FR2620449A1 - PROCESS FOR THE PREPARATION OF BENZODIAZEPINE-1,4 ONE-2 DERIVATIVES - Google Patents

Abstract

The invention relates to the preparation of derivatives of 2-oxo-2,3-dihydro 1H-benzo [f] diazepine-1,4 of general formula: (CF DRAWING IN BOPI) in which R represents hydrogen or a C1 -C4 alkyl radical, R1 represents a C1 -C4 alkyl, phenyl or C3 -C8 cycloalkyl radical, and R2 represents a halogen atom or a nitro radical, characterized in that one reacts a dihalo -5,7 oxo-2-dihydro-2,3 1H-benzo [f] diazepine-1,4 of the general formula: (CF DRAWING IN BOPI) in which R and R2 have the same meaning as above and X represents an atom d 'halogen, with an organometallic derivative of general formula: R1 -M in which M represents a -MnX' or -Cu-MgX 'radical in which X' represents a halogen atom and R3 represents an aryl group, then the complex formed.

Description

The present invention relates, in general, to a new

preparation process

  benzodiazepine-1,4-one-2 derivatives.

  More specifically, the invention relates to a new process for the preparation of oxo-2 derivatives.

  1,4-dihydro-1H-benzofluidazepine-1,4, of general formula

neral: I H2 C..N

R I

  in which R represents hydrogen or a C 1 -C 4 alkyl radical, R represents a C 1 -C 4 alkyl radical;

  C1-C4, phenyl or C3-C8 cycloalkyl and R2 represents

  a halogen atom or a nitro radical,

  preferably a chlorine or bromine atom.

  In this context, we mean

  "C 1 -C 4 alkyl aliphatic hydrocarbon radicals.

  saturated, linear or branched ticks containing up to 4 carbon atoms such as methyl, ethyl,

  n-propyl, isopropyl, n-butyl, isobutyl or tertiary

butyl.

  The compounds of formula I are particularly

  particularly useful as sedating agents of the

  central nervous system which have been described in Special Patent No. 4206 M.

  Some of these compounds are furthermore

  interesting in the synthesis of other 2-oxo-2,3-dihydro-1Hbenzoulffdiazepine-1,4 derivatives including the compounds of formula I above wherein R1 represents a cycloalkyl radical, in particular cyclohexyl. For example, the compounds of formula I wherein R is hydrogen or methyl, R1 is cyclohexyl and R2 is chlorine, are particularly useful for the final synthesis of "tetrazepam" or

  chloro-7 (cyclohexen-1-yl) -5 methyl-1 oxo-2-dihydro-

  2,3 1H-benzoCf7diazepine-1,4, a compound known for its

  valuable muscle relaxant properties.

  FR-A-2,294,708 discloses a process for the preparation of 3-oxo-3-fluoro-2,3-dihydro-1H-benzoulfdiazepine-1,4 substituted in the 5-position by

an aromatic group.

  According to this process, the benzodiazepine derivatives in question are prepared by reaction of an oxo-2

  3-fluoro-5-halo-2,3-dihydro-1H-benzo (diazepine)

  1,4 with aryl metal or pyridyl metal such as aryl or pyridyl lithium or aryl magnesium halide

or pyridyl magnesium.

  Attempts have been made to prepare the compounds of

  mule I, according to the method of this French patent, in particular chloro7-cyclohexyl-5-methyl-1-oxo-2,3-dihydro-1H-benzoif-diazepine-1,4 for the final synthesis of tetrazepam. For this purpose, the 5-dichloro-1-methyl-2-oxo-2,3-dihydro-2

  1H-1,4-benzoifldiazepine with cyclohexyl chloride

  hexyl magnesium in tetrahydrofuran. According to this method, only a maximum of 10X was obtained in

desired product.

