Note: Descriptions are shown in the official language in which they were submitted.
11(~1420
. - 2 -
This invention relates to novel aminoalkylthiodi-
benzoxepins and to their physiologically tolerable acid addition
salts which are useful as antidepressant, analgesic and anti-
convulsant agents, and to pharmaceutical and veterinary com-
positions containing such a compound as an essential activeingredient.
It is already known that Amethoclothepine of the formula
O(CH2)2N(CH3)2
possess central depressant activity by M. Protvia, et al. II
Farmaco XXI, 98 (1966).
Japanese Patent No. 47-28998 entitled "A Method of
Manufacturing Tricyclic Compounds Having an Enolic Ether Bond"
pertains to the preparation of compounds depicted by the
formula O-Rl-N ~ 2
~X
in which A is alkylimino, oxy, thio or sulfinyl, Rl is
alkylene, R2 and R3 each represent an alkyl group or may be
bonded cyclically either through an alkylimino group or not
through an alkylimino group and X stands for hydrogen, halogen,
alkyl, alkoxy, alkylthio, dialkyl sulfamoyl or nitro.
~'
;~
3 --
The compounds of the present invention conform to
the general ~ormula
S- (CH2)n-Z
. l
x~
wherein X and Y are the same or different and each can be
hydrogen, halogen, trifluoromethyl, C1-C6alkoxy, Cl-C6 alkyl,
5 Cl-C6alkylthio, Cl-C6alkylsul~onyl, Cl-C6alkylsulfinyl, amino,
or nitro; Z is halo~en or N 2 ; Rl is hydrogen, straight or
branched chain Cl-C6alkyl, cyano, cycloalkyl Cl-C6alkyl wherein
the cycloalkyl ring contains from 3 to 6 carbon atoms, phen-
oxycarbonyl of the formula -CO2 ~ X
wherein X is defined as above, Cl-C6alkoxycarbonyl, C2-C6alkenyl
or C2-C6alkynyl; R is straight or branched chain Cl-C6alkyl
or cycloalkyl Cl-C6alkyl wherein the cycloalkyl ring contains
from 3 to 6 carbon atoms; and when Rl and R2 are taken together
with the nitrogen atom to which they are attached, the group
Rl-N-R2 forms a heterocycle which is morpholino, piperidino,
pyrrolidinyl, piperazinyl or N~substituted piperazinyl in which
the N-substituent is Cl-C6alkyl and in which a nitrogen or
carbon atom of the heterocycle is attached to the termina~ carbon
atom of the (CH2) group; m is the integer 0 or 1; and n is an
integer of from 2 to 4; and a physiologically tolerable acid
addition salt thereof.
Acids useful for preparing the pharmaceutically
acceptable acid addition salts of the invention include inorganic
acids such as hydrochloric, hydrobromic, sulfuric, nitric,
1101420
-- 4 --
1 phosphoric and perchloric acid, as well as organic acids
such as tartaric, citric, acetic, succinic, maleic, fumaric,
and oxalic acids.
Compounds of the invention are prepared by the
methods given below. With the exception noted, X,Y,Z,R1,R2,
m and n are as defined earlier.
Method A
.
A 10,11-dihydro-10-hydroxy or -10-oxo-dibenz [b,f]
oxepin, of the formula R4
X ~ O ~ II
wherein R3 and R4 are different and each is hydrogen or hydroxy
or together represent oxygen, is reacted with aminoalkylthiol
of the formula HS-' / R
( 2)n N ~ R2
wherein Rl and R2 are the same or different and each can be
straight or branched chain Cl-C6alkyl to produce a compound
of the invention of the formula R
S-(CH ) -N -
X /~ Ia I
This reaction is carried out with a cataylst/dehydrating agent
; of boron trifluoride etherate and in the presence of a suitable
solvent such as glacial acetic acid at a temperature of about
ambient to reflux.
1420
,
.;
Method b
A compound prepared in Method A in which m is the integer
1 can be treated with magnesium in a suitable solvent to effect
reduction to its corresponding saturated aminoalkylthiodibenzoxepin.
