Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
lZ~233
This application is a divisional of Canadian Patent
Application Serial number 418,332, filed December 22, 1982.
The present invention relates to intermediates for the
preparation of 4-phenyl-1,3-benzodiazepins, and in parti-
cular interme~iates for the synthesis of the compourld 4,5-
dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepin, and
its optical antipodes and physiologically acceptable
salts.
The compounds 4,5-dihydro-4-phenyl-3H-1,3-benzo-
diazepins of the formula
R
Xm ~ ~ -R' (I)
~y
n
in which R is hydrogen or alkyl of from 1 to 5 carbon atoms;
R1 is hydrogen, alkyl of from 1 to 5 carbon atoms, cycln-
alkylalkyl of from 4 to 8 carbon atoms or aralkyl having
from 1 to 5 carbon atoms in the alkyl moi~ty; X and Y
are the same or different and each can be hydrogen,
chlorine, bromine, fluorine, methoxy, alkyl of from 1 to 3
carbon atoms, hydroxy or trifluoromethyl; m is the integer
1 or 2; and n is the integer 1, 2 or 3, their optic~l
antipodes and physiologically accep~able salts are useful
as antidepressants, analgetics and anticonvulsants. Of
particular interest for these purposes are the hydro-
chloride salts of the 4-phenyl-1,3-benzodiazepin of formula
(I), t~herein R and R' are both methyl, and X and ~ are both
hydrogen.
The 4-phenyl-1,3-benzodiazepins, methods for their
preparation and compounds useful as intermediates in their
preparation are known from published European Pat. Appl.
No. 0 009 800. The known methods of preparation require a
relatively large number of steps, the steps are relatively
complicated, the starting materials are costly and the
yields of the 4-phenyl-1,3-benzodiazepins are less than
.. .
~2~8~33
- 3 - HOE 81/S 023
. ,
desirable.
This invention provides novel intermediate compounds
utilized in the preparation of the ~-phenyl-1,3-benzodiaze-
pins of formula (I). The.se intermediates have the formula
NHCOR2
~ (II)
OH
where Y is -OH; halogen; -N -CH3; R1SO3-; where R1 is a
straight chain or branched chain alkyl group havin~ 1 to 5
carbon atoms, or aryl; and R2 is -C(C~H3)3 or -O-C(CH3)3
and
NHCOR2 (III)
HCH3
~ .
~
2 ( 3)3 O C(C~3)3.
This invention also provides methods for preparing
the compounds of the invent'on.
In addition, this invention provides for the use of
the compounds of the invention in the preparation of the
4-phenyl-1,3-benzodiazepins of formula (I).
When the compounds of the invention are utilized in the
synthesis of the 4-phenyl-1,3-benzodiazpins of formula (I),
a smaller number of process steps may be employed, and the
benzodiazepins may be prepared in high yields and increased
purity.
Preferred compounds of the formula II are thosein
which the substituent Y is hydroxyl, chlorine or bromine.
When Y is halogen, chlorine is particularly preferred.
When Y in formula (II) is R1SO3- and R1 is alkyl, a methyl
~Z~BZ33
- 4 - HOE 81/S 023
~ sulfonyl group is preferred. As used throughout the
specification and appended claims, the term "alkyl" shall
mean an acyclic hydrocarbon group containing no unsatura-
tion. When ~ in formula (II) is R1SO3- and R1 is aryl, the
substituent group will typically be a phenyl sulfonyl, a
p-chlorophenyl sulfonyl or a p-toluene sulfonyl group.
The compounds of formula (II) and the compounds of
formula (III) can be prepared according to the following
sequence of reaction.
1. An N-acylated-o-toluidine of the formula
O
N ~
~ 2 (IV)
CH3
is converted to a dilithio intermediate of the formula
~ ~ ~ Ol,i
C 2
where R2 is asdefined above. The N-acylatcd-o-toluidine of
formula (IV) is N-/ (2-methyl)-phenyl 7-2,2-dimethyl-
propanamide or N-t-butoxycarbonyl-o-toluidine. Lithiation
of aromatic compounds with an n-alkyllithium compound is
exemplified in J. M. Muchowski and M.Venuti, J.OrgO Chem.
45, 4798-4801 (1980) and W. Fuhrer and H.W. Gschwend, J.
