Note: Descriptions are shown in the official language in which they were submitted.
10~S;~8
BACKGROUNl) )F THE INVENTI(-)N
The pre~ent invention r-late~ to a proce~s for pre-
paring 2-halomethyl-1,4-benzodiazepine~ corresponding to the
following formula I:
f
R3 1~ N--C j
~ R2
and acid addition compounds thereof, whereln
Rl represents an alkyl group having from 1 to 4 car-
bon atoms,
R2 represents a hydrogen atom, a halogen atom or a
trifluoromethyl group,
R3 repre~ents a hydrogen atom or a halogen atom, and
~-~ X represents a chlorine or bromlne atom.
Particularly ~uitable halogen atom~ for R2 and R3 are
}~ fluorine, chlorine and bromine. The alkyl groups r~presentod by
; Rl are principally methyl, ethyl, propyl, isopropyl, butyl and
econdary butyl groups.
Compounds of the abovo formula I are described
in the published specification of Canadian Letters Patent
984,388 . Those substances possess valusble pharmacological
propertiss which characterise them as tranquilizer~. Addi-
.; . .; . , .
tional}y, those compounas are useful intermediates for thepreparation of other substances whlch have anticonvul~lve,
dative, muscle-relaxing, anxiety-relieving and anti-aggressive
propertles for use ln the treatm nt of psychically di~turbed
'~ ', '
. ~
lO~S;~
patients. According to Canadian Letters Patent No. 984,388
such useful derivatives can be obtained from compounds of the
general formula I above, for ex~mple, by replacing the X group
by various other group3, ~uch as hydroxyl, alkoxy, cyano, and
amino groups. Furthenmore, the compound~ corresponding to the
general formula I can be converted accordlng to Canadian
Letters Patent 1,008,857 by suitable oxidant~ into lactams
having the following formula Il~
~1 :'
R3 ~ C - N II
,.
wherein Rl, R2 and R3 are as previously defined. These com- -;
pounds include substances of accepted therapeutic util~ty, such
as, for example, 7-chloro-2H-1,3-dihydro-1-methyl-5-phenyl-1, -
4-benzodiazepin-2-one.
It will now be understood that the 2-halomethyl-1,4-
benzodiazepines of general formula I have extremely useful
properties and are particularly ~uitable for the preparation of
other valuable pharmaceutical products.
According to the teaching of Canadian~Letters
Patent No. 984,388, the 2-halomethyl-1,4-benzodiazepines of
:~ formula I can be produced by cyclising acyldiamines having the
following formula III:
2 OH
-C-NH-CH2-1H-CH2-N ~ R3 ` III
Rl :
- 2 -
- 10~8S28
wherein Rl, R2 and ~3 are as previously defined, using cycli-
sing a~ents, such as phosphorus oxyhalides alone or in mixture
with phosphorus pentoxide or phosphorus pentachloride at tem-
peratures of between 100 and 150C Under the stated reaction
conditions, cyclisation accompanied by ring contraction occurs
and th~ hitherto unknown 1,4-benzodiazepines of the above gen-
eral formula I substituted in the 2-position are obtained
SIJ MMARY OF THE INVF~NTION
It has now been found that the 2-halomethyl-1,4-
benzodiazepines of formula I can also be obtained by a two-
stage process which involves first reacting an acyldiamine
corresponding to formula III
R2 OH
~; <\ ~ ~ NH-CH2-CN-CH2-N ~ R3
~ ' ' . .
wherein Rl, R2 and R3 are as already defined, with a phosphorus
halide, such ~- phosphoru~ pentachloride and phosphoru~
pentabromide, in an inert solvent, such as benzene, toluene,
carbon tetr~chloride, 1,2-dichloroethane or chloroform, at the
boiling point of such a ~olvent so a8 to form an imidoyl
halide corresponding to the follow~ng formula IV - ~-
R2
~ ~ T N-CH2 CH C~2 7 ~ R3 IV
~
X R
wherein X repr-scnt- a c~lorine or bromine atom driYing off the
.
~olvent and the pbos~horu- oxyhalide which is formed, and then -`
dissolving the r~ulting residue ~n a suit~ble inert solvent,
~H such as nitromethan~, nitroethane, tetramet~ylene sulphone
preferably nitrobenz~ne, ~nd cycli~ing the imidoyl halide of
:;
~ ~ 3 ~
~., .
