Note: Descriptions are shown in the official language in which they were submitted.
CA 02297612 2000-02-14
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-1-
PROCESSES AND INTERMEDIATES FOR
PREPARING 3-AMINO-BENZO(B)AZEPINONES
This is a divisional application of Canadian Patent
Application No. 2,200,336 filed September 13, 1995.
The present invention relates to novel processes for
the preparation of intermediates useful for producing benzo-
[b]azepine-2-one CCK antagonists of formula VII, described
below, and to novel intermediates used in the processes.
The subject matter of this divisional application is
restricted to processes for producing compounds of the
formulae Ia and II, described below.
It should be understood that the expression "the
present invention" or the like used in this specification
encompasses not only the subject matter of this divisional
application but that of the parent application also.
PCT Patent Publication WO 93/15059, published
August 5, 1993, refers to the CCK receptor antagonist of
formula VII and processes for their preparation.
PCT Patent Publication WO 94/07483, published
April 14, 1994, refers to benzo-fused lactam derivatives that
are stated to be growth hormone release agents and are
prepared in a process analogous to that described in PCT
Patent Publication WO 93/15059.
PCT Patent Publication WO 94/07483, published
April 14, 1994, generically refers to benzo[b]azepine-2-ones,
but does not refer to any specific stereoisomers of these
intermediates.
Summary of the Invention
The present invention relates to the intermediate
(+)-cis-(3R)-amino-8-methyl-(5R)-phenyl-1,3,4,5-tetrahydro
benzo[b]azepine-2-one.
The present invention also relates to a process for
preparing the diasteriomeric salt (+)-cis-(3R)-amino-8-methyl-
(5R)-phenyl-1,3,4,5-tetrahydro-benzo[b]azepine-2-one~(D)-(+)-
dibenzoyltartarate or (-)-cis-(3S)-amino-8-methyl-(5S)-phenyl-
1,3,4,5-tetrahydro-benzo[b]azepine-2-one ~(L)-(-)-dibenzoyl-
CA 02297612 2000-02-14
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-la-
tartarate, comprising reacting (D)-(+)-dibenzoyltartaric acid
with either racemic or optically enriched cis-3-amino-8-
methyl-5-phenyl-1,3,4,5-tetrahydro-benzo[b]azepine-2-one, or
reacting (L)-(-)-dibenzoyltartaric acid with either racemic
or enantiomerically enriched cis-3-amino-8-methyl-5-phenyl-
1,3,4,5-tetrahydro-benzo[b]azepine-2-one in an organic solvent,
preferably acetone or ethyl acetate.
Preferably, the diastereomeric salt (+)-cis-(3R)-
amino-8-methyl-(5R)-phenyl-1,3,4,5-tetrahydro-benzo[b]azepine-
2-one~(D)-(+)-dibenzoyltartarate or (-)-cis-(3S)-amino-8-
methyl-(5S)-phenyl-1,3,4,5-tetrahydro-benzo[b]azepine-2-one~-
(L)-(-)-dibenzoyltartarate is neutralized to form, respectively,
(+)-cis-(3R)-amino-8-methyl-(5R)-phenyl-1,3,4,5-tetrahydro-
benzo[b]azepine-2-one or (-)-cis-(3S)-amino-8-methyl-(5S)-
phenyl-1,3,4,5-tetrahydro-benzo[b]azepine-2-one.
~
CA 02297612 2004-05-04
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-2-
Preferably, the diastereomeric salt (+)-cis-(3R)-
amino-8-methyl-(5R)-phenyl-1,3,4,5-tetrahydro-benzo[b]azepine-
2-one~(D)-(+)-dibenzoyltartarate or (-)-cis-(3S)-amino-8-
methyl-(5S)-phenyl-1,3,4,5-tetrahydro-benzo[b]azepine-2-
one~(L)-(-)-dibenzoyltartarate is neutralized with a base,
preferably sodium hydroxide.
The present invention also relates to a process for
the preparation of racemic compounds of formula:
Y NHZ
n
Ia
wherein X and NH2 are in the cis configuration in at
least 90~ of the molecules of formula Ia;
Y1 and Y2 are independently selected from hydrogen,
halo, nitro, amino, (Cl-C6)alkyl optionally substituted with
from one to three fluorine atoms and (C1-C6)alkoxy optionally
substituted with from one to three fluorine atoms; and
X is selected from the group consisting of phenyl,
(C1-Cg)straight or branched alkyl and (C5-Cg)cycloalkyl,
wherein the phenyl may optionally be substituted with one or
two substituents independently selected from the group
consisting of halo, (C1-C6)alkyl, (C1-C6)alkoxy, nitro, amino
and trifluoromethyl, and wherein the (C5-Cg)cycloalkyl may
optionally be substituted with one or two substituents
CA 02297612 2000-02-14
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-2a-
independently selected from (C1-C6)alkyl; which process
comprises reducing a compound of the formula:
X
Yz
Y1 ~ I N-O-CH3
N
H O
I I
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CA 02297612 2000-02-14
"a
-0-CH3
to I I
wherein X, Y' and Y= are defined as above, comprising
a) reacting a compound of the formula
t5 Y2 X
~~0
i
NH2
2o I V
wherein X, Y' and Y~ are defined as above, with a compound of formula
O,CH3
I
N
25 / 0
C1L
( CH3CH~0 )2-P
wherein Y', Y= and X are defined as above, with Raney-nickel and a hydrogen
source.
The present invention also relates to a process for tha preparation of a
compound of the formula
V
wherein L is hydroxy, chioro, -O=COR, and R is (C,-Ce)alkyi, or L is a group
of
the formula
Trade-mark
CA 02297612 2000-02-14
64680-960D
O~CH3
I
N
~0
,C
~0
( CH3CH20 >2-P~
0
V'
to form a compound of the formula
Y2 x 0
Y1 \ 0 0
' , ~~ ~OCH2CH3
N
H N \OCH2CH3
0
i
CH3
wherein X, Y' and YZ are defined as above, in an organic solvent, preferably
dichloromethane;
and wherein said reaction is carried out in the presence of a dehydrating
agent,
preferablydicyclohexylcarbodiimide,l-(3-dimethylaminopropyi)-3-
ethylcartiodiimide,or
diphenylphosphoryl azide, when L is hydroxy;
and said reaction is carried out in the presence of an acid scavenger,
preferably
triethylamine, N-methyl-morpholine, dimethyiaminopyridine or pyridine, when L
is other
than hydroxy; and
b) reacting said compound of formula Ill,wherein X, Y' and Y= are defined
as above, with a base, preferably potassium t-butoxide, in an organic solvent,
preferably
tetrahydrofuran.
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_5_
Detailed Description of the Invention
In the discussion and reaction schemes that
follow, X, Y1, Y2 and L are as defined above.
64680-960D
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-6-
Sch-
O,CH3
S Y2 X N 0
\ o (I
Y1 ~ + C-L
/ NH < CH3CHz0 )z-pb
z w
IV
V
y.z X X
~0 Y 2
Y / ~~OCH2CH3 Y1 N-0-CH3
H~P~ -. N
N OCH2CH3 H 0
I
0 II
i
CH3
Yz X X
,,"H
H
Y1~ NHz
NH2
N H3C
H 0 H 0
Ia I
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_7_
Sch,- e-
X H
I ~ ~°~o~ N H 2
H3C N
H 0
X H
..