Org. Chem. 44, 1133-1136 ~1979)o A preferred method
according to the present invention involves slowly adding
a solution of alkyllithium, such as n-butyllithium, sec-
butyllithium or tert-butyllithium, in a solvent therefor,
such as hexane, to a solution of the N-acylated-o-toluidine
in 2n ethereal solvent, such as diethyl ether, tetrahydro-
furan, dimethoxyethane, and a hydrocarbon solvent, such as
.
~2~ 33
- 5 - HOE 81/S 023
hexane. The preferred alkyllithium compound is n-butyl-
lithium. The ethereal solvent and hydrocarbon solvent
should be substantially inert to the alkyllithium to avoid
adverse side reactions. The temperature during tl1e
addition can range from about -70C to about 30~C,
preferably about -10~C to about 30~C. The resulting mixture
is aged from about one-half to about 5 hours, preferably
about 1 to about 2 hours. The reaction is conveniently
carried out at atmospheric pressure. The amount of alkyl-
lithium employed is up to about 10 % in excess of the 2molar equivalents required for the reaction. It is important
to excludc moisture from the reaction mixture. Accordingly,
th~ reaction is conveniently conducted in an atmosphere of
a substantially dry gas, such as substantially anhydrous
nitrogen.
2. In order to prepare a compound of formula (II) in
which Y is a hydroxyl group, the dilithio interrnediate of
formula (V) is quenched with benzaldehyde as an electro-
phile. The aqueous work up of the reaction mixture
provides the compound of formula (II) in which Y is hydroxyl.
The temperature of addition of the benzaldehyde can range
~rom about -78DC to about 35C, preferably from about 0 to
about 25C. The mixture is aged for a period of about 5
minutes to about one hour. The amount of benzaldehyde
employed is from about one to about 2 molar equivalents
based on the dilithio intermediate of formula (V). The
quenching with benzaldehyde is conveniently conducted at
atmospheric pressure and in a substantially dry e.g., dry
nitrogen, atmosphere.
In order to prepare a compound of formula (II) in
which Y is halogen, a compound of formula (II) in which
Y is hydro~yl is carefully halogenated to provide the
corresponding halide. This conversion can be conveniently
performed by any method known in the art or converting
a benzylic alcohol to the corresponding halide. For
instance, a compound according to formula (II) in which
8~:;33
- 6 - HOE 81/S 023
- Y is a hydroxyl group can be dissolved in a suitable
solvent therefor. Typical solvents are non-hydroxylic
solvents, such as non-hydroxylic halogenated sol~ents, or
non-nucleophilic amines, such as pyridine or a tertiary
amine, such as trimethyl amine. Reaction with about 1 to
about 2 equivalents, preferably about 1.1 equivalents, of
thionyl chloride at about 0 to about 50C, preferably
about 20 to about 30C, can be carried out for a period of
about 1 to about 16 hours. Ohter known chlorinating
agents, such as phosphorus oxychloride or phosphorus penta-
chloride can also be employed. The method selected should
not result in hydrolysis of the propanamide group or the
N-(t-butoxycarbonyl) sroup. For example, the hydroxy
compound can alternatively be reacted with a phosphorus
trihalide, such as phosphorus tribromide, under standard
reaction conditions. In a preferred method according to
this invention, a compound of formula (II) in which Y is
hy~roxy~ is preferably at least partial]y dissolved in a
solvent, such as methylene chloride or pyridine, and then
chlorinated by reaction with thionyl chloride. Preferably,
the thionyl chloride is employed in about a 10 % stoichio-
metric excess. The reaction is mildly exothermic and can
be carried out with additional heating until substantially
complete as evidenced by cessation in evolution of sulfur
dioxide and hydrogen chloride. The resulting halide can be
recovered and purified using conventional techniques.
If a ~ompound of formula (II) in which Y is a hydroxyl
group is reacted with an appropriate al~yl or aryl sulfonyl
chloride or alkyl or aryl sulfonyl anhydride, it is
possible to prepare compounds according to formula (II)
iIl which Y is R1SO3- as previously defined. For example,
reaction of the hydroxy compound (II) with an alkyl sulfonyl
chloride, such as methane sulfonyl chloride, will yield a
compound of formula (II) in which Y is an alkyl sulfonyl
3~ group. Similarly, reaction of the hydroxy compound (II)
with phenyl sulfonyl chloride or anhydride, p-chlorophenyl
1.2C~8~33
- 7 - HOE 81/S 023
sulfonyl chloride or anhydride or p-toluene sulfonyl
chloride or anhydride will yield the corresponding aryl
sulfonates. These reactions can be carried out by
employing well-known conditions for reacting hydroxy
compounds with alkyl or aryl sulfonyl chlorides and an-
hydrides to form the corresponding alkyl and aryl
sulfonates. Typically, the hydroxy compound of formula (II)
in ethereal or hydrocarbon solvents can be reacted with
alkyl or aryl sulfonyl chlorides or alkyl or aryl sulfonyl
anhydrides at a temperature of about -10C to about 70C,
preferably at a temperature o~ about 0C to about 40C.
