Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Case 4-11672/-
Process for the rearrangement of 10,11-~oxy-10211-dihydro-
dihydro-5H-dibenzlb,f]azeeine-5-carboxamide
The present invention relates to a process for the
rearrangement of 10,11-epoxy-10,11-dihydro-5H-dibenz[b,fl
azepine-5-carboxamide of the formula
~` CONH2
to 10-oxo-10,11-dihydro-5H-dibenz~b,f]azepiQe-5-car-
boxamide of the formula
. O
= _ ~ (II).
CONH2
The rearrangement, catalysed by lithium salts, of
epoxides to carbonyl compounds is known from J. Amer.
Chem. Soc. 90, 4193 (1968). Thus, for example, cyclohexene
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oxide, or the l-methyl or 1,2-dimethyl derivative thereof,
is rearranged with the aid of lithium bromide in benzene,
in the presence of tri~n-butylphosphine oxide, by means
of ring contraction to aldehydes or methyl ketones,
which are derived from cyclopentane. The information is
also given therein that l-methyl-cyclohexene oxide is
rearranged in benzene in the presence of lithium
perchlorate at 80 to 2-methyl-cyclohexanone with an 80%
yield, whilst under the same conditions 2,2-dimethyl-
cyclohexanone is obtained with 10% yield from 1,2-dimethyl-
cyclohexene oxide.
In J. Amer. Chem. Soc. 93, 1693-1700 (1971) is moreover `
described the conversion of cycloheptene oxide in the
presence of lithium bromide and hexamethylphosphoric acid
triamide in benzene at 80C, with cycloheptanone being
obtained with 26% yield. Cycloheptanone is obtained with
17% yield with the use of lithium perchlorate. According
to J. Org. Chem. 34, 2355-58 (1969), exo-bicyclo[4.2.0]-
octene-7 oxide is rearranged, by the action of lithium
iodide, by means of ring contraction to bicyclo[4.1.0]
heptane 7-carboxaldehyde.
From Acta Chemica Scandinavica 18, 1551-1552, (1964)
is known the isomerisation of aliphatic epoxides by means
of a mixture of methyl iodide and sodium iodide in dimethyl-
formamide, by 4 hours' refluæing, in quantitative yield
to the corresponding ketones. Finally, the isomerisation
of epoxycyclohexane, dissolved in dimethyl sulfoxide~ by
means of sodium iodide and n-propyl iodide to cyclohexanone
in 90% yield is described in Chemical Communications 1968,
227-229. The analogous application of these ~wo reactions
to the compound of the formula I yielded, according to the
thin-layer chromatogram using silica gel plates with ethyl
acetate as the eluant, in the first case a product which
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contained only traces oF the compoun~ o-F the ~ormula Tl, whilst in the second
case no corresponding compound was de~ec~able. I;urthermore, it was asc~rtained
that the rearrangement, glven in the foregoing as being known, o~ l-me~hyl-
cyclohexene oxide in benzene, in the -presence of lithium perchlorate, to
2-methylcyclohexanone yielded on analogous application to the compound of the
formula I a product which, according to the thin-layer chromatogram using
silica gel plates with ethyl acetate as the eluant, contained only traces
of the compound of the formula II.
It has now been found that, surprisingly, the rearrangement of
10,11-epoxy-10,11-dihydro-5H-dibenz~b,f]azepine-5-carboxamide of the formula
I to 10-oxo-10,11-dihydro-51-1-dibenzLb,f]azepin-5-carboxamide of the formula
II can be performed by means of a bromide or iodide of lithium, magnesium
; or calcium, without an addition of methyl iodide or n-propyl iodide being
; necessary. The iodides of the stated metals are preferred for the purpose.
The salts mentioned correspond accordingly to the formulae LiBr, LiI, MgBr2,
~lgI2~ CaBr2 and CaI2. These can be used in the dry form or as known compounds
with water (hydrates) or with organic substances.