0 Zi
~ .,''~~H H /
N N 2
i H Z
H3C N
H 0
VI
X H
H 0 Z 1
w ,, H
... y
~ .., N N Z 2
H
H3C N
0
R1
VII
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The CCK intermediate (+)-cis-(3R)-amino-&methyl-(5R).~henyi-1,3,4,5-
tetrahydro.
benzo[b]azepine-2-one of the invention has the formula I depicted in scheme 1
and can
be prepared according to the methods described in scheme t .
Referring to scheme 1, a compound of the formula IV is reacted with a
compound of the fomnula V, wherein L is defined as above, in an organic
solvent to
form a compound of !he formula III.
When L is hydroxy (-OH), then the reaction of the compound of formula IV with
a compound of formula V requires the presence of a dehydrating agent which
activates
the carboxylic functionality of the acid for reaction with the amine. Examples
of
suitable dehydrating agents are dicyclohexylcarbodiimide/hydroxyberuo-triazole
(HBT),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide/HBT, 2-ethoxy-1-ethoxycarbonyl-
1,2-
dihydroquinoline (EEDC~), carbonyl diimidazole (CDI)/HBT,
diethylphosphorylcyanide,
dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and
diphenylphosphoryl azide. Preferably, the dehydrating agent is 1-(3-
dimethylaminopropyi)-3-ethylcarbodiimide. The above reaction is generally
conducted
at a temperature from about -30 to about 80°C, preferably from about 20
to about
80°C. The reaction is conducted in an inert solvent, preferably an
aprotic solvent.
Suitable solvents include acetonitrile, dichloromethane, chloroform,
dichioroethane and
dimethyiformamide. The preferred solvent is dichloromethane.
When L is other than hydroxy, the reaction requires the presence of an acid
scavenger such as triethyiamine, N-methyl-morpholine, dimethylaminopyridine or
pyridine. Preferably the acid scavenger is dimethylaminopyridine. The above
reaction
is generally conducted at a temperature from about -30 to about 80°C,
preferably from
about 20 to about 80°C. The reaction is coriducted in an inert solvent,
preferably an
aprotic solvent. Suitable solvents include acetonitrile, dichloromethane,
chloroform,
dichloroethane and dimethylformamide. The preferred solvent is
dichloromethane.
The compound of formula III is cyclized to a benzazepine compound of formula
II by a Homer-Wadsworth-Emmons reaction. The compound of formula Ill is
treated
with a base, such as sodium hydride, sodium amide, potassium t-butoxide or
sodium
methoxide, preferably potassium t-butoxide. Reaction inert solvents that are
acceptable
for the above Homer-Wadworth-Emmons reaction include such solvents as ether,
tetrahydrofuran, or dimethyfformamide preferably tetrahydrofuran. The reaction
is
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performed at a temperature of from about 20°C to about 70°C,
preferably from about
40 ° C to about 70 ° C.
The compound of formulalz so formed is then reduced to a racemic amino of
formula la via olefin hydrogenation using a transition metal catalyst and a
hydrogen
source in an inert sohrent. The compound of formula la so formed encompasses a
mixture of four isomers including two cis isomers (formula I and I' below) and
two traps
isomers. The traps isomers are not shown. The two cis isomers ( wherein X and
NH=
are on the same side of the benzazepine ring) comprise in excess of 9096 of
the
molecules fom~ed in the reduction. Preferably, the two cis isomers (wherein X
and NH=
are on the same side of the benzazepine ring) comprise in excess of 9596 of
the
molecules formed in the reduction. The traps isomer accounts for less than
1096 of the
reaction product, preferably less than 596. The cis compounds of formula la
consist of
compounds of the formula
H3C
x
NHz
I
end
H
,,X
/ NH2
H3C
H
I'
Suitable transition metal catalysts that are useful for the reduction include
palladium on
carbon, palladium hydroxide on carbon,
tetrakis(triphenylphoshine)palladium(0), Raney
Trade-mark
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Nickel and rhodium(II) acetate. The preferred transition metal
catalyst is Raney*-Nickel. Suitable hydrogen sources include
hydrogen gas, ammonium formate, and formic acid. The preferred
hydrogen source is hydrogen gas, preferably used at a pressure
from about one to about three atmospheres. Suitable inert
solvents include (C1-C4) alcohols, N,N-dimethylformamide, ethyl
acetate, and acetic acid. The preferred solvent is methanol.
The reaction is generally run at a temperature from about 20°C
to about 75°C, preferably at a temperature from about 20°C to
about 30°C.
The racemic amine of formula Ia, wherein X is phenyl
Y1 is 8-methyl, and Y2 is hydrogen can be resolved to yield the
(3R, 5R) and (3S, 5S) isomers of formula I by formation of an
amine salt with (D)-(+)-dibenzoyltartaric acid or (L)-(-)-
dibenzoyltartaric acid in an appropriate solvent. The racemic
amine of formula Ia, wherein X is phenyl, Y1 is 8-methyl and Y2
is hydrogen, can be resolved by recrystallizing the racemate of
formula Ia with either (D)-(+)-dibenzoyltartaric acid or (L)-
(-)-dibenzoyltartaric acid in an organic solvent to yield a
diastereomeric salts of the formula:
X ~i
-- N H ~ ~ ~ C O
3
\ O /O
!!3C O 0 O!I
- ('=O
A
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-l0a-
and
X H
O
""NH 0 O O O-C
3
Ii3C ~ N fi O
O
O U OiI
O---C
B
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-11-
wherein X is phenyl. The salt so formed may be repeatedly recrystallized firom
tha
same or different solvent or may be directly converted to the pure enantiomer
of
formula I wherein X is phenyl.
Appropriate solvents for the foregoing resolutions of the (3R, 5R) and (3S,
5S)
isomers of formula I include any solvent capable of dissolving the reactants
and
selectively dissolving one of the two diastereomeric sans formed, while
causing the
other to precipitate out of solution. Examples of such solvents are acetone
and ethyl
acetate. The preferred solvent is acetone. The temperature of the foregoing
resolutjon
is from about 0°C to about 100°C, preferably at about room
temperature. The initial
salt may contain small amounts of the undesired diasteriomer salt.
A second crystallization can be performed by dissolving the enantiomerically
enriched dias'sreomeric salt of formula A or B, depicted above, in hot
methanol, adding
ethyl acetate to give a precipitate and finally distilling out most of the
methanol while
maintaining the volume by addition of fresh ethyl acetate. The final slurry is
then cooled
to room temperature and the pure salt of formula A or B wherein X is phenyl is
collected by filtration.
When (D)-(+)-dibenzoyftartarate is used as the resolving agent, as described
above, the (D)-(+)-dibenzoyttartarate salt (+)-cis-(3R)-amino-8-methyl-(5R)-
phenyi-
1,3,4,5-tetrahydro-benzo[b]azepine-2-one precipitates out of solution and can
be
physically separated and purfied by methods well known to those skilled in the
art.
The (D)-(+)-dibenzoyltartarate salt of the opposite enantiomer (-)-cis-(3S)-
amino-
8-methyl-{5S)-phenyl-1,3,4,5-tetrahydro-benzo[b]azepine-2-one remains in
solution.
When (L)-(-)-dibenzoyltartarate is used as the resolving agent, (-)-cis-(3S)-
amino-8-
methyl-{5S)-phenyl-1,3,4,5-tetrahydro-benzo[b]azepine-2-one precipitates out
of
solution, while (+)-cis-(3R)-amino-8-methyl-(5R)-phenyl-1,3,4,5-tetrahydro-
benzo[b]azepine-2-one remains in solution.