  It has been discovered, however,

  In this invention, it is possible to prepare the compounds of formula I. In particular chloro-7

  5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzoLfdiazepine

  1,4-and 7-chloro-5-cyclohexyl-1-methyl-2-oxo-di-hy-

  1H-2,3-benzorfydiazepine-1,2-d, according to an industrial process providing high yields, from a derivative of 2-oxo-2,3-dihydro-1H-benzo / f / diazepine-1, 4 using an organomanganese derivative

or organocuprate.

  Thus, the process of the invention for the preparation of the compounds of formula I consists in

  react, a dihalogeno-5,7-oxo-2-dihydro-2,3-H-benzo

  / f / diazepine-1,4 of the general formula:

R /

R

C II

C

2 X

  in which R and R 2 have the same meaning as before and X represents a halogen atom, such as chlorine or bromine, with an organometallic derivative of general formula:

R1-M III

  in which M represents a radical -MnX 'or Cu-MgX' I

S-R3

  in which X 'represents a halogen atom, such as chlorine or bromine, and R3 represents an aryl group,

  such as, for example, phenyl, then to hydrolyze the compound

  plex obtained to obtain the desired compound.

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

  conventional implementations of organometallic derivatives

  that is, in an anhydrous ether such as tetra-

  hydrofuran, dibutyl ether or dioxane and at a temperature between -40 ° C and room temperature. Similarly, the hydrolysis of the complex can be carried out according to known procedures, for example

  medium of an aqueous solution of ammonium chloride.

  The implementation of organomanganeux or

  organocuprates, according to the invention, instead of

  Corresponding ganolithians or organomagnesium compounds make it possible to obtain, by a notable increase, the yields of compounds of formula I. For example, in the case of 7-chloro-5-cyclohexyl-1-methyl-2-dioxo-2,3-dihydro-1Hbenzo-1,4-difdepepine yields have gone from

at 851.

  The compounds of formula II are known products which have been described in patent FR-A-1 485 645 or which can be prepared according to the process which is there

described.

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

R1-M 'IV

  in which R has the same meaning as above

  and M 'represents a lithium atom or a radical -MgX' in which X 'has the same meaning as above, by means of a manganese salt such as a halogenide, 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: R3-SH + n-C4H 9Li> R3-SLi R3-S-Li + CuX ')> R-S-Cu R-S-Cu + R1HgX' -R -Cu -MgX 3 1 It

S-R3

  X 'having the same meaning as before.

  The method of the invention can be implemented according to different procedures. For example, in

  where the use of a gold derivative is envisaged

  In one embodiment of the invention, the compound of formula III may be employed in one of the following embodiments: the magnesium derivative of formula IV is added to a suspension of manganese salt in an ether and, after formation of the manganese derivative, the compound of formula II to the clear solution obtained, - addition of the magnesium derivative of formula IV to a solution of manganese salt / lithium salt 1: 2 in an ether, for example a solution of manganese chloride / lithium chloride 1: 2 and then added of

  compound of formula II to the manganese derivative solution.

  nous. The manganese salt forms a suspension in ether such as tetrahydrofuran. In this case, the lithium salt has the effect of homogenizing the medium until a solution is obtained, adding the magnesium derivative of formula IV to a mixture of compound of formula II and of manganese salt in an ether. It is possible, in this case,

  to use only a minimum amount of salt of man-

  ganesis, for example 0.1 equivalent per equivalent of compound of formula II. The addition will however be done in such a way that the reaction medium does not contain

  no magnesian derivative of formula IV in excess.

  As indicated previously, chloro-7 cy-

  5-clohexyl-2-oxo-2,3-dihydro-1H-benzotfdiazepine-1,4, when used as an intermediate compound, can give access including tetrazepam. For this purpose, the method described in

  patents FR-A-1 455 048 and FR-A-1 545 694.