Hydrates to be mentioned are for example:
LiBr.H20, LiBr.2H20, LiBr.3}120, LiI.}120, LiI.21120, LiI.3H20, MgBr2.6H20,
~qgBr2 1H2, MgI2-8H20, MgIz.lOH20, CaBr2.61120, CaI2.~}120 and CaI2.6H20.
By organic substances in this connection are meant: lower alkanols,
namely lower primary, secondary or tertiary alkanols, for instance methanol,
ethanol, n-propanol, n-butanol, isopropanol or trimethylcarbinol; lower
dialkyl ethers such as diethyl ether, also dioxane, lower ketonesg for
example acetone, carboxylic acid esters, for example formic acid ethyl ester,
acetic acid methyl ester, acetic acid ethyl ester, acetic acid isobutyl
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ester, acetic acid et]lyl ester, acetic acid isobutyl ester or acetic acid
isoamyl ester, acetoaCetic acid ethyl esterS nlalonic acld diethyl ester,
orthoformic acid ethyl ester or succinic acid diet}lyl ester, also acetals
such as formaldehyde dimethylacetal or acetaldehyde diethylacetal.
As compounds of the stated salts with organic substances are
` mentioned for example:
LiBr~methanol, LiBr.4 ethanol, LiBr.dioxane, LiBr.2 acetone,
LiI.4 methanol, LiI 4 ethanol, LiI.4 n-propanol,
LiI.2 ~ioxane, Mg~r2.6 ethanol,
MgBr2.4 isopropanol, MgBr2.4 trimethylcarbinol,
MgBr2.2 diethyl ether,
~ MgBr2.2 orthoformic acid ethyl ester,
`- MgBr2.acetoacetic acid ethyl ester.diethy] ether,
MgBr2.malonic acid diethyl ester.diethyl ether,
MgBr2.succinic acid diethyl ester, MgBr2.2 dioxane,
MgBr2.2 formaldehyde dimethylacetal,
MgI2.6 methanol, MgI2.6 isopropanol,
MgI2.2 diethyl ether, MgI2.6 ~ormic acid ethyl ester,
MgI2.6 acetic acid methyl ester, MgI2.6 acetic acid ethyl ester,
MgI2.acetic acid isobutyl ester,
MgI2.acetic acid isoamyl ester, MgI2.dioxane,
MgI2.acetaldehyde diethylacetal, CaBr2.4 methanol,
CaBr2.4 ethanol, CaBr2.3-n-propanol,
CaBr2.3 n-butanol, CaBr2.2 acetone, CaBr2.2 dioxane,
CaBr2.diethyl ether, CaI2.6 methanol,
CaI2.3 acetone, CaI2.2 dioxane, CaI2.2 diethyl ether.
-- 4 --
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Salts and hydrates thereof or co~npounds thcreof with organic
substances which are ~entioned as being particularly suitable for the
process according to the invent;on arc: LiBr, liI.21120, MgI2.diethyletherate
and CaI2'4112
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The rearrangement according to the invention i5
performed in a solvent, for example in an unsubstituted
or halogen-substituted hydrocarbon of aliphatic or
aromatic character, such as in a halo-lower alkane such
as chloro-lower alkane, ~or example methylene chloride, -
carbon tetrachloride, ethylene chloride or difluoro-
chloromethane, preferably however in chloroform. As
solvents of aromatic character are mentioned for example
benzene and chlorobenzene~ It can be advantageous to
raise the solubility of the stated salts in the respective
solvent by the addition of a further solvent. Suitable
such solvents are preferably those of polar character,
for instance tetrahydrofuran or dioxane, or a derivative
of a phosphorus acid amide, for example hexamethyl-
- phosphoric acid triamide. The amount of polar solvent
added varies depending on the amount of salt used, and
up to 1 mol of further solvent per mol of employed salt
can be used.