Neutralization of the dibenzoyltartarate salts of (+)-cis-{3R)-amino-
8-methyl-(5R)-phenyl-1 ,3,4,5-tetrahydro-benzo [b]azepine-2-one~(D)-
(+)-dibenzoyltartarate or (-)-cis-f3S)-amino-8-methyl-(5S)-phenyl-1 ,3,4,5-
tetrahydro-benzo[b]azepine-2-one~{L)-(+)-dibenzoyltartarateto form the
corresponding
optically active free amines may be accomplished using methods well known in
the art.
For example, such neutralization may be accomplished by reacting the
dibenzoyltartarate salts with a base such as sodium hydroxide, potassium
hydroxide,
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-12-
sodium carbonate or potassium carbonate. Suitable solvents for the
neutratt~z~on step
include chlorohydrocarbons, ethers, benzene, toluene and water, as weO as
mbctiaes
of the foregoing solvents (e.g., diethyl ether, diisopropyt ether, methyiene
chloride, or
methylene chloride/water). Suitable temperatures nznge from about t5°C
to about
100 ° C, with room temperature (30 ° C) being preferred.
The compound of the formula I can be converted into compounds of the formula
VII, which are CCK antagonists, according to the methods of scheme 2 The
processes
of scheme 2 are descn'bed in detail in PCT Patent Publication W093/15059
published
August 5, t 993 .
Referring to scheme 2, the compound of formula I is converted ~to the
corresponding compound having formula VI by reacting it with an isocyanate of
the
formula C°H,Z'Z~NCO, wherein Z' and ZI are independently selected from
the group
consisting of halo, (C,-CJ alkyl, (C,-C~ thioalkyt, (C,-Ca alkoxy,
trifluaroms~hyt, (C,-CJ
carboalkoxy, amino and vitro. Approprtate reaction inert sohrents for this
rea~On
include hydrocarbons such as hexane, benzene and tohreno, halogenaded
hydrocarbons such as methylene chloride and 1,2-dichloroethane, ethereal
solvents
such as ethyl ether, tetrahydrofuran (THE and glyme, and pyridine. The
preferred
solvent is 1, 2~chloroethane or methylene chloride. Tertiary organic amines
may be
useful as catalysts. The reaction temperature may range from about 0°C
to about
150°C. The reflux temperature is preferred.
The isocyanate of the formula CeH,Z'Z~NCO used in the foregoing reacton can
be formed by procedures welt known to those slc~ed in the art or are
commercially
available. One such method involves mixing a benzoic acid derivative with
diphenylphosphorylazide, or an analogous reagent, in the presence of an
organic base
such as a trialkyiamine, preferably triethylamine or d-usopropytethytamine.
This n~ction
is usually conducted in an ethereal, hydrocarbon or chlorinated hydrocarbon
solvent,
preferably tetrahydrofuran or benzene, at a temperature from about room
temperature
to about 100°C, preferably at the reflux temperature of the solvent,
for a period from
about 20 minutes to about 24 hours, preferably about 1 hour.
The compound of formula Vt is then alkytated at the ring nitrogen by reaction
with a compound of the formula L'CH=R', wherein L' is bromine or iodine and R'
is
CO=RZ, SOZNR'R° or CONR'Rs, and wherein R~, R', R', R5 and R°
are independently
selected from hydrogen, (C,-C,z) alkyl and fused, saturated carbocyciic
systems
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containing two or three rings and phenyl, wherein said phenyl may optionally
be
substituted with one or two substituents independently selected from halo, (C,-
Ce) alkyl,
(C,-C°) alkoxy, vitro, amino and trifluoromethyl; and wherein L' Is
bromine when R' is
phenyl or substituted phenyl, and L is iodine when R' is -CO=R=, -
SO=NR'R° or
-CONR'R5; in tetrahydrofuran (THF~ in the presence of solid potassium
hydroxide and
a catalytic amount of tetra-n-butyl ammonium bromide. This reaction, which
yields the
corresponding compound of formula VII, is usually conducted at a temperature
from
about 25°C to about 35°C. It is preferably conducted at room
temperature (30°C).
The compounds of the formula VII which a: a basic in nature are capable of
forming a wide variety of different salts with various inorganic and organic
acids.
Although such salts must be pharmaceutically acceptable for administration to
animals,
it is often desirable in practice to initially isolate a compound of the
formula I or II from
the reaction mixture as a pharmaceutically unacceptable salt and then simply
convert
the latter back to the free base compound by treatment with an alkaline
reagent and
subsequently convert the latter free base to a pharmaceutically acceptable
acid addition
salt. The acid addition salts of the active base compounds of this invention
are readily
prepared by treating the base compound with a substantially equivalent amount
of the
chosen mineral or organic acid in an aqueous solvent medium or in a suitable
organic
solvent, such as methanol or ethanol. Upon careful evaporation of the solvent,
the
desired solid salt is readily obtained.
The compounds of formula VII and their pharmaceutically acceptable salts
(hereinafter referred to collectively as 'the active compounds') are useful as
selective
CCK-B receptor antagonists, i.e., they possess the ability to antagonize the
effects of
CCK at its B receptor site in mammals, and therefore they are able to function
as
therapeutic agents in treating or preventing pain, gastrointestinal disorders
such as
ulcer and colitis, and central nervous system disorders such as anxiety and
panic
disorders in an afflicted mammal.
The active compounds can be administered via either the oral, parenteral or
'.opical routes. In general, these compounds are most desirably administered
in
dosages ranging from about 5.0 mg up to about 1500 mg per day, although
variations
will necessarily occur depending upon the weight and condition of the subject
being
treated and the particular route of administration chosen. However, a dosage
level that
is in the range of about 0.07 mg to about 21 mg per kg of body weight per day
is most
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desirably employed. Variations may nevertheless occur depending upon the
species
of anima! being treated and its individual response to said medicament, as
well as on
the type of pharmaceutical formulation chosen and the time period and interval
at which
such administration is carried out. In some instances, dosage levels below the
lower
limit of the aforesaid range may be more than adequate, while in other cases
still larger
doses may be employed vrithout causing any harmful side effect, provided that
such
larger doses are fast divided into several small doses for administration
throughout the
day.
The active compounds may be administered alone or in combination with
pharmaceutically acceptable carriers or diluents by either of the three routes
previously
indicated, and such administration may be carried out in single or multiple
doses. More
particularly, the novel therapeutic agents of this invention can be
administered in a wide
variety of d'rfferent dosage forms, i.e., they may be combined with various
pharmaceutically acceptable inert carriers in the form of tablets, capsules,
lozenges,
troches, hard candies, powders, sprays, creams, salves, suppositories,
jellies, gels,
pastes, lotions, ointments, aqueous suspensions, injectable solutions,
elixirs, syrups,
and the tike. Such carriers include solid diluents or fillers, sterile aqueous
media and
various non-toxic organic solvents, etc. Moreover, oral pharmaceutical
compositions
can be suitably sweetened and/or flavored. In general, the therapeutically-
effective
compounds of this invention are present in such dosage forms at concentration
levels
ranging from about 5.096 to about 7096 by weight.
The activity of the active compounds as CCK-8 antagonists may be determined
by an assay that measures their ability to inhibit the binding of 125-I-BH-CCK-
8 to the
CCK-B receptor in a guinea pig cortical membrane preparation. This procedure
is
carried out as follows. The cortex is dissected from one male Hartley Guinea
pig and
homogenized (15 strokes) with a teflon homogenizer in 20 volumes (w./v.) of
the assay
buffer, which consists of 50 mM Tris (i.e., trimethamine, which is 2-amino-2-
hydroxymethyl-1,3-propanediol) hydrochloric acid having pH 7.4 and 5 mM of
manganese chloride at 4°C. The homogenate is centrifuged at 4°C
for 30 minutes at
100,000 x G. The pellet is resuspended in the same buffer and spun as
described
above. The final pellet is diluted to a concentration of 20 mg/ml with the
assay buffer
for use in the binding assay. The tissue is kept on ice at all times.
