PRODUCTION METHOD OF 6-AMINOMETHYL-6,11-DIHYRO-5H-
DIBENZ[b,e]AZEPIN
TECHNICAL FIELD
The present invention relates to a novel production
method of 6-aminomethyl-6,ll-dihydro-5H-dibenz[b, e]azepin
which is markedly important as an intermediate to produce 3-
amino-9,13b-dihydro-lH-dibenz[c,f]imidazo[1,5a]azepin
hydrochloric acid salt which is therapeutically useful while
characterized by antiallergic and antihistaminic actions.
BACKGROUND
6-Aminomethyl-6,ll-dihydro-5H-dibenz[b,e]azepin is an
important compound as a raw material of medicines. Known as
production methods of the aforesaid compound is a method in
which 6-cyano-llH-dibenzo[b,e]azepin is allowed to react, in
THF, with lithium aluminum hydride and aluminum hydride

prepared employing 100 percent sulfuric acid (Arzneim.-
Forsch., 40, 4, 440, (1990) and Japanese Patent Publication
No. 3-66311.
However, the aforesaid synthesis method necessitates an
anhydrous THF solvent which results in heavy load in terms of
cost and includes time consuming operations such as
filtration of an excessive amount of inorganic substances
deposited after the reaction.
Further, known is a method in which 6-
phthalimidomethyl-6,ll-dihydro-5H-dibenz[b,e]azepin is
r
isolated, which is formed by hydrogenating 2-(llH-
dibenz[b,e]azepin-6-ylmethyl-lH-isoindole-l,3(2H)-dione
employing formic acid as well as palladium carbon, and
subsequently is subjected to hydrazine decomposition.
(Japanese Patent Publication Open to Public Inspection No. 4-
346988).
However, since this method uses hydrazine, which is a
carcinogenic substance, in the industrial production,
operators' safety becomes a problem. Further, isolation is
required between the hydrogenation and the hydrazine
decomposition. During industrial scale production, it is
well known that a decrease in isolation is desirable.

SUMMARY OF THE INVENTION
An object of the present invention is to provide a
production method which enables to avoid the use of hazardous
substances as well as to shorten the process in the synthesis
of 6-aminomethyl-6,ll-dihydro-5H-dibenz[b,e]azepin from 2-
(11H-dibenz[b,e]azepin-6-ylmethyl)-lH-isoindole-1,3(2H)-
dione.
The inventors of the present invention conducted
diligent investigations to overcome the aforesaid problems.
As a result, it was discovered that 2-(11H-dibenz[b,e]azepin-
6-ylmethyl) -lH-isoindole-1,3(2H)-dione was allowed to react
with a metal hydride or a metal hydride complex, whereby it
was possible to reduce the imine portion as well the
phthalimide portion in one vessel. It is known in prior art
(Tetrahedron Letters, 25, 20, 2093, (1984)) that phthalimide
is subjected to deprotection (or cleavage) employing metal
hydrides. However, it was surprising that it was possible to
simultaneously reduce not only the phthalimide portion but
also the imine portion in the same molecule, and even when a
water based solvent was employed, the imine portion was
reduced to amine resulting in almost no hydrolysis. Further,
it was discovered that formed N-[(6,ll-dihydro-5-
Hdibenz[b,e]azepin-6-yl)methyl]-o-hydroxymethylbenzamide was

readily decomposable without an isolation process, and 6-
aminomethyl-6,ll-dihydro-5H-dibenz[b,e]azepin could be
prepared in one vessel. Thus, the present invention was
achieved.
Namely, the present invention include:
(1) a production method of 6-aminomethyl-6,ll-dihydro-5H-
dibenz[b,e]azepin via N-[(6,ll-dihydro-5H-dibenz[b,e]azepin-
6-yl)methyl]-o-hydroxymethylbenzamide which is prepared by
allowing 2-(llH-dibenz[b,e]azepin-6-ylmethyl)-lH-isoindole-
1,3(2H)-dione to react with a metal hydride or a metal
hydride complex,
(2) N-[(6,ll-dihydro-5H-dibenz[b,e]azepin-6-yl)methyl]-o-
hydroxymethylbenzamide,
(3) a production method of 6-aminomethyl-6,ll-dihydro-5H-
dibenz[b,e]azepin, described in (1) in which the metal
hydrides or the metal hydride complex is boron hydrides,
(4) a production method of 6-aminomethyl-6,ll-dihydro-5H-
dibenz[b,e]azepin, described in (1), characterized in that an
alcohol or a water based alcohol is employed as a solvent,
and
(5) a production method of 6-aminomethyl-6,ll-dihydro-5H-
dibenz[b,e]azepin, described in (1), characterized in that N-