Compounds according to formula (II) in which Y is
OH
-N-CH3 can be prepared by quenching the dilithio inter-
mediate of formula (V) with an appropriate nitrone. Moreparticularly, the temperature of addition of the nitrone
can range from about -78C to about 35C, preferably from
about 0 to about 25C. The mixture is aged for a period
of about 5 minutes to about one hour. The amount of nitrone
employed is from about one to about 2 molar equivalents
based on the dilithio intermediate of formula (IV). III a
preferred method according to the invention, the dilithio
intermediate of formula (IV) is reacted with about a
stoichiometric amount of ~-phenyl-N-methyl nitrone at about
0C to about 25C. The quenching is conveniently conducted
at atmospheric pressure and in a substantially moisture-
free, e.g., dry nitrogen, atmosphere. After aqueous work up,
the resulting compound can then be recovered and purified
usiny conventional techniques.
3. The conversion of the intermediate of formula ~II)
into a 2-methylamino-substituted compound haviny the
formula (III)
~ NHCOR2
~ ~ 3 (III)
~3
lZ~3233
- 8 - HOE 81/S 023
- wherein R2 is -C(CH3)3 or -O-C(CH3)3 can be carried out as
follows. When the substituent Y in for~ula (II) is a
hydroxyl group, the compound is first converted to the
corresponding halide or alkyl or aryl sulfonate as des-
cribed above. The halide or alkyl or aryl sulfonate is
reacted with monomethyl amine. The reaction can be carried
out in a solvent, such as 2~propanol, at a temperature of
about 80 to about 120C. The reaction can be conducted
for about 1 to about 12 hours at a pres~ure of about 1 bar
to about 6.8 bar. The amount of monomethyl amine will
typically be about 1 to about 10 molar equivalents based
on the halide or sulfonate of formula (II). A large
excess of monomethylamine is preferably employed to ensure
substantially complete conversion to the 2-methylamine-
substituted compound of formula (III). OH
When the substituent Y in formula (II) is -N-CH3,
the 2-methylamine-substituted compound of formula (III)
c~n be ~repared by reduction of an N-methyl hydroxylamine
of formula (II) with a noble metal catalyst, such as
platinum or palladium. For example, an N-methyl hydroxyl-
amine of formula (II) can be reacted in methanol and in
the presence of hydrogen gas with a palladium on carbon
catalyst. The reaction can generally be carried out at
about room temperature and atmospheric pressure until
substantia]ly complete. The reaction time will typically be
about one hour .
An alternate method of preparing the compound of
formula (II) via alkyl and aryl sulfonates is as follows.
The dilithio intermediate of formula (V) is quenched with
benzaldehyde as described in stage 2 above. Instead of
working up the reaction mixture in aqueous phase at the
end of the reaction, an alkyl or aryl sulfonic anhydride is
added to the reaction mixture. For example, about 1 to
about 2 equivalents of methane sul~onic anhydride can be
added to the reaction mixture. The resulting reaction is
carried out at about 0~ to about 20C until substantially
~2al8233
- 9 - HOE ~1/S 023
- complete, which will typically be about 30 minutes to
about 1 hour. An al~yl or aryl sulfonate intermediate is
formed, which can be converted to the compound of formula
(III) by reaction with monomethyl amine. More particularl~7,
monomethyl amine can be bubbled into the reaction mixture
containing the sulfonate intermediate. The amine should
be added slowly to avoid side reactions. Typically, about
3 to about 5 equivalents of monomethyl amine are added
during the course of the reaction. The reaction can be
carried out at about 0 to about 80C, preferably at about
0 to about 20C, until complete, typically for ahout 1 to
about 2 hours. The compound of formula (III) can then be
recovered from the reaction mixture and purified using con-
ventional techniques.
4. The compound of formula (III) is then hydrolyzed
to provide an N-methyl-2-amino-~-phenylphenethylamine as a
free base of the formula
/~H 2
~ ~ ~ICH3 (VI)
~,
~ .
or as its salt, e.g., dihydrochloride. The aromatic amine
of formula (VI) is the immediate precursor of the 4-
phen~l-1,3-benzodiazepins of formula (I). Thus, it will
be understood that the salts of the compound of formula
(VI) can be general be the same as the salts of the
compounds of formula (I).