64680-960D
CA 02297612 2000-02-14
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An incubation mixture is prepared, which consists of SOuI_ of the tissuo
preparation, prepared as described above, 100uL 125-I-BH-CCK-8 (to give a
concentration of 50 pM in the final assay), 20uL of a blank or the compound
being
tested, and 30uL of Tris with 496 dimethylsutfoxide (DMSO). All drugs and
dDutions are
made using 496 DMSO in the assay buffer yielding a final assay DMSO
concentration
of 196.
The reaction is initiated with the addition of tissue to a 96-well plate
containing
125-I-BH-CCK-8 and the appropriate blank or compound being tested. Non-specfic
binding is estimated using 1 uM sulphated CCK-8. The reaction is terminated by
spinning the plates in a H1000B rotor fitted on a Sorvall RT6000 refrigerated
centrifuge
at 4°C. The supernatant is discarded, and the pellets washed with 200uL
of assay
buffer, and the plate is spun as above. The supernatant is decanted again, and
the
pellet is harvested onto Betaplate filters (which have been soaked in 0.296
polyethyleneimine for a minimum of 2 hours) using a Skatron cell harvester at
setting
222 using Tris HCI pH 7.4 as the wash buffer. The flltermats are counted on a
Betaplate counter for 45 seconds per sample.
Data are expressed as ICs° values (the concentration which inhibits
5096 of the
specific binding of 125-I-BH-CCK-8). The data is analyzed using non-linear
regression
analysis.
The following Examples illustrate the preparation of the intermediates of the
present invention. Commercial reagents were utilized without further
purification.
Melting points are uncorrected. NMR data are reported in parts per million (d)
and are
referenced to the deuterium lock signal from the sample solvent. Specific
rotations
were measured at room temperature using the sodium D line (589 nm). Unless
otherwise stated, all mass spectra were performed using electron impact (EI,
70 e1n
conditions. Chromatography refers to column chromatography performed using 32-
63,um silica gel and executed under nitrogen pressure (flash chromatography)
conditions. Room temperature refers to 20-25 ° C.
64680-960D
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EXAMPLE 1
I+)-Cis-(3R)-amino-8-methyl-(5R1-chenyl-1 3 4 5~tetrahydro-
benzotblazepine-2-one:
A. Ethyl3-bromo-2-(methoxyimino)-propionate:
Ethyl bromopyrwate (50 g, 0.23 mol) and methoxylamine hydrochloride (23.2
g, 0.27 mol) were dissolved in 2B ethanol (185 ml) at 35°C and stirrsd
overnight. Most
of the alcohol was then evaporated in vacuo to provide a semi-solid which was
taken
up in methylene chloride (300 ml) and 0.5 M HCI. The organic layer was
separated and
washed a second time with 0.5 M HCI followed with a brine wash and then dried
over
magnesium sulfate. Fltration and evaporation in vacuo provided the oxime ester
as a
yellow oil; 48.1 g, 9396 yield. This was used without further purification.
B. Triethyl3-phosphono-2-(methoxyimino)-propionate:
Ethyl 3-bromo-2-(methoxyimino)-propionate (48 g, 0.214 mol) and methyl
phosphate (35.5 g, 0.214 mol) were combined and heated under a nitrogen
atmosphere
to 150 - 155°C for 5 hours. The reaction was cooled to room
temperature. 'H NMR
showed the resulting oil to be largely the desired phosphonate. This was used
as is
in the following hydrolysis step. ' H NMR (chloroform-d, CDCI,) d 4.29 (q, 2),
4.05 (m
and s, 7), 3.25 (d, 2, J = 24 Hz), 1.25 (m, 9).
C. Diethyl 3-c~hosphono-2-(methoxyimino)-proplonic acid:
Sodium hydroxide 1 N NaOH (45 ml, 45 mmol) was added to a solution of methyl
3-phosphono-2-(methoxyimino)-propionate (11.6 g, 41 mmol) in ethanol (30 ml)
and the
reaction was stirred at room temperature for 5 hours. The reaction mixture was
then
extracted twice with ether, then acidified with 1 N HCI (50 ml) and extracted
3 times with
methylene chloride. The methylene chloride layers were combined, washed with
brine,
and dried over sodium sulfate. Fltration of the drying agent and evaporation
in vacuo
provided the acid, as an oil which crystallized upon refrigeration. This was
used without
further purification. ' H NMR (CDCI,) d 9.20 (s, 1, CO~, 4.20 - 4.05 (m, 7),
3.34 (d, 2,
J = 24 Hz), 1.30 (t, 6).
D. ~Diethyl3-phosphono-2-(methoxyimino)-propionamidoy~
4-methylbenzophenone:
Diethyl 3-phosphono-2-(methoxyimino)-propionic acid (1.7 g, 7.17 mmol),
2-amino-methylbenzophenone (1 g, 5 mmol) and 1-(3-dimethylaminopropyl)-
3-ethylcarbodiiminde hydrochloride (1.5g, 7.8 mmol) were refluxed in methylene
64680-960D
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chloride (20 ml) for 8 hours. The reaction was then washed with water, 2N
hydrochloric
acid (HC1), aqueous sodium bicarbonate and brine. The solution was dried over
magnesium sulfate and evaporated in vacuo to an oil. This oil was purified by
column
chromatography through silica gel with an eluant of 596 ethyl acetate in
chloroform to
remove unreacted benzophenone. The product was isolated as a crystalline
solid, 0.91
g, 4196. mp 115-18 °C. ' H NMR (CDCI,) d 11.97 (s, 7 ), 8.59 (s, 1 ),
7.70 - 7.42 (m, 6),
6.9C (d, 1 ), 4.19 (s, 3), 4.13 (q, 4), 3.40 (d, 2, J = 24 Hz). 2.42 (s, 3),
1.32 (t, 6).
E. 8-Methyl-5-phenyl-1 H-benzolblazepine-2.3~lione 3-(O-methyl.cxime):
2-(Diethyl 3-phosphono-2-(methoxyimino)-propionamidoyl)-4-methyl
benzophenone (17.6 g, 39.5 mmol) was dissolved in tetrahydrofuran (160 mt) at
room
temperature under a nitrogen atmosphere. The reaction was cooled with ice
water to
4°C and potassium t-butoxide (9.32 g, 79 mmol) was added in one
portion. The
cooling bath was removed and the reaction was heated to reflux for 0.5 hours.