S A preferred method of carrying out this reduction involves the
use of magn~sium shavings with a solvent of methanol.
Method c
A compound prepared in Method a or b, wherein Rl and
R2 are each methyl, can be treated with a cyanogen halide
such as cyanogen bromide in a suitable solvent and acid sca-
venger to obtain a mixture of one compound of the invention
of the formula
S(CH ~ h 1
~ m ~ Ib
and another compound of the invention of the formula
S(CH ~ ~ CH3
X = Ic
` This reaction is carried out at a temperature of from about
ambient to reflux. These two compounds of the invention may
be isolated and collected by column chromatography.
11~1420
- 6 -
Method d
A compound prepared in Method c) of formula Ib can be re-
acted in a known fashion with a suitable amine to obtain the
corresponding compound of the invention of the formula
Rl
~S~(C~12)n-~
~ _) ~ Ia
10- wherein R1 is hydrogen, straight or branched chain C1-C6alkyl,
cycloalkylC1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl~ R2 is
straight or branched chain C1-C6alkyl or cycloalkylC1-C6-
alkyl; and when R1 and R2 are taken together with the nitrogen
atom to which they are attached, the group R1-N-R forms a
heterocycle which is piperazinyl, N-substituted piperazinyl,
morpholino, piperidino or pyrrolidinyl. A preferred method is
carried out with a dimethylformamide solvent, a catalyst such
~s sodium bicarbonate and a reaction initiator such as potassium
iodide at a temperature of from ambient to the reflux tempera-
20 ~ure of the reaction mixture.Method e
A compound prepared in Method a) or b) can be treated
~ith a chloroformate, e.g. an alkyl or phenyl chlo00formate,
- at a temperature of from 25 to 125C, in a solvent such as
methylene chloride, toluene or benzene to provide the corre-
sponding compound of the invention in which Z is N'R2 with R
being C1-C6alkoxy- or phenoxy carbonyl.
.
."' '' ' ' ' ~ ~ .
` _ 7 ~ 1420
Method f
A compound prepared in Method e) is treated with an or-
ganic base such as triethylamine or an inorganic base such as
sodium or potassium hydroxide in a solvent such as water,
ethanol, or ethylene glycol at a temperature of from ambient
to reflux to provide the corresponding compound of the inven-
tion in which R1 is hydrogen.
Met.hod q
A compound prepared in Method f) is treated with a
10 straight or branched chain C1-C6alkyl halide, C2-C6alkenyl,
halide, C2-C6-aLkynyl halide or cycloalkylC1-C6alkyl halide
under conditions normaL for such reactions to provide the
corresponding compound of the invention in which R1 is straight
or branched chain C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or
cycloalkyLC1-C6alkyl. A preferred method is to carry out
this substitution in the presence of a solvent such as di-
methyl.formamide, an acid scavenger such as sodium bicarbonate
and a reaction initiator such as potassium iodide at the:re-
f~ux temperature of the solvent.
. .
, ' ' '
:' ~ " " '
.
14~0
~ethod h
....
A compound prepared in any of the above methods,
which ~ncludes a nitro group can be reduced by a conventional
method to produce the corresponding amino compound. Such
conventional methods include but are not limited to use of
metallic zinc and acetic acid or platinum on carbon.
As is appreciated by those skilled in the art,
specific conditions in any of the above methods are dependent
and are a function of the ingredients of each procedure.
The compounds of the present invention are useful
in the treatment of depression in mammals, as demonstrated
by their abiLity to inhibit tetrabenazine-induced depression
in mice [International Journal o Neuropharmacology 8, 73
(196g)], a standard assay for useful antidepressant properties.