10l~S;~8
formula IV in the presence of a Lewis acid which can be used as
a Friedel-Crafts catalyst, such as boron trifluoride, boron
trichloride,aluminum chloride, aluminum bromide, titanium '
tetrachloride, tin tetrachloride, antimony pentachloride,
iron(III) chloride or zinc chloride, at a temperature of from
about 20C and about 80C, and finally isolating the 2-halo-
methyl-1,4-benzodiazepine of formula I in the form of the
base or an acid addition compound thereof.
The further working up of~ the reaction products and -
the isolation and purification of the 2-halomethyl-1,4-benzo-
diazepines of formula I can be carried out in a conventional
manner. For instance, the reaction solution may be decomposed -
by the addition of ice, and the organic phase separated from
the aqueous phase. From such an organic phase, the hydrochlo--
ride of the product can then be extracted using dilute hydro-
chloric acid. The free base can be separated from these solu~
- tions by adding a solution of sodium hydroxide until thé reac-
tion is alkaline.
; For further purification, the 2-halomethyl-1,4-benzo-
diazepine of formula I can be dissolved in a suitable solvent,
such as ether, the solution washed with a saturated solution of
common salt, the solvent distilled off, the residue taken up
~ .
in a suitable solvent, such as acetone, and the corresponding
hydrochloride precipitated by adding a solution of gaseous HCl
in ether. The hydrochloride may then be further recrystallised
~. ~
from a suitable solvent, such as ethanol, isopropanol, acetone
or ethyl acetate or from a mixture of such solvents.
For the purpose of purifylng the raw base o~tained as
described above, an alternative would be a conventional chroma-
3~ tographic separation on 10 to 30 times the quantity of alumina
.
1~8S;~8
or silica gel of suitable activity with a solvent ~uch a8 benzene,
toluene, ether or chloroform.
It is also within the scope of this in~ention to per-
form the halogenation of the acyl diamines of formula III to the
imidoyl halides of formula IV in two stages. This can be done by
converting an acyl diamine corresponding to formula III~
~2 OH
C-NH-CH2-CH-CH2-N ~ 3 III
Rl
at a temperature of from about 20C to about 80C into a corres-
ponding haloacyldiamine corresponding to the following formula
V: R2 X
~C-N~-C~2-1~-C~2-~ V
O . Rl : `
in which Rl, R2,-R3 and X are as hereinbefore defined, using a
; halogenation agent, such as phosphorus oxychloride, phosphorus
-~ trichloride, thionyl chloride, phosphorus oxybromide and phos- -~-phorus tribromide, in an invert solvent, such as benzenè, toluene,
xylene or 1,2-dichlor~ethane, or in an excess of such a halogena-
-~ ` tion agent, and removing the halogenation agent and the solvent
by distillation. The haloacyldiamine residue is then treated
with a phosphorus halide, such as phosphorus pentachloride or
:
phosphorus pentabromide, to form the corresponding imidoyl
halide of formula IV. For this reaction`, 1,2-dichloroethane,
, . ~
carbon tetrachloride and chloroform are especially suitable
sol~ents and temperatures between about 20C and the boilinq
point of the solvent may be maintained.
- 5 -
8S28
One ~dvantage of this procedure ls that ~t per,mits
secondary products to be removed by an intermediate purific~-
tion of the haloacyldiamine, for example, by recrystallization ~,
from a suitable solvent.
Compared to the process described in German PatentApplication No. 2,221,558, the process of th~ invent~on has
the advantage that it can be performed at lower temperatures
and more quickly. Generally, the cyclisation will require from ~ '
about two to about four hour~. The reaction time is conse- ,
quently as much a8 twenty hours less than that of the previous~
; ly proposed proce~s and gives rise to fewer undesirable secon-
~ dary reactions which reduce the yield. This can be demonstra-
i~ ted in a convincing manner by the following comparison of -
yields. For example, if an acyldiamine having the followinq
formula VI: ~ OH '~ ~'
~C~NN~c~2_1~ C~2 1 ~ Cl VI
is cyclised to form the corresponding 1,4-benzodia~epine
derivative having the following formul~ VII:
` ~: f 3 ~ 2Cl
Cl ~ > CH2
, C ~ N VII
F
by the method de~cribed in ~erman P~tent Application No.