The
reaction was once again cooled and then diluted with ethyl acetate (100 ml)
and
washed with water and brine. After drying over magnesium sulfate, the solvent
was
evaporated in vacuo to afford a solid that was crystallized from isopropanol;
10 g, 87%
yield, mp 234 - 37°C. 'H NMR (CDCI,) a 9.71 (s, 1 NH), 7.38 (bs, 5),
7.05 (s, 1), 6.96
(d, 1, J = 8.1 Hz), 6.84 (d, 1, J = 8.1 Hz), 6.67 (s, 1, vinyl), 4.13 (s, 3,
NOCHl), 2.35
(s, 3). 'sC NMR (CDC1,) a 167.53, 149.09, 144.69, 141.73, 140.33, 135.03,
131.45,
129.14, 128.50, 128.43, 126.14, 125.13, 122.26, 118.68, 63.62, 21.08. Analysis
Calculated for C"H"NZO~: C, 73.96; H, 5.52; N, 9.58. Found: C, 74.22; H, 5.69;
N,
9.52. The structure was confirmed by single crystal X-ray analysis.
F. Cis-3-Amino-8-methyl-5~henyl-1.3.4.5-tetrahydro-benzotblazepine-
2-one:
Raney-nickel (Aldrich Chem., 40 g of aqueous slurry) washed once with water
and three times with methanol (each time the excess solvent was drawn off by
syringe
under nitrogen) was diluted with a slung of 8-methyl-5-phenyl-1,3,4,5-
tetrahydro-benzo[b]azepine- 2,3-dione 3-(0-methyl-oxime) (10 g, 34 mmol) in
methanol
to produce a final volume of about 600 ml. The reaction was shaken at 50 psi
hydrogen pressure for 24 hours. Thin layer chromatography of an aliquot showed
the
reduction was complete at this point. The hazy solution was twice filtered
through
Celitem to give a clear solution which was evaporated in vacuo to provide the
amine as
a white solid; B g, 8896yield. 'H NMR (CDCI,) b 7.52 (s, 1), 7.80 - 7.05 (m,
6), 6.96 (d,
Trade-mark
CA 02297612 2000-02-14
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-1 &
1 ), 6.71 (s, 1 ), 4.30 (q, 1 ), 3.61 (q, 1 ), 2.82 (m, 1 ), 2.50 (m, 1 ),
2.32 (s, 3), 1.70 (bs, 2,
NHz).
G. (+)-Cts-(3R)-Amino-8-methyl-l5R)-phenyl 1 3 4 5 tetrahvdro
benzofblazepine-2-one (+)-dibenzoyltartarate:
Cis-3-Amino-8-methyl-5-phenyl-1,3,4,5-tetrahydro-benzo[b]azepine-2-one (7.81
g, 29 mmol) and D-(+)-dibenzoyltartaric acid (10.5 g, 29.3 mmol) were combined
in
acetone (300 mi) and stin-ed at room temperature. This initially gave a clear
solution
followed by crystallization. After stirring for 4 hours, the solids were
collected, washed
with acetone and dried in vacuo at 40°C to produce 7.89 grams of a
salt. This initial
salt (6.74 g) was dissolved in methanol (75 ml) with heating to give a clear
solution.
Ethyl acetate (205 ml) was added to the hot solution over 5 minutes to cause
crystallization. A total of 280 ml of distillate was collected at atmospheric
pressure,
while adding additional ethyl acetate to maintain the original volume. The
slurry was
allowed to cool to room temperature over one hour and the solids were
collected and
washed with ethyl acetate. The yield of the recrystallization was 6.2 g, 9296
or 4096 for
the overall resolution. The material was a white solid, mp 193-4°C
(dec.). (o°] 180.6°
(c = 0.205, methanol, MeOH). The structure and absolute configuration was
determined by a single crystal X-ray analysis.
H. (+)-Cis-(3R)-amino-8-methyl-(5R)-ahenyl 1 3 4 5 tetrahydro
benzo(blazepine-2-one:
The dibenzoyl tartarate salt (6.98 g, 11.2 mmol) was dissolved in a mixture of
O.SN NaOH and methyfene chloride (50 ml). The layers were separated and the
aqueous layer was extracted with methylene chloride (30 ml). The organic
layers were
combined, washed with water, and dried over magnesium sulfate. This was
filtered and
concentrated in vacuo to about 25 ml at which point hexanes (50 ml) were added
slowly. This process was repeated with more hexanes and the product was
collected
and dried in vacuo; 2.9 g, 9896 yield. (a°J 259.5° (c = 0.264,
MeOH). 'H NMR (CDCI,)
same as racemic amine. "C NMR (CDCI,) d 177.0, 143.5, 138.0, 135.8, 133.1,
131.6,
128.3, 127.2, 126.6, 126.2, 123.7, 61.1, 51.3, 45.8, 42.0, 20.9.
646$0-960D
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EXAMPLE 2
Cis-3-Amino-5-cyclohexyl-1.3,4, 5-tetrahydro-benzo (bl azeplne-2-one:
D. i2-f2-(Cyclohexylcarbonyl~phenylcarbamoyl]-2-methox~rlm(no-ethyi~-
phosphonic acid diethyl ester:
The title compound was prepared from the readily available phenone according
to the
methods of procedures A through D of Example 1.
Yeld 5.65 g, 6696. mp 96 - 8°C. IR (potassium bromide, K8r) 1682,
1655 cm''.
' H NMR (CDCI,) a 12.56 (s, 1 ), 8.77 (d, 1 ), 7.92 (d, 1 ), 7.54 (t, 1 ),
7.15 (t, 1 ), 4.22 (s,
3), 4.14 (m, 4), 3.40 (d, 2), 3.30 (m, 1 ), 1.92 - 1.20 (m, 11 ).
E. 5-Cyclohexyl-1 H-benzofblazepine-2.3-dione 3-(O-methyl-oxime):
The title compound was prepared from the produce of step D described above
in a methoc: analogous to procedure E in Example 1.
geld 1.7 g, 5396. mp 192 - 200 ° C. I R (K8r) 1675, 1629 cm'' . ' H NMR
(CDCI1)
a 9.50 (s, 1 ), 7.50 (d, 1 ), 7.39 (t, 1 ), 7.29 (m, 2), 6.40 (s, 1 ), 4.04
(s, 3), 2.69 (bt, 1 ), 1.95
- 1.70 (m, 5), 1.47 - 1.18 (m, 5). "C NMR (CDCI,) d 168.6, 149.6, 148.8,
134.5, 129.9,
129.0, 127.1, 124.6, 122.6, 116.8, 63.42, 43.1, 33.23, 26.7, 26.2. Mass
spectrum: m/e
285 (M + 1). Analysis Calculated for C,~H~aNzO~: C, 71.81; H, 7.09; N, 9.85.
Found:
C, 71.80; H, 7.37; N, 9.96.
F. Cis~-Amino-5-cyclohexyl-1,3,4.5-tetrahydro-benzolblaze~~ine-
2-one:
Under similar hydrogenation conditions as described above in method F of
Example 1, the product of step E was reduced to the title compound.
geld 0.78 g, 86°,6. ' H NMR (CDCI,) d 7.68 (s, 1 ), 7.27 - 7.18 (m, 1
), 7.10 (d,
2), 6.92 (d, 1 ), 3.50 (q, 1 ), 2.63 - 2.49 (m, 2), 2.01 (m, 2), 1.78 - 1.47
(m, 6), 1.30 - 0.78
(m, 5), 0.55 (m, 1 ).
EXAMPLE 3
Cis~-Amino-5-cyclohexyl-8-methyl-1.3.4,5-tetrahydro-benzofblazepine
2-one:
D, i2-f2-(Cyclohexylcc~bonyl)-5-methyl-pherwlcarbamoyrll-2-
methoxyimino-ethyl-Qhosphonic acid diethyl ester:
The title compound was prepared from the readily available phenone according
to the methods of procedures A through D in Example 1.
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geld 3.14 g, 52°,x. mp 64 - 6°C. IR (KBr) 1680, 1643, 1612,
1570, 1530 cm-'.