Thus, for instance, the intraperitoneal dose at which the
following compounds effect a 50% inhibition of the ptosis o~
the tetrabenazine-induced depression (ED50) in mice are:
ED50
~E~--nd m~
2-~luoro-11-[~-~ethylamino)ethylthio]dibenz[b,f]- 0.3
oxepin malea~e
10-1~-(methylamino)ethylthio]dibenz[b,f]oxepin
oxalate 3.4
2-chloro-10,11-dihydro--11-[(~-dimethylamino~-
ethylthio]dlbenz[b,f]oxepin oxalate 3.5
2-fluoro-11-[~-(dimethylamino)ethylthio]-
dibenz[b,f]oxepin hydrobro~ide 4.3
10,11-dihydro-10-[(~-dimethylamino)ethylthio]-
dibenz[b,f]oxepin oxalate 7.0
2-L luoro-10,11-dihydro-11-[~-~dimethylamino)- "
ethylthio]dibenz[b,f]oxepin oxalate 7.6'`
*oral dose
..
.. . . _ . . .
.
~ 9 ~ ll~l~ZO
These data illustrate that the compounds of the
invention are useful in the treatment of depression in
mammals when administered in an a~.ount ranging from 0.1 to
SO mg per kg of body weight per day.
Compounds of the invention are further useful as
analgesic agents due to their ability to alleviate pain in
mammals. The analgesic utility of compounds of this invention
is demonstrated in the phenyl-p-quinone writhing assay in mice,
a standard assay for analgesia [Proc. Soc. Exptl. Biol Med.,
95 729 (1957)]. Thus for instance, the subcutaneous dose
effecting an approximately 50% inhibition of writhing (ED50
in mice produced in this assay is as follows:
ED50
Compound m~/kg
15 2-fluoro-10,11-dihydro-11-~-(dimethylamino)-
ethylthio]dibenz[b,f]oxepin oxalate 1.9
2-fluoro-11-[~-(methylamîno)ethylthio]-
diben~[b,r]oxepln maleate 2.3
10-[~-(methylamino)ethyltllio]dibenz-
[b,f]oxepin oxalate 2.3
These data illustrate that the compounds of this
invention are useful for the alleviation of pain in mammals
when administered in an amount ranging ~rom 0.1 to about 50
mg per kg of body weight per day.
Compounds of the present invention are still further
useful as anticonvulsant agents for mammals, as determined by
the method of l~oodbury, L.A.and Davenport, V.D~, in Arch. Int.
Pharmacodynam, Vol. 92. ~1952) at pages 97 to 107. Thus, for
instance, the following intraperitoneal doses at which an
approximately 50% protective (ED50) from the e~fect of supra-
maximal electro shock in mice are:
- 10 -
1101420 l~D50
Compound mg/lcg
dihydro-10-[B-(dimethylamino)ethylthio]- 7 7
dibenz[b,f]oxepin oxalate
2-fluoro-10,11-dihydro-11-[~-(dimethylamino)-
ethylthio]dibenz[b,f]oxepin o~alate 9.0
2-fluoro-11-[~-(dimethylamino)ethylthio]dibenz-
lb.f]oxepin hydrobromide . 9 2
2-fluoro-11-[~-(methylamino)ethylthio]dibenz-
[b,f~oxepin maleate 9.9
2-chloro-10,11-dihydro-11-[~-(dimethylamino)-
ethylthio]dibenz[b,f]oxepin oxalate 19.4
10-[~-(methylamino)ethylthio]dibenz[b,f]-
oxepin oxalate 21
These data il.lustrate the utility of compounds of
the invention for the treatment of convulsion in mammals ~hen
adminis~ered in an amount ranging from about 0.1 to 100 mg
per kg of body ~eight per day.
Other examples of compounds of the invention include:
11-~y-(dimethylamino)propylthio]-2-ethylsulfonyldlbenz[b,f]oxepin;
B-(bromoethyl)thic]-2-methQxy-lo~ll-dihydrodibenz[b~f]oa;epin;
2-ethyl-11-[~-(methylamino)ethylthio]dibenz[b,f]oxepin;
B-(ethylmethylamino)ethylthio]-2-methylsulfiTlyldiben
[b,f]oxepin;
~ .