. ~ ~
'~ 2,221,SS8, the product i~ obtained ~ith a yield of 25.5~.
By contrast a y~eld of 50~2~, l.e~ twice thQ ~bovo, i~ obtained
~,.
. .,~;
10~8~;~8
by the proce~s according to thl~ invention as hereinafter
specifically de~cribed ~n Example 1.
The proces~ of this invention will now be described
in more detail and merely by way of illu~tration in the
following Examples.
Example 1
20 g of Nl-(2'-fluorobenzoyl)-N2-methyl-~2-(4'-chlorophenyl)-
-2-hydroxy-1,3-diaminopropane having a melting point between lOS
and 107C were dissolved in 100 ml of 1,2-dichloroethane and
the resulting solution was refluxed for two hours with 12.6
g of phosphoruQ pentachloride. The solvent and the phosphoru~
oxychloride which was formed were then distilled off in vacuo.
The resulting residue was then dissolved in 100 ml of
nitrobenzene and heated at 70 to ?5C for four hours after 16.6
g of aluminum chloride had been added.
After cooling, the reaction solution wa~ poured onto
a mixture of 100 g of ice and 100 ml water and then diluted
~ with 200 ml of ether. After the addition of 50 ml of concen-
,~ trated hydrochloric acid, the layers were separated and the
organic phase waæ extracted three times each with 50 ml of
10% hydrochloric acid. The combined aqueous hydrochloxic solu-
tions were then extracted with 100 ml of ether and next ren-
dered alkaline by the addition of a 25~ solution of caustic
oda while being cooled with ice. The separated base was then
t~ken up in 200 ml of ether, washed with a saturated solution
of common salt and dried o~er 90dium ~ulphate. After the
~ solvent had been distilled off, 15 g of residue remained and
-~ that residue wa~ then dissolved in acetone and treated with a
solution of HCl ga~ in ether. T~e precipitated hydrochloride
was next recrystallised from acetone. 11.1 g corresponding to
~ _ 7 _
. .
, .,
1~8S;~8
a yield of 50.2~ of 7-chloro-1-methyl-2-chloromethyl-5-
(2'-fluorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydro-
chloride were obtained. The product had the followin~ phy~i-
cal properties:
Melting point: 220 - 222C
~R-spectrum ~in KBr):- æ ~ t 2200-3000 cm 1
C'N : 1621 cm 1
W -spectrum (~n alkaline CH30H):- ~ = 236 m~
max
~ = 269 m~
max
- 366 m~
max
According to German Patent Application No. 2,221,558,
a derivati~e of thi~ compound melts between 161 and 165C.
~ Example 2
.t~ Nl-(2'-chlorobenzoyl)-N2-methyl-N2-(4'-chlorophenyl)-
2-hydroxy-1,3-diaminopropane having a melting point between
113 and 115C was halogenated using phosphoru~ pentabromide
~: in 1,2-dichloroethane ~nd cyclised u~ing aluminum bromide in
i~ ., .
nitrobenzene in the manner described in Example 1 to give 7-
chloro-l-methyl-2-bromomethyl-S-(2'-chlorophenyl)-lH-2,3-
dihydro-1,4-benzodiazepine hydrochloride having ~ melting point
of 186 to 188C.
Example 3
~: Nl-~2'-tr$fluoromethylbenzoyl)-N2-methyl-N2-(4'-
chlorophenyl)-2-hydroxy-1,3-diam~nopropane havin~ a mel~ing
point between 107 and 109C wa~ halogenated using phosphorus
pentachloride in 1,2-dichloroethane and cyclised using alumin-
1~`
um chloride in nitrobenzene in the manner de~cribed in Example
1 to give 7-chloro-1-methyl-2-chloromethyl-5-t2'-trifluoro-
~; methylphenyl)-lH-2,3-dihydro-1,4-benzodiazepine in the form of
- 8
la~ss;~
an oily base showin~ an IR-absorpt-on band (oil) at 1640 cm 1
indicating a C=N linkaqe.