' H NMR (CDCI,) d 12.66 (s, 1 ), 8.63 (d, 1 ), 6.93 (d, 1 ), 4.20 (s, 3), 4.12
(q, 4), 3.39 (d,
2), 3.28 (m, 1 ), 2.38 (s, 3), 1.90 - 1.19 (m with t at 1.27, 16). "C NMR
(CDC11) d 207.0,
161.0, 146.0, 145.8, 145.5, 7 40.4, 130.5, 123.5, 121.5, 119.6, 63.6, 62.3,
622, 61.0,
46.5, 29.7, 25.9, 25.8, 23.6, 22.1, 21.8, 16.3, 16.2. Analysis Calculated for
CZ=H~,NzOeP:
C, 58.40; H, 7.35; N, 6.19. Found: C, 58.44; H, 7.46; N, 6.24.
E. 8-Methyi-5-cyclohexyi-1 H-benzofblazep(ne-2,3-dione
3-(O-methyl-oxime):
The title compound was prepared from the product of step D, described above,
in a method analogous to procedure E in Example 1.
Yeld 0.41 g, 529'0. mp 222 - 226 ° C. IR (K8r) 1679, 1631, 1617, 1563.
cm'' . ' H
NMR (CDCI,) ~ 9.53 (s, 1 ), 7.49 (d, 1 ), 6.99 (m, 2), 6.34 (s, 1 ), 4.02 (s,
3), 2.66 (t, 1 ),
2.33 (s, 3), 1.91 - 1.69 (m, 5), 1.44 - 1.12 (m, 5). "C NMR (CDCI,) 3 168.4,
149.8,
148.8, t 39.3, 134.3, 127.1, 125.6, 122.7, 116.0, 89.0, 63.4, 43.0, 33.2,
26.8, 26.2, 20.9.
Mass spectrum: m/e 298 (M'), 267 (M'-OMe). AnalysisCalculatedforC,eH~~NzO~:
C, 72.46; H, 7.43; N, 9.39. Found: C, 72.42; H, 7.51; N, 9.45.
F. Cis-3-Amino-5-cyclohexyl-8-methyl-1.3 4 5-tetrahydro-
benzo (blazepine-2-one:
Under similar hydrogenation conditions as described above in method F of
2C Example 1, the product from step E was reduced to the title compound.
Yeld 0.22 g, 7996. ' H NMR (CDCI,) b 8.03 (s, 1 ) , 6.99 (d, 1 ), 6.90 (d, 1
), 6.75
(s, 1 ), 3.50 (q, 1 ), 2.61 - 2.42 (m, 2), 2.30 (s, 3), 1.98 (m, 2), 1.78 -
1.45 (m, 6), 1.26 -
0.73 (m, 5), 0.51 (m, 1 ).
EXAMPLE 4
5-Methyl-1 H-benzo(blazepine-2.3-dione~-(O-methyl-oxime):
D. 2-(Diethyl 3-Qhosphono-2-(methoxyimino)-pro~ionamidoyri)-
acetophenone:
The title compound was prepared from the readily available phenone according
to the methods of procedures A through D from Example 1.
Yeld 1.5 g, 41 °,6. ' H NMR (CDCI,) a 12.62 (s, 1 ), 8.79 (d, 1 ), 7.89
(d, 1 ), 7.55
(t, 1 ), 7.11 (t, 1 ), 4.19 (s, 3), 4.10 (m, 4), 3.40 (d, 2, J = 25 Hz), 2.66
(s, 3), 1.27 (t, 6).
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E. 5-Methyl-1 H-benzo(blazeatne-2.3-dlone-3-(O-methyl-oxime):
The title compound was prepared from the product from step D, described
above, in a method analogous to procedure E in Example 1.
Yield 0.45 g, 5296. mp 190 - 3°C. IR (KBr) 1669, 1630 cm''. 'H NMR
(CDCI,)
d 9.61 (s, 1 ), 7.48 (d, 1 ), 7.33 -7.13 (m, 3), 6.54 (s, 1 ), 4.06 (s, 3),
2.35 (s, 3). "C NMR
(CDCIz) d 167.3, 148.7, 139.5, 134.2, 129.6, 129.0, 127.8, 124.4, 122.3,
118.7, 63.5,
23.8. Mass spectrum: m/e 217 (M + 1). Analysis Calculated for C,zH,~NzO~: C,
66.65;
H, 5.59; N, 12.95. Found: C, 66.71; H, 5.72; N, 13.05.
EXAMPLE 5
Cis-3-Amino-7.8-dimethoxy-5-methyl-1,3.4,5-tetrahydro-
benzofblazepine-2-one:
D. 2-(Diethyl-3-phosphono-2-(methoxyimino)-oropionamidoyl)-4,5-
dimethox~-acetophenone:
The tide compound was prepared from the readily available phenone according
to the methods of procedures A through D in Example 1.
Yield 4.62 g, 7596. mp 103 ° C. IR (KBr) 1675, 1646, 1609, 1586 cm'' .
' H NMR
(CDCI,) 3 12.88 (s, 1 ), 8.56 (s, 1 ), 7.29 (s, 1 ), 4.20 (s, 3), 4.20 (q, 4),
3.99 (s, 3), 3.90
(s, 3), 3.40 (d, 2), 2.61 (s, 3), 1.28 (t, 6). Analysis Calculated for
C,BH~~NzOQP: C, 50.23;
H, 6.32; N, 6.51. Found: C, 50.36; H, 6.37; N, 6.73.
E. 5-Methyl-7.8-dimethoxY 1H-benzofblazepine-2.3-dione
3-(O-methyl-oxime):
The title compound was prepared from the product of step D described above
in a method analogous to procedure E in Example 1.
Yield 1.68 g, 5296. mp 233 - 35°C. IR (KBr) 1659, 1627, 1615, 1583
cm~'. 'H
NMR (CDCI,) a 9.80 (s, 1 ), 6.88 (s, 1 ), 6.73 (s, 1 ), 6.41 (s, 1 ), 4.00 (s,
3), 3.90 (s, 3),
3.85 (s, 3), 2.31 (s, 1 ). "C NMR (CDCI,) a 166.9, 149.9, 148.8, 145.6, 139.1,
128.5,
121.5, 117.1, 110.0, 105.2, 63.3, 56.2, 56.1, 23.9. Analysis Calculated for
C"H,eN~O,:
C, 60.85; H, 5.84; N, 10.14. Found: C, 61.07; H, 5.91; N, 10.34.
F. Cis-3-Amino-7,8-dimethoxy-5-methyl-1, 3. 4. 5-
tetrahydro-benzofblazepine-2-one:
Under similar hydrogenation conditions as described above in method F of
Example 1, the product from step E above was reduced to the title compound.
64680-960D ca o229~6i2 2000-o2-i4
-22-
Yeld 7396. ' H NMR (CDCI,) a 7.60 (s, 1 ), 6.69 (s, 1 ), 6.50 (s, 1 ), 3.88
(s, 3), 3.84
(s, 3), 3.49 (q, 1 ), 3.00 (m, 1 ), 2.74 (m, 1 ), 1.71 (dt, 1 ), 1.60 (bs, 2),
1.30 (d, 3).
EXAMPLE S
Cis-6-Amino-7.7a-dihydro-4H.6H-fluoreno-f1,9-bclazepine-5-one:
D. 1-(Diethyl3-phosphono-2-(methoxyimino)-propionam(doyi)-
fluorenone:
The title compound was prepared from the readily available phenone according
to the methods of procedures A through D in Example 1.
geld 1.68 g, 3996. mp 104 - 7°C. IR (KBr) 1695, 1653, 1614, 1602 crn''.