[(6,ll-dihydro-5H-dibenz[b,e]azepin-6-yl)methyl]-o-
hydroxymethylbenzamide is processed with a acid or a base
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows 2-(11H-dibenz[b,e]azepin-6-ylmethyl)-1H-
isoindole-1,3(2H)-dione.
Fig. 2 shows N-[(6,ll-dihydro-5H-dibenz[b,e]azepin-6-
yl)methyl]-o-hydroxymethylbenzamide.
Fig. 3 shows 6-aminomethyl-6,ll-dihydro-5H-
dibenz[b,e]azepin.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the present invention, the reaction is conducted by
successively charging raw materials, a solvent, and a metal
hydride or a metal hydride complex into a reaction vessel.
Stirring is continued until completion of the reaction.
Thereafter, an acid or a base is added, and the resulting
mixture is heated while stirring to undergo decomposition.
Subsequently, by employing a method such as extraction, 6-
aminomethyl-6,ll-dihydro-5H-dibenz[b,e]azepin is obtained in
the form of a syrup. If desired, it is possible to obtain it
in the form of crystals by forming a salt with a mineral acid
or an organic acid. Further, after formation the salt, it is

possible to purify the resulting crystals by extracting
impurities employing an organic solvent..
The used amount of a metal hydride or a metal hydride
complex is customarily 6-60 times with respect to the
theoretical amount, is preferably 12 - 30 times, and is most
preferably 12 - 20 times. When it is less than 6 times,
unreactants tend to remain, while when it exceeds 60 times,
such an added amount is not economically preferable.
Addition may be carried out in the form of powder, or after
dissolved in a solvent, the resulting solution may be added
dropwise.
Examples of reaction solvents employed are alcohols as
well as water base alcohols. Preferred alcohols include n-
butanol, isobutanol, n-propanol, isopropanol, ethanol, and
methanol, as well as solvent mixtures thereof. Of these,
particularly preferred is isopropanol. The concentration of
water in a water based alcohol is customarily 1-99 percent
by weight, but is particularly preferably 18 percent by
weight. The used amount of a solvent (including water) is
customarily 1-50 times by volume with respect to the weight
of 2-(HH-dibenz[b,e]azepin-6-ylmethyl)-lH-isoindole-1,3(2H)-
dione, is preferably 2-20 times, and is most preferably 10
- 15 times.

If desired, in order to accelerate the reaction, added
may be inorganic salts. Even though not particularly
limited, preferable inorganic solts are zinc chloride,
magnesium chloride, and cobalt chloride.
The reaction temperature is 0 °C - refluxing
temperature, and is preferably 30 - 40 °C. The reaction at a
temperature of 0 °C or less is not economical due to
excessively low production rate.
N-[6,ll-dihydro-5H-dibenz[b,e]azepin-6-yl]methyl]-o-
hydroxymethylbenzamide may undergo decomposition in the
presence of either acids or bases. Examples of acids
employed may be mineral acids as well as organic acids. Of
these, preferred are hydrochloric acid, sulfuric acid,
methanesulfonic acid, acetic acid, and formic acid, and
hydrochloric acid as well as acetic acid is particularly
preferred. Examples of bases employed may be inorganic bases
as well as organic bases. Of these, preferred are salts or
hydroxides of alkaline metals as well as alkylamines, and
sodium hydroxide is particularly preferred.

EXAMPLES
The present invention will now be specifically
described with reference to examples. However, the present
invention is not limited to these.
A raw material, 2-(11H-dibenz[b,e]azepin-6-ylmethyl)-
lH-isoindole-1,3(2H)-dione was synthesized based on the
method described in J. Heterocycle. Chem., 17, 2, 341,
(1980).
Example 1
Charged into a 100 ml flask fitted with a stirrer, a
reflux cooler, and a thermometer were 3.0 g (8.5 millimoles)
of 2-(11H-dibenz[b,e]azepin-6-ylmethyl-lH-isoindole-l,3(2H)-
dione, 45.0 ml of isopropanol, and 7.5 ml of water.
Thereafter, while stirring at room temperature, 1.3 g (35.1
millimoles) of sodium borohydride was added over 30 minutes
while maintaining a maximum temperature of 30 °C. After
addition, the resulting content, in the form of a white
slurry, was stirred at room temperature for 24 hours. After
decomposing the residual sodium borohydride by dripping 10.7
g of acetic acid into the resulting reaction composition at
room temperature, the resulting mixture was stirred at 80 °C
for 1.5 hours and was left standing until its interior
temperature was allowed to equilibrate to room temperature.