Processing of the reaction mixture in the customary
manner yields the rearrangement product in good yield
and in an excellent degree of purity.
The reaction temperature is within a range of 20 -
120C, preferably between 40 and 80C. The compounds
of the formulae I and II are known.
The organic substances or the compoùnds of the stated
salts with organic substances to be used in the process
according to the invention are known, or, in the case
where they are new, they can be obtained by methods known
per se. Thus, for example, a magnesium salt-di-lower alkyl
etherate, for example magnesium iodide diethyl etherate,
to be used in the process according to the invention, can
be obtained by reaction of magnesium chips in a lower dialkyl
ether, for example diethyl ether, with iodine.
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The ollowing Examples serve to illustrate the
invention. The temperatures are given in degrees Centigrade.
Example 1
5.0 g of lithium iodide dihydrate is added to a
suspension of 5.0 g of 10,11-dihydro-10,11-epoxy-5H-
dibenzlb 9 f]azepine-5-carboxamide in 50 ml of chloroform.
The suspension is heated to reflux temperature, and is
stirred for 30 minutes at this temperature. The solution
is subsequently cooled to room temperature, and washed
with 50 ml of water and afterwards with 20 ml of water.
The chloroform solution is evaporated to dryness, and the
residue is recrystallised from methanol. The yield after
drying is 4.1 g (82% of theory) of 10,11-dihydro-10-oxo-
5H-dibenz[b,f~azepine-5 carboxamide, m.p. ~14.
Example 2
6.2 g o~ magnesium iodide diethyl etherate is added to
a suspension of 5.0 g of 10,11-dihydro-10,11-epoxy-SH-
dibenz[b,f]azepine-S-carboxamide in 50 ml of chloroformO
The suspension is heated to reflux temperature, and is
stirred for 30 minutes at this temperature. The solution is
then cooled to room temperature, and washed with 50 ml of
water and afterwards with 20 ml of water. The chloroform
solution is evaporated to dryness, and the residue is
recrystallised from methanol. The yield after drying is
4.0 g (80% of theory) of lO,ll~dihydro-10-oxo-SH-dibenz
[b,f]azepine-5-carboxamide, m.p. 214.
The magnesium iodide diethyl etherate used as starting
material is produced as follows:
4.0 g of iodine is added portionwise to 1.5 g of
magnesium chips in 40 ml of absolute diethyl ether. The
mixture is stirred under reflux for a further 60 minutes;
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it is then ~iltered off from the unconsumed magnesium,
and concentrated by evaporation to thus yie].d the
starting material in the form of viscous, slightly
coloured oil.
Example 3
1.8 g of hexamethylphosphoric acid triamide and 1.7 g
of lithium bromide are added to a suspension of 2.3 g of
lo~ dihydro-lo~ll-epoxy-5H-dibenz~b~f]azepine-5-
carboxamide in 20 ml of chlorobenzene. The suspension is
heated to 70 and stirred for 30 minutes at this tempera-
ture. The solution is then cooled to room temperature,
and distributed between 50 ml of water and 50 ml of ethyl
acetate, The ethyl acetate solution is evaporated to
dryness, and the residue is recrystallised from me~hanol.
The yield after drying is l.S g (65% of theory) of 10,11-
dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide,
m.p. 214.
5.0 g of calcium iodide tetrahydrate is added to a
suspension of 10.0 g of 10,11-dihydro-10,11-epoxy-5H-
dibenz~b,f]azepine-5-carboxamide in 25 ml of chloroform.
The suspension is heated to reflux temperature, and stirred
for 60 minutes at this temperature. The solution is then
cooled to 0; it is subsequently stirred with 25 ml of
water and filtered off with suction from the precipitate
which has separated out. The yield after drying is 7.8 g
(78% of theory) of 10,11-dihydro-10-oxo~SH-dibenz[b,f]
azepine-5-carboxamide, m~p. 214.
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