'H
NMR (CDCh) a 11.25 (s, 1 ), 8.41 (d, 1 ), 7.62 (d, 1 ) 7.51 - 7.41 (m, 3),
7.28 (dt, 1 ), 7.20
(d, 1 ), 4.24 (s, 3), 4.11 (m, 4), 3.40 (d, 2, J = 25 Hz), 1.29 (t, 6).
E 4H-Fluorenof1.9-bclazepine-5,6-dione-6-(O-methyl-oxime):
The title compound was prepared from the phosphonate amide described in
step D above in a method analogous to procedure E in Example 1.
Yeld 0.59 g, 6196. mp 254 - 61 °C. IR (KBr) 1681, 1667, 1637, 1615
crri'. 'H
NMR (CDCI3) d 8.75 (s, 1 ), 7.70 (d, 1 ), 7.75 (s, 1 ), 7.69 (d, 1 ), 7.46 -
7.31 (m, 4), 6.82
(d, 1 ), 4.28 (s, 3). "C NMR (CDCI,) d 160.7, 149.1, 140.9, 140.0, 139.3,
137.4, 134.8,
132.3, 130.6, 128.4, 122.4, 122.2, 121.2, 118.1, 115.7, 110.0,63.8. Analysis
Calculated
for C"H,ZNzOz: C, 73.90; H, 4.38; N, 10.14. Found: C, 74.05; H, 4.51; N,
10.40.
F. Cis-6-Amino-7.7a-dihydro-4H.6H-fluoreno(1.9-be]azepine-5-one:
Under similar hydrogenation conditions as described above in method F of
Example 1, the product from step E above was reduced to the title compound.
geld 0.29 g, 8096. ' H NMR (CDCI,) a 7.88 (s, 1 ), 7.75 (d, 1 ), 7.60 (d, 1 ),
7.49
- 7.30 (m, 4), 6.93 (d, 1 ), 4.10 (t, 1 ), 3.61 (q, 1 ), 2.71 (q, 1 ), 2.40
(m, 1 ), 1.70 (bs, 2).
PREPARAT10N 9
A. ~+)-3L ~f3-(3-Chloro-phenyl)-ureidol-8-methyl-2-oxo-5(R)-phenYl-
1.3,4.5-tetrahydro-benzo (bl azepine:
(+)-Cis-(3R)-amino-8-methyl-(5R)-phenyl-1 ,3,4,5-
tetrahydro-benzo(bJazepine-2-one (2 g, 7.52 mmol) was suspended in
1,2-dichloroethane (40 mi) and stirred under nitrogen while 3-chlorophenyi
isocyanate
(1.2 g, 7.9 mmol) in 1,2-dichloroethane (10 ml) was added dropwise over two
minutes.
This gave an initial solution followed by a thick precipitate. The mixture was
heated at
a gentle reflux for one hour, which gave a solution and then was allowed to
cool to
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room temperature. The precipitate was collected, washed with dichloroethane
and then
hexanes, and dried in vacuo; 2.82 g, 8996 yield. mp 1330°C. [afl)
49.6° (c = 0.42,
MeOH) 'H NMR (CDCI, with several drops dimethylsulfoxide DMSO-da) d 8.83 (s,
1),
8.48 (s, 1 ), 7.30 (s, 1 ), 6.90 - 6.71 (m, 8), 6.61 (d, 1 ), 6.54 - 6.38 (m,
3), 4.20 (q,1 ), 4.03
(q, 1 ), 2.70 (m, 1 ), 2.15 (m, 1 ), 1.96 (s, 3).
Under similar conditions as described above, the following cis-3-amino-
5-substituted-1,3,4,5-tetrahydro-benzazepin-2-ones were reacted with 3-
chlorophenyl
isocyanate to provide the corresponding ureas.
B. 3-f3-(3-Chlorophenyl)ureidol-5-cyclohexyl-2-oxo-1.3.4.5-tetrah~rdro-
benzo(blazepine
Yeld 1.17 g, 9196. mp 222 - 5°C. IR (KBr) 1694, 1651 cm-'. 'H NMR
(DMSO
-de) a 9.88 (s, 1 ), 8.99 (s, 1 ), 7.60 (t, 1 ), 7.30 - 7.06 (m, 5), 6.98 (d,
1 ), 6.90 (d, 1 ), 6.60
(d, 1 ), 4.20 (m, 1 ), 2.58 (m, 2), 1.96 (m, 2), 1.76 - 1.43 (m, 4), 1.22 -
0.77 (m, 5), 0.53
(m, 1 ). Mass spectrum: m/e 412 (M + 1 ).
C. 3-t3-(3-Chlorophenyl)ureidol-5-cyrclohexyl-8-methyl-2-oxo-1.3.4.5-
tetrahydro-benzoiblazeQine
Yeld 0.193 g, 6296. mp 162 - 9 ° C. IR (KBr) 7 674, 1619, 1592, 1554,
1515 cm'' .
' H NMR (DMSO -da) a 9.78 (s, 1 ), 8.96 (s, 1 ), 7.59 (s, 1 ), 7.20 (t, 1 ),
7.10 (d, 1 ), 7.04 (d,
1 ), 6.90 (d, 2), 6.76 (s, 1 ), 6.58 (d, 1 ), 4.19 (m, 1 ), 2.51 (m, 3), 2.27
(s, 3), 1.90 (m, 2),
1.71 - 1.43 (m, 4), 1.18-0.72 (m, 5), 0.48 (m, 1 ). Mass spectrum: m/e 426 (M
+ 1 ).
D. 3-f3-(3-Chlorophenyl)ureidol-5-methyl-7,8-dimethoxy-2-oxo-l ,3~4.5-
tetrahydro-benzo bbl azepine:
geld 0.33 g, 8296. mp 208 - 10 ° C. IR (KBr) 1725, 1707, 1696, 1676
crn'' . ' H
NMR (DMSO -de) d 9.68 (s, 1 ), 9.00 (s, 1 ), 7.60 (t, 1 ), 7.20 (t, 1 ), 7.10
(dd, 1 ), 6.91 (dd,
1 ), 6.85 (s, 1 ), 6.61 (s,1 ), 6.55 (d, 1 ), 4.29 (m, 1 ), 3.28 (s, 3), 3.71
(s, 3), 3.04 (m, 1 ),
2.72 (m, 1 ), 1.63 (t, 1 ), 1.20 (d, 3). Analysis Calcd. for
Cz°H~zN,O,CI: C, 59.47; H, 5.49;
N; 10.40. Found: C, 59.28; H, 6.25; N, 9.76.
E. 6-f3-(3-Chlorophenyt)ureido~-7,7a-dih~rdro-4H,6H-fluoreno 1,9-bcl-
azepine-5-one:
geld 0.28 g, 6796. mp 221 - 225 ° C. IR (K8r) 1663, 1617, 1593, 1552
crn-' . ' H
NMR (DMSO-da) a 10.29 (s, 1 ), 9.04 (s, 1 ), 7.90 (d, 1 ), 7.71 (d, 1 ), 7.56
(m, 2), 7.48 -
7.33 (m, 3), 7.20 (t, 1 ), 7.09 (d, 1 ), 6.99 (d, 1 ), 6.90 (d, 1 ), 6.76 (d,
1 ), 4.30 - 4.14 (m,
2), 2.80 (q, 1 ), 2.30 (m, 1 ).
64680-960D
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PREPARAT10N 10
N-tert-Butyl-2-13(R)-L3-(3.chlona-phenyl)-ureidol-8-methyl-2-oxo-5(R~henyl.