In one method, the compound of formula (III) is
reacted with about 2 molar equivalents of a strong mineral
acid, such as hydrochloric acid, hydrobromic acid or
sulfuric acid. 6 N hydrochloric acid is the acid of
choice. The reaction is conveniently conducted at atmospheric
8233
- 10 - HOE 81/S 023
pressure and at a temperature of from about 70 to the
reflux temperature of the solvent employed in the reaction
for a period of about 12 to about 48 hours to provide a
diacid salt, which can then be recrystallized. A solvent,
such as ether or an aromatic solvent, is employed to remove
any side products while retainin~ the diacid salt in
aqueous phase. If desired, the diacid salt can be basified
to provide the free base.
5. The aromatic amine of forn,ula (VI) in free base or
salt form can be cyclized with a compound of the formula
C2H5l 3l
C H O-C-CH or CH30-C-CH3
2 5 CH30
(VII) (VIII)
to provide the 4-phenyl-1,3-benzodiazepins of formula (I).
This cyclization can be carried out in the presence of an
acid catalyst, such as ethanolic hydrochloric acid
Alternatively, the monoacid or diacid salt of the compound
of formula (VI) can be cyclized with a compound of formula
(VII) or formula ~VIII) in a polar solvent, such as aceto-
nitrile or acetic acid. Use of acetonitrile makes it
unnecessary to add an acid catalyst to the reaction mixture.
The reaction can be conducted at a temperature of from
about 25C to the reflux temperature of the reaction mixture
and at atmospheric pressure for at least about 1 hour,
typically about 1 to about 8 hours. About 1 to about 5
molar equivalents, preferably about 2 molar equivalents, of
the compound of formula (VII) or formula iVIII) are
employed.
The invention is described in greater detail in the
followin~ examples in which all parts,proportions, ratios
and percentayes are by wei~t unless otherwise indicated.
Z33
- 11 - HOE 81/S 023
Example 1 - Synthesis of trimethylacetyl chloride
A solution of trimethylacetic acid (204.3 g, 2.0 mol)
in methylene chloride (400 ml) containing a catalytic
amount of DMF (0.5 g) was stirred under a dry nitrogen
atmosphere and treated ~ith SOCl2(258 g, 2.06 mol).
Following the addition of SOCl2 (about 5 minutes) the
reaction temperature dropped from 21C to 13C; at the
same time, a vigorous evolution of HCl and SO2 occurred.
After 5 hours, the reaction was heated to reflux and
maintained at this temperature for 2 hours. At this time,
the conversion of trimethylacetic acid to trimethylacetyl
chloride was quantitative. The crude product, without
concentration or distillation, can be employed directly in
the synthesis of N~ methyl)phenyl_ 7- 2,2-dimethyl
propanamide.
Example 2 - ~ynthesis of N-t (2-methyl)phenyl_ 7-
2,2-dimethyl propanamide
(a) A biphasic solution o~ o-toluidine (107.2 g,
1.0 mol) in methylene chloride (500 ml) and water (150 ml)
containing sodium carbonate (69 y, 0.65 mol) was treated
with trimethylacetyl chloride (120.6 g, 1.0 mol). The rate
of addition of trimethylacetyl chloride was adjustcd so as
to maintain the reaction at ~entle reIlux. After ~5
minutes the addition was complete. The oryanic layer was
separated, washed with water, and concentrated in vacuo.
The crude N-/ (2-methyl)phenyl_/-2,2-dimethylpropanamide
was slurried iJl 2 % aqueous HCl, filtered and washed with
H2O until the filtrate was neutral. After drying in vacuo
(50C, 20 mm), N-/ (2-methyl)phenyl_7-2,2-dimethylpropan-
amide (178 g, 0.93 mol~ was obtained in 93 % yield (m.pO
1 09-1 1 0C) .