Subsequently, 24.0 ml of water as well as 24.0 ml of toluene
was added and the resulting mixture was subjected to
extraction by adjusting the pH to 11 by addition of a 25
percent NaOH solution. The resulting extract was
concentrated under vacuum, whereby 3.1 g of a brown syrup was
prepared. The resulting brown syrup was dissolved in 1.8 ml
of methanol, followed by dripping of 0.89 g of fumaric acid
dissolved in 18 ml of methanol. After confirming the
deposition of crystals at room temperature, stirring was
carried out at 0 °C for 3 hours and filtration under vacuum
was carried out. The resulting cake was washed with 1.0 ml
of cooled methanol and subsequently dried.
Yield: 2.0 g of 6-aminomethyl-6,ll-dihydro-5H-
dibenz[b,e]azepin-fumaric acid salt (69.0 percent of the
theoretical amount)
Example 2
Charged into a 300 ml flask fitted with a stirrer, a
reflux cooler, and a thermometer were 3.0 g (8.5 millimoles)
of 2-(11H-dibenz[b,e]azepin-6-ylmethyl-lH-isoindole-l,3(2H)-
dione, 45.0 ml of isopropanol, and 7.5 ml of water.
Thereafter, while stirring at room temperature, 1.3 g (35.1
millimoles) of sodium borohydride was added over 30 minutes
while maintaining a maximum temperature of 30 °C. After

addition, the resulting content in the form of a white slurry
was stirred at room temperature for 24 hours. After
decomposing the residual sodium borohydride by adding 140 ml
of 1 N hydrochloric acid into the resulting reaction
composition, the resulting mixture was stirred at 80 °C for
1.5 hours and was left standing until its interior
temperature was allowed to equilibrate to room temperature.
Subsequently, 24.0 ml of toluene was added. After
separation, extraction was carried out employing 24.0 ml of
toluene by adjusting the pH of the water layer to 11 by
addition of a 25 percent NaOH solution. The resulting
extract was concentrated under vacuum, whereby 3.0 g of a
brown syrup was prepared. The resulting brown syrup was
dissolved in 1.8 ml of methanol, followed by dripping of 0.89
g of fumaric acid dissolved in 18 ml of methanol. After
confirming the deposition of crystals at room temperature,
stirring was carried out at 0 °C for 3 hours and filtration
under vacuum was carried out. The resulting cake was washed
with 1.0 ml of cooled methanol and subsequently dried.
Yield: 2.2 g of 6-aminomethyl-6,ll-dihydro-5H-
dibenz[b,e]azepin-fumaric acid salt (76.1 percent of the
theoretical amount)
Example 3

Charged into a 300 ml flask fitted with a stirrer, a
reflux cooler, and a thermometer were 3.0 g (8.5 millimoles)
of 2-(11H-dibenz[b,e]azepin-6-ylmethyl-lH-isoindole-l,3(2H)-
dione, 45.0 ml of isopropanol, and 7.5 ml of water.
Thereafter, while stirring at room temperature, 1.3 g (35.1
millimoles) of sodium borohydride was added over 30 minutes
while maintaining a maximum temperature of 30 °C. After
addition, the resulting content in the form of a white slurry
was stirred at room temperature for 24 hours. After
decomposing the residual sodium borohydride by dripping 5.0
ml of MeOH into the resulting reaction composition, 3.0 ml of
a 25 percent NaOH solution was added, the resulting mixture
was stirred at 80 °C for 1.5 hours and was left standing
until its interior temperature was allowed to equilibrate to
room temperature. Subsequently, 24.0 ml of toluene was
added. After separation, the resulting extract was
concentrated under vacuum, whereby 3.0 g of a brown syrup was
prepared. The resulting brown syrup was dissolved in 1.8 ml
of methanol, followed by dripping of 0.89 g of fumaric acid
dissolved in 18 ml of methanol. After confirming the
deposition of crystals at room temperature, stirring was
carried out at 0 °C for 3 hours and filtration under vacuum