25 10,11-dihydro-10-[~-(piperi~ino)ethylthio]dlbenz[b,f]oxepin;
lo~ll-dihydro-lo-[y-(piperazinyl)propylthio]dibenz[b~f]oxepin;
lO,ll-dihydro-10-[~ -(piperidino)-n-butylthio]dibenz[b~f]oxepin;
(~ referring to position on piperidino ring);
10-[~-(pyrrolidino)ethylthio]dibenz[b,f]oxepin;
3-chl~ro-lo-[B-(ethylmethylamino)ethylthio]dibenz[b~f]oxepin;
-- lo-~B-(ethylamino)ethylthio~lc~ll-dihydro-4-nitrodiben
[b,f]oxepin;
8-chloro-10,11-dihydro-10-[~-(dimethylamîno)ethylthio]-2-
methyldibenz[b,f]oxepin;
- 35 . 2-bromo-7-fluoro-11-[~-(dimethylamino)ethylthio]dibenz[b,f]oxepin;
.
,
- " llQ1~20
10-[~-(ethy].a~nino)ethyltllio]-3-tri~l.uoromethyldibenz[b,f]-
- ox~pin;
2-amino~-O-~-(ethylamino)eth~ilthio]dibenz[b,f~oxepin;
lo~ (ethylamino)eth~lthio]-3-methoxvdibenz[b~f]oxepin;
5 10-[~-(diethylamino)ethylthio]-2-n-propyldibenæ[b,f]oxepin;
10-[~-(methylamino)ethylthio]-3-methylthiodibenz[b,f]oxepin;
3-fluoro-11--[~-(me~hylamino)ethylthio]dibenz[b,~]oxepin;
3-ethyl-ll-[~-(methylamino)ethylthio3dibenz[b,f30xepin;
l~-[s-(ethylamino)et}lylthio]-4-nitrodibenz[b~f]oxepin; and
2-methyl-11-~ -me~hyl-N-methoxycarbonyl)aminoethylthio]-
dibenz[b,f]oxepin.
Effective quantities of the compounds of the invention
may be administered to a patient by any one of various methods,
- for example, orally as in capsules or tablets, parenterally in
the form of steri]e solutions or suspensions, and in some cases
intravenously in the form of sterile solutions. The free base
i.nal products, while effective themselves, may be formulated
and administered in a form of their pharmaceutically acceptable
addition salts for purposes of stability, convenience or crystal-
lization, increased solubility and the like.
The active compounds of the present invention maybe orally administered, for example, with an inert diluent
or with an edible carrier, or they may be enclosed in gelatin
capsules, or tney may be compressed into tablets. For the
- 25 purpose of oral therapeutic administration, the active com-
pounds of the inven~ion may be incorporated with excipients
and used in the form of tablets, troches, capsules, elixirs,
suspensions, syrups, wafers, che~ing gum and the like. These
preparations should contain a~ least 0.5~ of active compound,
.
,
. ~, . _ ___ . . ... .. .. . .. . .
- l2 ~ 14ZO
but may ~e ~aried ~epending upon the particular form and
may conveniently be between 4% to about 70% of the weight
of the unit. The amount of active compound in such com-
positions is such that a suitable dosage will be obtained.
S Preferred composltions and preparations according to the
present invention are prepared so that an oral dosage unit
form contains between 1.0-300 milligrams of active compound.
The tablets, pills, capsules, troches and the like
may also contain the following ingredients: a binder such
. 10 as microcrystalline cellulose, gum tragacanth or gelatin;
and excipient such as starch or lactose, a disintegra~ing.
agent such as alginic acid, Primogel, corn starch and the like;
a lubricant such as magnesium stearate or Sterotex; a glidant
such as colloidal silicon dioxide; and a sweetening agent
such as sucrose or saccharin may be added or a flavoring agent
such as peppermint, methyl salicylate, or orange ~lavoring.
~en the dosage unit form is a capsule, i.t may contain, in addi.~ .
~ion to ~aterials of the above type, a liquid carrier such as
a fatty oil. Other dosage unit forms may contain other various
materials ~hich modify the physical form of the dosage unit,
for example, as coatings. Thus tablets or pills may be coated
with sugar, shellac, or other enteric coating agents. A syrup
may contain, in addition to the active compounds, sucrose as
a sweetening agent and certain preservatives, dyes and colorings
and flavors. Materials used in preparing these various com-
positions should be pharmaceutically pure and non-toxic in the
amounts used.