(b) A biphasic solution of o-toluidine (214.4 y,
2.0 mol) in methylene chloride (200 ml) and water (250 ml)
containing sodium carbonate (117 g, 1.1 ~mol) was treated
with trimethylacetyl chloride (about 2.0 mol in methylene
chloride from ~xample 1). The addition of trimethylacetyl
chloride ~as complete after 50 minutes; the temperature
J.,2~ 33
- 12 ~ HOE 81 /S 023
ranged between 37-50C during the addition. The ~arm
organic phase was separated and the aqueous phase was
extracted with methylene chloride 12 x 100 ml). The
combined methylene chloride solution was washed with 1N
HCl (2 x 100 ml), ~l2 (3 x 200 ml), 10 % NaCl (100 ml),
and concentrated in vacuo ( 25C at 30 mm) to give free
flowing crystalline N-/ (2-methyl3phenyl_7-2,2-dimethyl-
propanamide. Final drying (at 60C, 30 mm, 24 hours) gave
N-/ (2-methyl)phenyl 7-2,2-dimethylpropanamide (379 g,
1.98 mol) in 99 % yield. The melting p~int of the product
was 108-111 C. This product can be used directly in
Example 3 without recrystalliæation~
Example 3 - Synthesis of N-[2-(2-hydroxy-2-phenyl-
ethyl)-phenyl]-2,2-dimethylpropanamide
A stirred solution of N-[(2-methyl)phenyl]-2,2-dimethyl-
propanamide (95.6 g, 0.5 mol) in THF (500 ml) was cooled
to 0C and treated with 1.6M n-butyllithium in hexane
(628 ml, 0.1 mol). The addition of n-butyllithium was
complete after 45 minutes. During the addition, the tempe-
rature of the mixture was maintained below 10C with
external cooling. The resultant dianion solution was aged
for 2 hours at 0C until the homogeneous orange so]ution
became a yellow heterogeneous slurry. The dianion was then
quenched with benzaldehyde (63.6 g, 0.6 mol) and aged for
15 minutes at about 24C. The reaction mixture was diluted
with ~ther (200 ml), treated with crushed ice (200 ~), and
stirred for 5 minutes. The organic phase was separated,
washed with saturated sodium chloride (250 ml), dried over
anhydrous magnesium sulfate, filtered and concentrated in
vacuo. The residual oil was crystallized from hexane,
filtered and recrystallized from dichloromethane (500 ml
reflux) to give N-[2-(2-hydroxy-2-phenylethyl)-phenyl]-
2,2-dimethylpropanamide (87 g, 0.29 mol) in 58 % yield.
The product had a melting point of 183 to 184C.
Example 4 - Synthesis of N-[2-(2-chloro-2-phenylethyl)
phenyl]-2,2-dimethylpropanamide
N-12-(2-hydroxy-2-phenylethyl)phenyl]-2,2-dimethyl-
8Z3~
- 13 - HOE 81/S 023
propanamide ~29.74 g, 0.1 mol) was partially dissolved in
dichloromethane (120 ml). Thionyl ch]oride (12.69 g,
0.11 mol, 1.1 equiv.) was added over a 3-minute period to
the resulting mixture. A substantially homogeneous solution
formed with moderate evolution of hydrogen chloride and
sulfur dioxide. The reaction mixture was maintained below
27C. When evolution of gas ceased, the reaction mixture
was worked up by washing the mixture with saturated sodium
bicarbonate solution until the aqueous phase remained
neutral (pH = 6.5 to 7). The organic phase was separated,
washed with saturated sodium chloride solution, dried
over anhydrous magnesium sulfate, filtered and concentrated
in vacuo ti give 31.89 g of product. The product was
purified by silica gel chromatography (CH2Cl2/hexane,
50:50, followed by CH2C12) to give a quantitative yield of
an off-white crystalline product having a melting point
of 87-92C.
Exam~le 5 - Synthesi~ of N-[2-(2-methy]~mino-2-
phenylethyl)-phenyl]-2,2-dimethylpropanamide
N-[2-(2-chloro-2-phenylethyl)phenyl~-2,2-dimethyl-
propanamide (1.0 g, 3.17 mol) was reacted with monomethyl
amine (7 g o~ 40 % aqueous solution) in 2-propanol ~3 g).
The mixture was heated to 80C and stirred for 1 hour.
Formation of product was indicated by TLC (silica gel/
70 ethyl acetate/30 methanol).
Example 6 - Synthesis of N-methyl-2-amino-~-phenyl-
phenethylamine dihydrochloride
~ a) N-[2-(2-methylamino-2-phenylethyl-phenyl]-2,2-
dimethyl-propanamide (62 g, 0.2 mol) was dissolved in 5 N
HCl (124 g) and stirred under a nitrogen atmosphere at
100C for 24 hours. The warm reaction mixture (about 35-
40C) was extracted with toluene (2 x 100 ml) to effect
recovery of trimethylacetic acid. The aqueous phase was
dried by azeotropic distillation with toluene ~200 ml)
using a Dean-Stark phase separator. The product was collec-
ted by filtration, slurried in hot 2-propanol (200 ml),
3233
- 14 - HOE 81/S 023
refiltered and dried in vacuo (30 mm) at 45C for 12
hours to give N-methyl-2-amino-cl.-phenylphenethylamine di-
hydrochloride (58.7 g, 0.196 mol) in 98 % yield~ The
product had a melting point of 251-253C.
