a halogen   lithium nickel, an alkali metal bicarbonate or amine. 11. Process according to claim 7 or 8, characterized in that R represents a methyl radical   and R2 represents a chlorine atom.