.
- 13 - ¦10 ~ 4 20
For the purpose o~ paren1eral therapeutic administration
- the active compounds of the invention may be incorporated into a
solution or suspension. These preparations should contain at
least 0. l~/o of active compo~md, but may be varied to be between
0.5 and about 30% of the ~eight thereof. The amount of active
compound in such compositions is sùch that a suitable dosage ~Jill
be obtained. Preferred compositions and preparations according
to the present invention are prepared so that a parenteral
dosage unit contains between 0.5 to 100 milligrams of active
compound.
The solutions or suspensions may also include the
~ollowing components: a sterile diluent such as water for in-
jection, saline solution, fixed oils, polyethylene glycols,
glycerine, propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl parabens;
; antioxidants such as ascorbic acid or sodium bisulfite; chelating
agents such as ethylenediaminetetraacetic acid; buffers such as
~cetates,citrates or phosphates and agents for the adjustment
of tonicity such as sodium chloride or dextrose. The parenteral
'~ preparation can be enclosed in ampuls, disposable syringes or
multiple dose .ials made of glass or pIastic.
.
.
,, ' ` .
.
.
- 14 -
L420
Examl~ 1 e
A mixture of 1.6 g of 10,11-dihydro-10-hydroxydibet-z-
lb,f]oxepin, 2.2 g o~ ~-dimethylaminoethylthiol hydrochloride
and 4 ml of boron trifluoride etherate in 8 ml of glacial
acetic acid which ~as permitted to stand at ambient tem?erature
for 64 hours is added dropwise to a stirring, cold 20C/o sodium
hydroxide solution. The liberated amine is extracted into
ether, washed successively with sodium hydroxide and a saturated
sodium chloride solution and dried. The e~her is removed under
~ 10 reduced pressure leaving a thick oil which is dissolved in
,~ .
acetone and converted to its crystalline oxa].ate. The salt
is recrystalli~ed from a methanol-acetone mixture leaving color-
less crystals, mp 163-169C, o~ 10,11-dihydro-10-[~.-(dimethyl-
amino)ethylthio]dibenz E b,f]oxepin o~alate.
Analysis:
Calculated for C18H21r~0S C2H24
Foun~: 61.50~C; 6.01%H; 3.54%N; 8.38%S.
~xample 2
.
A solution of 2.5 g of 10,11-dihydro-10-hydroxydibenz-
[b,f]oxepin, 4.01 g of ~-diethylaminoethylthiol hydrochloride,
8:ml of boron trlfluoride etherate in 13 ml of ~lacial acetic
acid which was permitted to stand for 48 hours is concentrated
and then poured into a cold 25% sodium hy~lroxide solution. The
resulting oi.l is extracted into ether. ~he ether extracts are
combined, and washed successively ~Jith dilute sodium hydroxide
and water, and then dried. The dried solution is filtered and
- the filtrate evaporated to dryness leaving an oil. The oil is
.
.
.' ~ ' .
- 15 - 1 1~ 14 2 0
stirred witl~ a 40% sodium hydroxide s~lution and then
extrac~ed into cther and dried. The ethereal solution is
filtered, and the ether removed leaving another oil which
is chromatographed through a silica gel column ~7ith a 20%
methanol in chloroform eluant. The chromatographed product
is converted to its oxalate, the white salt, mp 109-111C, of
10-[~ -(diethylamino)ethylthio~-10,11-dihydrodibenz[b,f]-
- oxepin oxalate.
Analysis: -
,.-~ ..
~ .
Calculated for C20H24NOS C2H2O4 6~44~oC; 6 29V/~ll; 3 36-N-
Found: 63~54/~C; 6~57/li; 3~23%1~1~
.