2.3.4,5-tetrahydro-benzo tblazepin-1~r1~-acetamide:
(+)-3(R)-[3-(3-Chloro-phenyl)-ureidoJ-8-methyl-2-oxo-5(R)-phenyl-1,3,4,
5-tetrahydro-benzo[b)azepine (2.5 g, 6 mmol), N-tert.-butyl iodoacetamide
(1.72 g, 7.15
mmol) and tetrabutyl3tnmonium bromide (0.2 g, 0.6 mmol) were dissolved in dry
tetrahydrofuran (50 ml) under a nitrogen atmosphere. Powder potassium
hydroxide
(0.45 g, 8 mmol) was added in one portion and the reaction was stirred at room
temperature for 4 hours. The reaction was diluted with ethyl acetate (50 ml)
and was
washed with water and brine. After drying over magnesium sulfate, the solvent
was
removed in vacuo to provide a foam that was purified by flash chromatography
over
silica gel with 1:1 ethyl acetate : hexanes. The fractions with the product
spot were
combined and the material was crystallized from methanol and water to provide
a white
solid, 2.2 g, 7196 yield. mp 156 - 170 ° C. [ao] 124.5 ° (c =
0.52, CHlCIz). ' H NMR
(CDCh) a 8.01 (s, 1 ), 7.60 (s, 1 ), 7.32 (d, 1 ), 7.24 (m, 2), 7.15 (m, 4),
7.02 (m, 2), 6.90
(d,1 ), 6.83 (d, 1 ), 6.75 (bs, 1 ), 5.88 (s, 1 ), 4.63 (t, 1 ), 4.29 (d, 1 ),
3.88 (d, 1 ), 3.02 (d, 2),
2.89 (d, 1), 2.39 (s, 3), 1.32 (s, 9).
PREPARAT10N 11
N-tert-But~rt-2-~3-I3-(3-chloro-phenyl)-ureidol-2-oxo-5-cYclohexrt-
1.3.4,5-tetrahYdro-benzo (b1 azepin-1~1 ~-acetamide:
Following the previous experimental procedure, 3-[3-(3-chloro-phenyl)-ureido]-
2-
oxo-5-cyciohexyl-1,3,4,5-tetrahydro-benzo[bJazepine (0.4 g, 1 mmol) was
alkylated with
N-tert.-butyl iodoacetamide (0.28 g, 1.2 mmol) to provide the title compound
as a white
solid, 0.3 g, 59°6 yield. mp 222 - 5°C. 'H NMR (CDCI,) a 8.03
(s, 1), 7.59 (t, 1), 7.34
- 7.15 (m, 3), 7.10 (d, 1 ),7.01 (t, 1 ), 6.91 (d, 1 ), 6.83 (d, 1 ), 6.43
(bd, 1 ), 6.31 (s, 1 ), 4.95
(d, 1 ), 4.54 (m, 1 ), 3.59 (d, 1 ), 2.66 (m, 1 ), 2.53 (t, 1 ), 2.18 (bd, 1
), 1.78 (m, 1 ), 1.59 (m,
1 ), 1.4 (s, 9), 1.29 - 0.78 (m, 6), 0.58 (m, 1 ).
PREPARAT10N 12
3-TTert.-butoxycarbonylamlnol-8-methyl-2-oxo-5~henyl-
1 3.4,5-tetrahydro-benzofblazepine:
3-Amino-8-methyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-benzojb]azepine (1 g, 3.76
mmol) was suspended in methylene chloride (10 ml) under a nitrogen atmosphere.
Triethylamine (0.38 g, 3.76 mmol) and di-t-butyl Bicarbonate (0.82 g, 3.76
mmol) were
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added and the reaction was stirred at room temperature for 2 hours. The
reaction was
washed with 1 N HCI and brine, dried over magnesium suHate, and evaporated in
vacuo.
The desired carbamate was isolated as a white foam which was used in the
foAowing
reaction without further purification. ' H NMR (CDCI,) d 7.69 (s, 1 ), 7.24 -
7.06 (m, 6),
6.94 (d, 1 ), 6.73 (s, 1 ), 5.73 (d, 1 ), 4.49 (m, 1 ), 4.40 (m, 1 ), 2.99 (m,
1 ), 2.50 (m, 1 ), 2.30
(s, 3), 1.43 (s, 9).
PREPARATION 13
N-tent-Butyl-2-~3-[tert.-butoxycarbonylamlnol-8-methyl-2-oxo-5-
phenyl-1.3.4.5-tetrahyrdro-benzo[blazepin-1-yrl~-acetamide:
3-[Tert.-butoxycarbonylamino]-8-methyl-2-oxo-5-phenyl-1,3,4,5-
tetrahydro-benzo[b]azepine (1.4 g, 3.8 mmol), N-t-butyl iodoacetamide (1.1 g,
4.56
mmol) and tetrabutylammonium bromide (85 mg, 0.26 mmol) were dissolved in dry
tetrahydrofuran (25 ml) under nitrogen. Powder potassium hydroxide (0.3 g, 4.5
mmol)
was added in one portion and the reaction was stirred for 5 hours. The
reaction was
diluted with ethyl acetate (25 ml) and washed with water (2 X 50 ml) and
brine. After
drying over magnesium sulfate, the solvent was evaporated in vncuo to provide
the
desired product as a foam; 2 g, > 10096 yield. This contained some excess
iodoacetamide, but was suitable for use in the next reaction. IR (KHr) 1720,
1680, 1659,
1614 cm'' . ' H NMR (CDCI,) d 7.28 - 7.07 (m, 6), 7.00 (d, 2), 6.05 (s, 1 ),
5.49 (d, 1 ),
4.34 (m, 1 ), 4.08 (d, 1 ), 3.62 (d, 1 ), 2.95 (dt, 1 ), 2.63 (t, 1 ), 2.60
(d, 1 ), 2.33 (s, 3), 1.41
(s, 9), 1.32 (s, 9).
PREPARATION 14
N-to rt-Butyl-2-~3-a m i no-8-methyl-2-vxo-5 phenyl-1 ,3.4.5-
tetra ~dro-benzo fblazeein-1-yl~-acetamide:
N-tent-Butyl-2-{3-[tert.-butoxycarbonylamino]-8-methyl-2-oxo-5-
phenyl-1,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-acetamide (1.2 g, 2.5 mmol) was
dissolved in methylene chloride (10 ml) under a nitrogen atmosphere and cooled
to
5°C in an ice bath. Trifluoroacetic acid (10 ml) was added dropwise
over 15 minutes
and the reaction was stir-ed at ice bath temperature for four hours. The
reaction was
evaporated in vacuo and the residue was dissolved in ethyl acetate. The
organic
solution , was extracted with 1 N HC1 (3 X 30 ml). The acidic aqueous layers
were
combined, ethyl acetate was added and the pH was adjusted to pH 10.5 by the
addition of solid sodium carbonate. The organic layer was separated and the
aqueous
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layer was extracted with ethyl acetate again. The combined ethyl acetate
solutions
were washed with brine, dried over magnesium sulfate, and evaporated in vacuo
to
provide the amine as a white foam, 0.62 g, 656 yield. ' H NMR (CDCh) d 7.28 -
6 96
(m, 8), 6.00 (bs, 1 ), 4.14 (d, 1 ), 3.62 - 3.50 (m, 2), 2.79 (m, 1 ), 2.61
(m, 2), 2.35 (s, 3),
2.08 (bs, s), 1.30 (s, 9).