Example 4
Nl-(2'-chlorobenzoyl)-N2-methyl-N2-(4'-fluorophenyl)-
2-hydroxy-l,3-diaminopropane having a melting point between 92
and 94C was halogenated using phosphorus pentachloride in
1,2-dichloroethane and cyclised using aluminum chloride in the
manner described in Example l in nitrobenze~e to give 7-fluoro-
l-methyl-2-chloromethyl-S-(2'-chlorophenyl)-lH-2,3-dihydro-
1,4-benzodiazepine hydrochloride having a melting point of
180 to 184C.
Example S
20 g of Nl-(2'-chlorobenzoyl)-N2-methyl-N2-(4'-chloro-
phenyl)-2-hydroxy-1,3-diaminopropane were dissolved at room
temperature, while being cooled with ice, in 100 ml of phos-
phorus oxychloride and then heated at 70C for S.5 hours.
The phosphorus oxychloride was then distilled off
in vacuo and the resulting residue was dissolved in 100 ml of
chloroform and thoroughly mixed by stirring with 100 g of ice
and 100 ml of water. The chloroform solution was then separa-
ted off, washed twice with water and finally thoroughly stirred ~ -
for 30 minutes with a 10% solution of sodium hydroxide. The
chloroform phase was then separated, washed until neutral with
water and dried over sodium sulphate. After the solvent had
been distilled off, the residue was recrystallised from lS0 ml
of toluene. 17 g corresponding to a yield of 81~ of Nl-(2'-
chlorobenzoyl)-N2-methyl-N2-(4'-chlorophenyl)-2-~hl~ro-1,3-
diaminopropane melting between 137 and 139C were obtained.
11 g of this haloacyl diamine compound were next dis-
solved in 50 ml of 1,2-dichloroethane and refluxed for 3 hours
_ g _
i.~l
1~8852t~
together with 3.5 g of phosphorus pentachloride. The ~olvent
and the phosphoru~ oxychloride were then distilled off in
vacuo and the residue dissolved in S0 ml of nitrobenzene and
heated at 70C for 4 hours with 8.3 g of aluminum chloride.
The product was then purified and recovered in the manner de~-
cribed in Example 1. From the ether/nitrobenzene phase, 5.5 g
of the product could be recovered but, after the purification
procedure, 4.0 g, corresponding to a yield of 62.8%, based on -
the weight of the starting material, of 7-chloro-1-methyl-2-
: 10 chloromethyl-5-(2'-chlorophenyl)-lH-2,3-dihydro-1,4-benzodiaze-
pine hydrochloride were obtained. ~he reaction product had
the following phy~ical properties:
Melt~ng point: 178 - 180 C
~: IR-~pectrum (in KBr~ N-H 2 2128-3125 cm 1
C-N : 1642 cm 1
W -~pectrum (in alkal~ne C~30R):- ~ ~ 233 n~
max
A - 270 n~ -
l~ A - 355 ny
.~ max
ExamPle 6
t;" Nl-benzoyl-N2-methyl-N2-(4'-chlorophenyl)-2-chloro-
3-diaminopropane having a melting point between 87 and 90C
was prepared from Nl-benzoyl-N2-methyl-N2-(4'-chlorophenyl)-
2-hydroxy-1,3-diaminopropane having a melting point between
136 and 137C using pho~phoru~ oxychloride at 70C ~nd then
~`~; treated first with pho~phorus pentachloride in 1,2-dichloro-
~ ethane and then with aluminum chloride in nitrobenzene in the
,r`~ manner described in Example 5. 7-chloro-1-methyl-2-chloro-
~ methyl-5-phenyl-lH-2,3-dihydro-1,4-bensodiazepine hydrochloride
j~ 30 was obtained and the cry~talline product contained one mole of
i
~i - 10 -
8S;~8
isopropanol and had a melting point of 110 to 112C.
Example 7
In the manner described in Example 5, Nl-(2'-fluoro-
benzoy~)-N2-ethyl-N2-(4'-chlorophenyl)-2-hydroxy-1,3-diamino-
propane having a melting point between 88 and 92C wa~ treated
with phosphorus oxychloride at 70C to give an oily product
comprising Nl-(2'-fluorobenzoyl)-N2-ethyl-N2-(4'-chlorophenyl)-
2-chloro-1,3-diaminopropane. The latter product was then
treated first with phosphorus pentachloride in 1,2-dichloro-
ethane and then with aluminum chloride in nitrobenzene e~sen-
tially as described in Example 5 to give 7-chloro-1-ethyl-2-
chloromethyl-5-(2'-fluorophenyl)-lH-2.3-dihydro-1,4-benzodiaze-
pine in the form of an oily phase showing an IR-absorption
band (oil) at 1640 cm 1 indicating a C=N linkage.