(b) N-[2-~2-methylamino-2-phenylethyl)phenyl]-2,2-
dimethyl-propanamide t155 g, 0.5 mol) was dissolved in
6 N HCl (310 g) and stirred under a nitrogen atmosphere
at 100C for 28 hours. The reaction mixture was cooled
to 23C and toluene (200 ml) was added. Stirring was
continued until the product had crystallized from the aqueous
phase. The product was collected by filtration, washed
with toluene (2 x 50 ml) and dried in vacuo (30 mm) at
60C for 60 hours to give N-methyl-2-amino-~-phenylphenethyl-
amine dihydrochloride (139 g, 93 % yield). The melting
point of the product was 252-254C. The organic phase of
the filtrate was concentrated in vacuo ti give a 58 %
recovery of trimethylacetic acid. The aqueous phase of the
filtrate afforded a second crop Ol N-me~hyl-2-a~ o-c-.-
phenylphenethylamine dihydrochloride (9.3 g, 6 ~). The
total yield of product was 99 %.
Example 7 - Synthesis of 2,3-dimethyl-4-3H-1,3-
benzodiazepin hydrochloride
A heterogeneous mixture of N-methyl-2-amino-c~.-phenyl-
phenethylamine dihydrochloride (150 g, 0.5 mol) in aceto-
nitrile (500 ml) was treated with triethylorthoacetate
(202 ml, 1.1 mol) and heated to 70C for 2 hours with
stirring under a dry nitrogen atmosphere. The reaction mix-
ture was filtered, concentrated in vacuo, and the residual
solid recrystallized from 2-propanol at -10C to give
2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepin hydrQchloride
(118 g, 0.413 mol) in 83 % yield. The product had a
melting point of 239.5-241C.
Examp_e 8 - Synthesis of 2,3-dimethyl-4-phenyl-3H-
1,3-benzodiazepin (free base)
A heterogeneous mixture of the c~ihydrochloride salt of
N-ethyl-2-amino-c~-phenylphenethylamine (9 g, 0.03 mol)
~2~8~3~
- 15 - HOE 81/S 023
in acetonitrile (36 cc dried over 4 ~ molecular sieves3
was treated with triethylorthoacetate (9.73 ~, 11 cc,
0.06 mol) and heated to 70C with stirring under a dry
nitrogen atmosphere. At 50C (after about 15 minutes of
heating) the reaction mixture became homogeneous. The
reaction reaction mixture was concentrated in vacuo and
partitioned between 100 ml toluene and 50 ml 5 % NaOH.
The toluene phase was washed with 10 % NaCl, dried over
sodium sulfate, filtered and concentrated in vacuo ti give
a light yellow-brown solid product, which was shown by GC
to be 96.7 % 2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepin.
This crude product free base was recrystallized from
15 ml 2-propanol at 82C, diluted with 30 ml he~ane and
dried at 45C (30 mm for 12 hours). 4.64 g tO.01~5 mol) of
product with a melting point of 144.5-145.4C were
obtained at a yield of 61.8 %. A second crop was re-
crystallized from 5 ml 2-propanol, washed with 3 ml hexane
and dried at 40C (30 mm for 12 hours). 1.92 g (0.0077 mo]~
of product with a melting point of 193.5-144.5C were
obtained at a yield of 25.6 %. The mother liquor (0.64 g)
from the first crop contained 0.24 g of product representing
yield of 3.2 %.
Ex_mple 9 - ~onversion of 2,3-dimethyl-4-phenyl-3H-
1,3-benzodiazepin (free base) to hydro-
chloride salt
1.9 g (0.0759 mol) of the free base 2,3-dimethyl-4-
phenyl-3H-1,3-benzodiazepin was dissolved in 2-propanol
and treated at 5-10C with an excess of 2-propanol
saturated with anhydrous HCl. The monohydrochloride salt
of the 2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepin was
recrystallized from solution and recovered by filtration.
The monohydrochloride salt had a melting point of 241-
242C. The salt was dried 160C, 30 mm, 24 hours) to yield
1.50 g of a white crystalline powder.
