Method of making diazepine derivatives

Details Method of making diazepine derivatives Method of making diazepine derivatives

2000-05-08

2001-08-28

Kifle, Bruck (Department: 1604)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C540S506000

Reexamination Certificate

active

06281353

ABSTRACT:

BACKGROUND
Conventional means for making intermediate products used in the maufacture of imidazo[1,5-a][1,4]diazepine derivatives have been chracterised by low yields resulting in higher production costs for the final products. The low yields of the conventional production methods have also lead to problems regarding the disposal of unwanted byproducts which are concomitantly produced with the production of the desired intermediates.
SUMMARY OF THE INVENTION
The present invention relates to a process for manufacturing diazepine derivatives of the general formula
wherein
R
1
is lower alkyl;
R
2
is hydrogen; or
R
1
and R
2
are together —(CH
2
)
n
— and n is 2 or 3;
R
3
is halogen, lower alkyl, lower alkoxy and m is 0, 1 or 2; and
R
4
is hydrogen or lower alkyl.
The compounds of general formula I are valuable intermediate products for the manufacture of imidazo[1,5-a][1,4]diazepine derivatives, like for instance 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][1,4]benzodiazepin-6-one, which diazepine derivatives show excellent psychopharmacological properties as agonists of the central benzodiazepine receptors.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of general formula I are obtained by the known process consisting of reacting a compound of general formula
wherein
R
3
is halogen, lower alkyl, lower alkoxy and m is 0, 1 or 2; and
R
4
is hydrogen or lower alkyl.
,
with a compound of general formula
wherein R
1
is lower alkyl;
R
2
is hydrogen; or
R
1
and R
2
are together —(CH
2
)
n
— and n is 2 or 3.
This reaction step takes place in a polar solvent such as for instance DMF, under atmospheric pressure and at a temperature between 110° C. and the boiling point of the reaction mixture.
The compounds of formula II can be obtained, on their turn, by reacting a compound of formula
wherein
R
3
is halogen, lower alkyl, lower alkoxy and m is 0, 1 or 2.
,
with:
a) phosgene and hydrochloric acid in THF; or
b) ethyl haloformiate, e.g. ethyl chloroformiate, in dioxane and subsequent treatment with acetylchloride.
Both steps take place in a batch system, under atmospheric pressure and at the boiling temperature of the reaction mixture (see e.g. G. M. Coppola, “The Chemistry of Isatoic Anhydride”,
Synthesis
, Georg Thieme Verlag, (1980), pp 505-535).
The last step of the mentioned production pathway is characterised by low yields. This is mainly due to a low conversion of the reactants and, in certain cases, also to a low selectivity towards the desired product because of the formation of a side product of general formula
These low yield and selectivity imply higher costs for the production of the compounds of formula I and lead to important disposal problems since the compounds of formula V cannot be used for other purposes and must be therefore destroyed or recycled.
The above elucidated problems are addressed by the present invention by providing a process for manufacturing the compounds of general formula I which can overcome the disadvantages mentioned above.
The problem is solved, according to the present invention, by a process for manufacturing diazepine derivatives of the general formula I, comprising the step of reacting a compound of general formula II with a compound of general formula III, characterised in that said compound of general formula II and said compound of general formula III undergo chemical reaction in the absence of a solvent or in the presence of an apolar solvent.
It has been surprisingly found that the conversion, and in certain cases also the selectivity, towards the compound of formula I strongly increases if the reaction components (i.e. compounds of formula II and III) are not solvated in the reaction mixture. This situation can take place only if no solvent at all is added to the reaction mixture or if the reactants and/or products are not soluble in a given solvent. Being the present compounds of polar nature, apolar solvents can be used in the process of the invention for achieving the wished results.
Particularly preferred solvents are substituted benzene rings, such as xylenes, mesitylene, ethylbenzene, isopropylbenzene, etc. Most preferably, p-xylene or a mixture of xylenes are used as solvent for carrying out the process according to the present invention.
The reaction temperature is preferably set from 0 to 30° C. under the boiling temperature of the reaction mixture.
The process of the present invention is particularly suitable for the manufacture of 6-Chloro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione.


REFERENCES:
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patent: 4352817 (1982-10-01), Hunkeler et al.
patent: 4352818 (1982-10-01), Hunkeler et al.
patent: 059 389 (1982-09-01), None
patent: 059 390 (1982-09-01), None
patent: 059 386 (1982-09-01), None
Kamal et al. (Synlett (1999), (8), 1251-1252), 1998.*
Jolivet-Fouchet (Heterocycles (1999), 51(6), 1257-1273.*
Dudasko et al. (Conf. Org. Chem. Adv. Org. Chem., 22nd (1997), 142-143).*
Pfaendler et al. (Heterocycles (1995), 40(2), 717-727).*
Bhat et al. (Tetrahedron (1993), 49(46), 10655-62).*
G.M. Coppola, The Chemistry of Isatoic Anhydride, Synthesis, Georg Thieme Verlag, pp. 505-536 (1980).

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