CH524608A - Halo-5-alkyl-10-oxo-10,11-dihydrodibenz (b,f) azepines - useful as pharmaceutical intermediates, prepd by cyclisn of 2-methyl-2'-methoxy - Google Patents

Abstract

Cpds. of formula (I): (where R1 = 1-5C alkyl, one X is Cl and the others are H) are prepd. by cyclisation. of a cpd. of formula (II): with lithium diethylamide in a mixt. of anhydrous benzene and P(NMe2)3 at ca -20 degrees C (I) are intermediates for pharmacologically active 10,11-dihydrodibenz b,f azepines esp. the corresp. 10-amino derivs.

Description

  

  
 



  Process for the preparation of dibenzazepine derivatives
 The present invention relates to a process for the preparation of ketones derived from 10,11-dihydro-dibenzo [b, f] azepine of general formula:
EMI1.1
 in which Rt represents an alkyl radical containing 1 to 5 carbon atoms and one of the symbols X represents a chlorine atom, the other symbols X each representing a hydrogen atom.



   According to the invention, the new ketones of general formula (I) are prepared by cyclization of a product of general formula:
EMI1.2
 in which Rt and X are defined as above, by the action of lithium diethylamide in an anhydrous mixture of benzene and hexamethylphosphorotriamide at a temperature of -200 (: approximately.



   The products of general formula (II) can be obtained by carrying out the following series of reactions which all make use of the usual methods in organic chemistry:
EMI1.3
  
EMI2.1

 The 2-methylbenzanilide used as a starting material can be obtained from o-toluidine.



   The 2-methyl-3-chloro benzanilide used as the starting material can be obtained according to the process described by P. Cohn, Monatsh. Chem., 22, 484 (1901).



   The 2-methyl-4-chloro benzanilide used as starting material can be obtained by the usual methods from 2-methyl-4-chloro aniline, the preparation of which has been described by E. Lillmann and C. Klotz,
Ann., 231, 317 (1884).



   The 2-methyl-5-chloro benzanilide used as starting material can be obtained from 2-methyl-5-chloro aniline, the preparation of which has been described by
H. Goldschmidt and M. Honig, Ber., 19, 2440 (1886).



   The 2-methyl-6-chloro-2'carboxy-diphenylamine intermediate can be prepared according to the method described by
O. Hromatka, Monatsh. Chem., 97, 1125 (1966).



   The new ketones of general formula (I) can optionally be purified by the usual methods in organic chemistry such as distillation, crystallization or chromatography.



   The ketones of general formula (I) are useful intermediates for the preparation of pharmacologically active derivatives of dihy dro-10,11 dibenzo [b, f] azepine, in particular amines of general formula:
EMI2.2
 in which Rt and X are defined as above and R and R ', identical or different, represent a hydrogen atom or an alkyl, hydroxyalkyl, hydroxyalkyloxyalkyl or phenylalkyl radical in which the phenyl nucleus is optionally substituted by one or more atoms of halogen and / or alkyl, alkyloxyl, amino or trifluoromethyl radicals, it being understood that the alkyl radicals and the alkyl portions of the various other radicals contain 1 to 5 carbon atoms.



   The following examples show how the invention can be put into practice. The nomenclature of the products used in these examples is based on the following representations:
EMI2.3

X representing a chlorine atom
 Example I
 85 g of 1-chloro-1-methyl-dihydro-10,1 1 dibenzo [b, f] azepinone-10 (mp = 1290 C) are obtained by the action of 206 g of lithium diethylamide dissolved in a mixture of benzene and 'hexamethylphosphorotriamide on 129 g of 2-methyl-3-chloro-2'-methoxycarbonyl-2'N methyldiphenylamine in solution in ether, at - 200 C approximately.



   The starting 2-methyl-3-chloro-methoxycarbonyl-N-methyldiphenylamine can be prepared as follows: - Preparation of 2-methyl-3-chloro-benzanilide (P.F.



   = 170-1710 C) according to P. Cohn, Monatsh. Chem., 22,
 484 (1901).



  - Preparation of 256 g of 2-chlorophenylchloromethy
 6-lenylamino toluene per action of 202 g of penta
 phosphorus chloride on 238 g of 2-methyl-3-chloro
 benzanilide, at approximately 950 C.



     - Preparation of 378 g of chloro-2 (methoxycarbonyl-2
 phenoxy) phenylmethylenylamino - 6 toluene (P.F.



     = 6su C) per action of 174 g of sodium derivative of sali
 methyl cylate, in methanolic solution, on 256 g
 2-chloro-phenylchloromethylenylamino-6 toluene,
 in solution in tetrahydrofuran, at 200 C approx.
 ron.