  According to this method, the benzodiazepine derivative in question is subjected to the action of an N-halogenated derivative of a carboxylic or sulphonic amide, by

  N-chlorosuccinimide, for example, to form chloro-

  7 (1-chloro-cyclohexyl) -5-oxo-2,3-dihydro-1H-benzoate

  -4-diazepine-1,4 which is treated, hot, with a mixture of lithium carbonate and lithium bromide and then with methyl iodide in the presence of

sodium methoxide.

  The following nonlimiting examples illustrate

process of the invention.

EXAMPLE 1

  Preparation of 7-chloro-7-cyclohexyl-1-methyl-2-oxo-2,3-dihydro-1H-benzoyl-1,4-diazoin-1,4 In a 50 ml three-necked flask, 1.51 g were suspended in 15 ml of dry tetrahydrofuran.

  (0.012 moles) anhydrous manganese chloride. We are

  The medium is cooled to 0 ° C. under an inert atmosphere (argon) and 7.75 ml (0.012 mole) of a solution of cyclohexylmagnesium chloride, 1.55 M in tetrahydrofuran, are added dropwise. We leave the middle

  under agitation and at O'C for one hour.

  Then, drop by drop, a solution of

  2.43 g (0.01 mole) of 5,7-dichloro-1-methyl-2-oxo-2,3-dihydro-1H-benzo-1,4-diazepine-1,4 dissolved

  in 15 ml of dry tetrahydrofuran, keeping all

  days the temperature of the medium between 0 'and 5'C. The reaction is instantaneous and complete. After hydrolysis of the reaction medium with an ammonium chloride solution, the tetrahydrofuran is removed under vacuum and the residue is taken up in toluene. This toluene phase is washed 3 times with water, it is dried and

  concentrated under vacuum. 2.75 g of

  gross yield (yield: 951). By chromatography on

  silica column, 2.45 g of 7-chloro-cyclohexane are isolated.

  5-hexyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] azide

pine-1.4.

Yield: 85X.

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 to 0.8

ppm (m, 10H).

EXAMPLE 2

  Preparation of 7-chloro-7-cyclohexyl-1-methyl-2-oxo-2,6-dihydro-1H-benzo fide-1,4-diazine In a three-necked flask of 100 ml, placed under an inert atmosphere, 1.26 g (0.01 mol) of manganese chloride are introduced. anhydrous, 0.85 g (0.02 mol) of

  anhydrous lithium chloride and 25 ml of tetrahydro-

  dry furan. Stirred until a solution is obtained

  then the medium is cooled to between 0 ° C and 5 ° C. We add

  to the previous solution, 6.25 ml (0.01 mole) of

  1.6 M cyclohexylmagnesium solution in the tetra-

  hydrofuran maintaining the temperature of the medium between 0C and 5'C and then the solution is left for 30 minutes with stirring. A solution of 19.5 g (0.08 mol) of 5,7-dichloro-1-methyl-2-oxo-dihydro-2,3H-benzofulfidiazepine-1,4 is then added, the temperature always being maintained above 5 ° C. The reaction is instantaneous. After hydrolysis of the reaction medium with an ammonium chloride solution, the tetrahydrofuran is removed under vacuum and the residue is taken up in toluene. This toluene phase is washed 3 times

  with water, dried and concentrated under vacuum.

  2.32 g of crude product are thus obtained (yield:

  Z) which, after recrystallization from isopropyl ether,

  can be used to isolate 1.67 g of 7-chloro-cyclohexane

  5-hexyl-1-methyl-2-oxo-2,3-dihydroxy-1H-benzo [

zépine-1,4.

Yield: 72%.