Example 8
Similarly, Nl-(2'-fluorobenzoyl)-N2-methyl-N2-phenyl-
2-chloro-1,3-diaminopropane, an oily product, wa~ prepared in
the manner described in Example 5 from Nl-(2'-fluorobenzoyl)- `~-
~:~ N2-methyl-N2-phenyl-2-hydroxy-1,3-diaminopropane having a melt-
ing point of 89 to 91C using phosphorus oxychloride at 70C
and that intermediate wa~ then treated first with phosphorus
pentachloride in 1,2-dichloroethane and then with aluminum
chloride in nitrobenzene as described in Example 5 to give
: l-methyl-2-chloromethyl-5-(2'-fluorophenyl)-lH-2,3-dihydro-1,4-
benzodiazepine in the form of an oily base having an IR-ab~orp-
tion band (oil) at 1640 cm 1 indicating a C=N linka~e.
~ Example 9
: 6.8 g of Nl-benzoyl-N2-methyl-N2-(4'-chlorophenyl)-
2-chloro-1,3-diaminopropane having a melting point between 87
and 90C were obtained from Nl-benzoyl-N2-methyl-N2-~4'-chloro-
-- 11 --
~.
,.._,j
10~
phenyl)-2-hydroxy-1,3-diaminopropane by treatment of the latter
with phosphorus oxychloride at 70C and were then dissolved in
35 ml of 1,2-dichloroethane and refluxed for 2 hours with 4.3 g
of phosphorus pentachloride. The solvent and the phosphorus
oxychloride which had formed were distilled off in vacuo. The
resulting residue was then dissolved in 35 ml of nitrobenzene
and heated for 4 hours at 70C with 4.8 ml of tin(~V) chloride.
After cooling, the reaction solution was poured into a mixture
of 100 g of ice and 100 ml of water and then alkalised with a
concentrated solution of sodium hydroxide. The resulting
aqueous alkaline solution was extracted with 200 ml of toluene
and the toluene solution was then extracted four times with 100
ml of a dilute (20%) hydrochloric acid. A water-insoluble oil
separated which together with the aqueous hydrochloric acid
was alkalised by the addition of a concentrated solution of
sodium hydroxide, with cooling. The separated base was then
extracted three times each with 100 ml of ether, the ether
phase being washed with a saturated solution of common salt,
dried over sodium sulphate and the ether distilled off in
~acuo. The residue was then taken up in isopropanol and a
solution of gaseous HCl in ether added. The hydrochloride
precipitated and was recrystallised from isopropanol, giving
. ~ .
3.1 g corresponding to a yield of 37~ of 7-chloro-1-methyl-2-
chloromethyl-S-phenyl-lH-2,3-dihydro-1,4-benzodiazepine hydro-
` ~:
chloride. The product contained 1 mole of isopropanol and had
a melting point of 110 to 112C.
Example 10
;``e
`~ ~ 10.1 g of Nl-(2'-fluorobenzoyl)-N2-methyl-N2-(4'-
, ~
chlorophenyl)-2-chloro-1,3-diaminopropane having a melting
30 point between 88 and 90C were obtained from ~1-(2'-fluoro-
- 12 -
10t~8S;~8
benzoyl)-N2-methyl-N2-(4'-chlorophenyl)-2-hydroxy-1,3-diamino-
propane by treatment of the latter with phosphor~s oxychloride
at 70C and were then refluxed for 2 hours in S0 ml of 1,2-di-
chloroethane with 3.1 g of phosphorus pentachloride. The sol-
vent and the phosphorus oxychloride that had formed were dis-
tilled off and the residue was disQolved in 50 ml of nitroben-
zene and heated at 70C for four hours with 8.2 g of zinc
chloride. The pro~uct was purified and recovered as described
in Example 1. 7-chloro-1-methyl-2-chloromethyl-5-(2'-fluoro-
phenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydrochloride was
obtained and had the following physical properties:
IR-spectrum (in XBr):- -=N-H :2200-3000 cm 1
; C=N :1621 cm 1
Melting point: 220 - 222C.
; 20
. :