  - Preparation of 268 g of 2-methyl-3-chloro-methoxy
 carbonyl-2 'N-benzoyldiphenylamine (M.P. = 1250 C)
 by Chapman's transposition, at 205-210 C, 370 g
 2-chloro (2-methoxycarbonyl phenoxy) phenyl
 6-methylenylamino toluene.



  - Preparation of 189 g of N- (2-methyl chloro-3
 phenyl) anthranilic (M.P. = 2100 C) by the action of
 240g of caustic potash on 274.4g of 2-methyl chloro -3 methoxycarbonyl -2 'N - benzoyldiphenyl-
 amine, in dimethylsulfoxide containing 80/0
 of water, 90-950 C.



  - Preparation of 190 g of N- (2-methyl-3-chloro-phenyl)
 methyl anthranilate (M.P. = 70O C) by the action of
   110g of thionyl chloride then an excess of
 methanol on 184 g of N- (2-methyl-3-chloro phe
 nyl) anthranilic, in the presence of 3 yokes of hexame
 thylphosphorotriamide, in chloroform at a
 temperature between 0 and 200 C.



  - Preparation of 165 g of 2-methyl-3-chloro-methoxy
 carbonyl-2 'N-methyldjphenylamine (M.P. = 910 C)
 per action of 24 g of sodium hydride, then 252 g
 of methyl iodide on 195 g of N- (2-methyl-3-chloro
 methyl phenyl) anthranilate, in dimethoxy
 1.2 ethane, at approximately 600 C.



   Example 2
 4.4 g of 4-chloro-5-methyl-10,1-dihydro-dibenzo [b, f] azepinone-10 (mp = 1400C) are obtained by the action of 7.6 g of lithium diethylamide prepared in a mixture of benzene and hexamethylphosphorotriamide at about 200 C, on 6.2 g of 2-methyl-6-chloro-2'-methoxycarbonyl-N-methyldiphenylamine in ethereal solution at - 250 C approximately.



   The starting 2-methyl-2-chloro-2-methoxycarbonyl-N-methyldiphenylamine can be prepared as follows: - Preparation of 2-methyl-6-chloro-2-carboxy-diphe
 nylamine (m.p. = 2100 C) according to O. Hromatka et al.,
 Monatsh. Chem., 97, 1127 (1966).



  - Preparation of 10.3 g of 2-methyl-6-chloro-methoxy
 2 'carbonyl diphenylamine (M.P. = 930 C) per action
 6.9 g of thionyl chloride in the presence of
 10.4 g of hexamethylphosphorotriamide, then a
 excess anhydrous methanol in the presence of 10.4 g
 of hexamethylphosphorotriamide, on 11.4 g of me
 2-thyl-6-chloro-2'carboxy-diphenylamine, in the
 chloroform, respectively at approximately 00 C and 200 C
 about.



  - Preparation of 8.15 g of 2-methyl-6-chloro-methoxy
   carbonyl -2 'N - methyldiphenylamine (M.P. = 660 C)
 per action of 2.4 g of sodium hydride then
   12, read of methyl iodide on 9.65 g of 2-methyl
 6-chloromethoxycarbonyl-2 'diphenylamine, in the
   1,2-dimethoxyethane at approximately 700 C.



   By operating in the same way, from suitable raw materials, the following ketones can be obtained: - 3-chloro-5-methyl-10,11-dihydro dibenzo [b, f]
 azepinone-II, melting at 1620C; - 4-chloro-5-methyl-10,11-dihydro dibenzo b, f]
 azepinone-ll melting at 800C; - 2-chloro-5-methyl-10,11-dihydro dibenzo [b, f]
   azepinone- 10, mp 1460 C; - 3-chloro-5-methyl-10,11-dihydro dibenzo [b, f]
 azepinone-10, melting at 1300 C; - 2-chloro-5-methyl-10,11-dihydro dibenzo [b, f]
   azepinone-ll, melting at 1060 C.

 

Claims (1)

CLAIM Process for preparing a ketone derived from 10,11-dihydro-dibenzo [b, f] azepine of general formula: EMI3.1 in which R1 represents an alkyl radical containing 1 to 5 carbon atoms and one of the symbols X represents a chlorine atom, the other symbols X each representing a hydrogen atom, characterized in that a product of general formula: EMI3.2 by the action of lithium diethylamide in an anhydrous mixture of benzene and hexamethylphosphorotriamide at a temperature of about - 200 C.