M.p .: 150'C

  Sepctre R.M.N .: identical to that of

Example 1

EXAMPLE 3

  Preparation of 7-chloro-7-cyclohexyl-1-methyl-2-oxo-2,6-dihydro-1Hbenzo-1,4-diazione-1,4 In a 50 ml three-necked flask placed under an argon atmosphere, 0.12 g (0.001 mole) of manganese chloride was introduced. anhydrous, 2.43 g (0.01 mol) of 5,7-dichloro-1-methyl-2-oxo-2,3-dihydro-1H-1,4-diazepine diazepine and 25 ml of dry tetrahydrofuran. The mixture is stirred and cooled to 0 ° C. 6.25 ml (0.01) are then added dropwise over 1 hour.

  mole) of a 1.6 M solution of cyclohexyl chloride

  magnesium in tetrahydrofuran maintaining the temperature of the medium at 0 ° C. At the end of the addition, we

  keep stirring for 30 minutes,

  lyse the reaction medium with a chlorine solution

  In the presence of ammonium chloride, the tetrahydrofuran is removed in vacuo and the residue is taken up in toluene. This toluene phase is washed 3 times with water, dried and then concentrated in vacuo. 2.61 g of crude product are thus obtained (yield: 92%). After passing on

  column of silica, 2.03 g of 7-chloro-cyclohexane are isolated.

  5-hexyl-1-methyl-2-oxo-2,3-dihydro-1H-benzolfydiazole

pine-1.4. Yield: 70Z

M.p .: 148 ° C

  R.M.N .: spectrum identical to that of

Example 1

EXAMPLE 4

  Preparation of 7-chloro-7-cyclohexyl-1-methyl-2-oxo-2,6-dihydro-1H-benzo-1,4-diazepine To 1.77 g (0.016 mol) of thiophenol in 15 ml of tetrahydrofuran is added, under

  of argon and at -10 ° C., 8 ml of a solution of n-butyllithium

2M thium in cyclohexane.

  The medium is left stirring at -10 ° C. for 10 minutes and then allowed to return to

  ambient temperature. With the aid of a syringe,

  then add this solution, at the temperature of

  + 10 ° C., to a suspension of 3.05 g (0.016 mol) of iodine

  copper in 15 ml of tetrahydrofuran. After stirring for 10 minutes at + 10 ° C., the medium is cooled to -40 ° C. and 10 ml (0.016 mol) of a solution of cyclohexylmagnesium chloride (about 1.6M) in

tetrahydrofuran.

  The mixture is left stirring at -40 ° C. for 5 minutes and the temperature is then allowed to rise to O'C in 10 minutes. The suspension of heterocuprate thus obtained is then cooled to -40.degree.

  dropwise, a solution of 3.88 g (0.016 mol) of

  chloro-5,7-methyl-1-oxo-2,3-dihyro-1H-benzo [

  zepine-1,4 in 25 ml of tetrahydrofuran. Allowed to warm to room temperature and hydrolyzed with ammonium chloride solution. The tetrahydrofuran is removed in vacuo and the residue is taken up in toluene. This toluene phase is washed 3 times

  with water, the mixture is dried and then concentrated under vacuum.

  3.65 g of 7-chloro-cyclohexane are thus obtained.

  5-hexyl-1-methyl-2-oxo-2,3-dihydro-1H-benzof-7diazepine-1,4. Yield: 84Z

  An analytical sample can be obtained

  after recrystallization from the isopropyl ether

pylique.

M.p .: 150'C

  N.M.N .: spectrum identical to that of the Ex-

example 1.

EXAMPLE 5

  Preparation of 7-chloro-n-butyl-1-methyl-1-oxo-2,3-dihydro-1H-benzorfldiazole-1,4 In a 50 ml three-necked flask placed under an argon atmosphere, 1.25 g (0.01 mol) of anhydrous manganese chloride suspended in 25 ml of anhydrous tetrahydrofuran. Cool to -10'C and

  3.75 ml (0.0075 mole) of a

  2M n-butyllithium in hexane. The temperature is allowed to return to 0 ° C and the manganous derivative thus prepared is maintained at this temperature for 30 minutes. 1.21 g (0.005 mol) is gradually added

  of 5-dichloro-1-methyl-2-oxo-2,3-dihydro-1H-benzoate

  EfJdiazepine.-11, 4 in 9 ml of anhydrous tetrahydrofuran

  by maintaining the temperature of the reaction medium

  at O'C. At the end of the addition, the medium is left under stirring.

  tation and O'C for 30 minutes. It is hydrolyzed with a solution of ammonium chloride, the tetrahydrofuran is removed under vacuum and the residue is taken up in toluene. This toluene phase is washed 3 times

  with water, dried and concentrated under vacuum.