was carried out. The resulting cake was washed with 1.0 ml
of cooled methanol and subsequently dried.
Yield: 2.1 g of 6-aminomethyl-6,ll-dihydro-5H-
dibenz[b,e]azepin-fumaric acid salt (72.4 percent of the
theoretical amount)
Example 4
Charged into a 100 ml flask fitted with a stirrer, a
reflux cooler, and a thermometer were 3.0 g (8.5 millimoles)
of 2-(llH-dibenz[b,e]azepin-6-ylmethyl-lH-isoindole-l,3(2H)-
dione, 45.0 ml of isopropanol, and 7.5 ml of water.
Thereafter, while stirring at room temperature, 1.3 g (35.1
millimoles) of sodium borohydride was added over 30 minutes
while maintaining a maximum temperature of 30 °C. After
addition, the resulting content in the form of a white slurry
was stirred at room temperature for 24 hours. The residual
sodium borohydride was decomposed by dripping 5.0 ml of MeOH
to the resulting liquid reaction composition at room
temperature. Crystals deposited by dripping 4 0 ml of water
were colleted by filtration and dried whereby N-[(6,ll-
dihydro-5H-dibenz[b,e]azepin-6-yl)methyl]-o-
hydroxymethylbenzamide was isolated.
1H-NMR (DMSO) 83. 7-3. 8 (m, 1H), 3. 9-4. 1 (m, 2H), 4. 4 (d,
1H) , 4. 7 (d. 2H), 5. 1 (m, 1H) , 5. 3 (t, 1H) , 5. 8 (d, 1H) ,

6. 6-6, 7 (m, 2H), 6. 9-7. 1 (m, 2H) , 7. 3-7. 7 (m, 8H), 8. 7
(t, 1H)
INDUSTRIAL APPLICABILITY
Based on the production method of the present
invention, it is possible to produce 6-aminomethyl-6,11-
dihydro-5H-dibenz[b,e]azepin employing a simple operation
requiring no isolation of the intermediates while avoiding
the use of high toxic raw materials and also to markedly
decrease its production cost.

1. A method for producing 6-aminomethyl-6,11 -dihydro-5H-dibenz[b,3]azepin
comprising the steps of:
(i) allowing 2-(11H-dibenz[b,e]azepin-6-ylmethyl)-1H-isoindole-
1,3(2H)-dione to react with a metal hydride or a metal hydride
complex in an amount of 6-60 times with respect to the
theoretical amount at a temperature of 0°C-refluxing
temperature to form N-[6,11-dihydro-5H-dibenz[b,e]azepin-6-
yl)methyl]-o-hydroxy methylbenzamide; and
(ii) transforming the formed N-[6,11-dihydro-5H-dibenz[b,e]azepin-
6-yl)methyl]-o-hydroxymethylbenzamide into 6-aminomethyl-
6,11-dihydro-5H-dibenz [b,e]azepin.
2. N-[6,11 -dihydro-5H-dibenz[b,e]azepin-6-yl)methyl]-o-hydroxymethyl
benzamide.
3. The production method as claimed in claim 1, wherein the metal hydride
or the metal hydride complex is boron hydride.
4. The production method as claimed in claim 1, wherein an alcohol or a
water based alcohol such as herein described is employed as a solvent in
the step (i) and (ii).

5. The production method as claimed in claim 1, in the step (ii), N-[6,11-
dihydro-5H-dibenz[b,e]azepin-6-yl)methyl]-o-hydroxymethylbenzamide is
processed with an acid or a base such as herein described.

Title: PRODUCTION METHOD OF 6-AMINOMETHYL-6, 11-DIHYRO-5H
DIBENZ [b,e] AZEPIN
A method for producing 6-aminomethyl-6,11-dihydro-5H-dibenz[b,3]azepin
comprising the steps of:
(i) allowing 2-(11 H-dibenz[b,e]azepin-6-ylmethyl)-1 H-isoindole-1,3(2H)-dione
to react with a metal hydride or a metal hydride complex in an amount of 6-
60 times with respect to the theoretical amount at a temperature of 0°C-
refluxing temperature to form N-[6,11-dihydro-5H-dibenz[b,e]azepin-6-
yl)methyl]-o-hydroxy methylbenzamide; and
(ii) transforming the formed N-[6,11-dihydro-5H-dibenz[b,e]azepin-6-yl)methyl]-
o-hydroxymethylbenzamide into 6-aminomethyl-6,11-dihydro-5H-dibenz
[b,e]azepin.