  After passing through a column of silica, 1 g of

  7-chloro-n-butyl-1-methyl-2-oxo-2,3-dihydro-1H-ben-

  Zolf / Tdiazépine-1,4. Yield: 72Z NMR Spectrum (CDCl3): 7.2-7.7 ppm (m, 3H); 4.6 ppm (d, 1H); 3.7 ppm (d, 1H); 2.9 ppm (s, 3H); 2.85 ppm (t, 2H); 1.9-0.7 ppm (m, 7H).

EXAMPLE 6

  Preparation of 7-chloro-1-methyl-5-ethyl-5-oxo-2,3-dihydro-1H-benzoenzfdiazepine-1,4 In a 100 ml three-necked flask, placed under an argon atmosphere, 2.77 g (0.022 mol) are introduced.

  of manganese choride, 1.87 g (0.044 mole) of chlorine

  lithium chloride and 60 ml of tetrahydrofuran. The medium is maintained under stirring until complete disappearance of the precipitate and then cooled to -5'C. 10 ml of phenyllithium are then gradually added in an ethyl ether / benzene mixture, so as to maintain the temperature of the medium at -5 ° C. and then the medium is left at -5 ° C. with stirring for 15 minutes. 0.73 g is then added to this solution.

  (0.003 moles) of 5,7-dichloro-1-methyl-2-oxo-dihydric

  1,2,3-D-1H-1,4-benzolfydiazepine dissolved in 9 ml of tetrahydrofuran maintaining the temperature of the medium with stirring and 0'C for 30 minutes. It is hydrolysed with a solution of ammonium chloride, the tetrahydrofuran is removed under vacuum and it is resumed.

  the residue in toluene. This toluene phase is washed

  3 times with water, dry and concentrate in vacuo. After purification by chromatography on

  column, 0.435 g of 7-chloro-methyl-1-phenol are isolated.

  5-nyl-2-oxo-2,3-dihydro-1H-benzorfdiazepine-1,4.

  Yield: 50Z NMR Spectrum: 7.8-7.2 ppm (m, 8H); 4.85

  ppm (d, 1H); 3.8 ppm (d, 1H); 3.4 ppm (s, 3H).

Claims (5)

  1. Process for the preparation of oxo-2 derivatives   2,3-dihydro-1H-benzyl-1,4-diazepine-1,4 of general formula ral: 0 I2 R x R I / CN R X C-- N   Wherein R is hydrogen or a C1-C4 alkyl radical, R1 represents an alkyl radical;   C1-C4, phenyl or C3-C8 cycloalkyl, and R2 represents   a halogen atom or a nitro radical,   characterized in that a 5,7-dihalo-5-oxo-2,3-dihydro-1H-benzohefdiazepine-1,4 is reacted with the following general formula: R N -C CH 2 2 X   in which R and R 2 have the same meaning as above and X represents a halogen atom, with an organometallic derivative of general formula: R1 -M   wherein M represents a radical -MnX 'or -Cu-MgX' wherein X 'represents a halogen atom S-R3 S -R3 and R3 represents an aryl group, and then hydrolyzing the formed complex to obtain the desired compound.   2. The process according to claim 1, wherein   characterized in that R represents a hydrogen atom or   a methyl radical and R 1 represents a cyclo radical hexyl.   3. The process according to claim 1, wherein   characterized in that M represents a radical -MnX '.   4. Process according to claim 1,   characterized in that R represents a methyl radical, R represents a cyclohexyl radical and R2 represents a atom of chlorine.   5. Process according to claim 4,   characterized in that X represents a chlorine atom.