Example 3
A solution of 0.55 g of 10,11-dihydro-10-[~-
(dimethylamino~ethylthio~dibenz[b,f]oxepin, free base of
~xample 1, in 10 ml of chloroform is ad{led dropwise to a
solution of 0.28 g of cyanogen bromide ~nd 0.6 g of potassium
carbonate in 5 ml of chloroform. After total addition the re-
action mixture is permitted to stand fo~ 10 minutes and then
filtered. The filtrate is concentrated to dryness leaving 2
thick oil~ich crystallizes upor.standin~. T~ cryst~lline mass
- is recrystallized from 10~J boiling petroleum ether to give
colorless needles, mp 77-78C, of 10-(~-bromoethylthio~10,11-
dihydrodibenz[b,f]oxepin.
Analysis:
Calculated or C16H15BrOS: 57.32~/oC, 4.51%H; 23.84%Br.
- ~ - Found: 57.58~/oC; 4.5~ H; 24.20%Br.
. ', ~ .
~ 16 ~ 420
~xaml~le 4
A mixture of 1.5 g o~ 10-(~-bromoethylt.hio)-
10,11-dihydrodibenz[b,f]o,cepin, Example 3, 0.5 g of N-
methylpipera~ine, l.0 g of sodium bicarbonate, 1.0 g of
potassium iodide in lS ml of dimethylformamide is stirred
at 80C for 16 hours. The ~ixture is permitted ~o cool
before bein~ diluted ~ith water. The biphasic mixture is
extracted thrice with 100 ml portions of ether. the ether
extracts combined and shaken vigorously ~ith a large excess
of 2N hydrochloride acid. The acidic solution is basified
to liberate the free amlne. The amine is extracted into
benzene, the benzene solution dried and the benzene removed
- under vacuun~ leaving a pale yello~ish oil. The oil is dis~
solved in ether an~ converted to a crystalline dihydrobromide
which is recrystallized from a methanol-acetone mixture to
give white needles, mp 180-182.5C, of 10,11-dihydro-10-
[B-(4-met}lylDiperazin-l-yl)ethyl~hio]dlbenz[blf]oxepin di-
hydrobromide.
Analysis:
',
Calculated for C21H21N2OS 21~Br: 48.84%Ci 5-46'~H; 5-42%11-
Found: 48.g3%C; 5.66%H; 5.29%1d.
~:xample 5
A mixture of 1.5 g of 10-(~-bromoethylthio)-10,11-
dihydrodibenz[b,f]oxepin, ~xample 3, O.S g of morpholine,
1.0 g of sodium bicarbonate and 1.0 g of potassium iodide in
lS ml of dimcthylformamide is s~irred at 60-70C for 64 hours.
.. . .
___.,.. _.. ,.. _
- 17 ~ 1420
The reaction mixture is permi.tted to cool before being
diluted ~.Jith ~ater. The biphasic mixture is extracted with
ether and the combined ether extracts are shaken ~ith a larg~.
excess of 2N hydrochloric acid. The acid solution is basified
witl~ potassium carbonate liberating the amine as an oi]. which
is ~xtracted into ether. The ethereal solution is dried and
the ether is removed under vacuum regeneratin~ an oil which
is converted to i~s oxalate. The salt is recrystallized from
a methanol-acetone-ether mixture to give co].orless plates, mp
,.
196-198C of 10,11-dihydro-10-(~-morpholinoethylthio)dibenz-
[b,f]oxepin oxalate.
Analysis:
Calculated for C20H231lO2S C2~I2. 4
Found: 60.77%C; 5.88%l-l; 3.20%N.
E.xample 6
A sample of 3.8g of 2.-chloro-10,11-dihydro-11-
hydroxydibenz[b,f~oxepin is treated with 3.3g of ~-dimethyl-
aminoethylthiol hydrochloride in a manner consistent ~Jith
the procedure of Example 1, to provide granular crystals, mp
139-141C of 2-chloro-10,11-dihydro~ [~-(dimethylamillo)-
ethylthio]-dibenzlb,f]oxePin oxalate.
Analysis:
Calculated for C18H28ClMOS-C2~1~04: 56.66%C; 5.23%H; 3.31%~1.
Found: 56.58%C; 5.27%H; 3.31C/~
.. . _ ., _.,. _ . ,_ .. .. ~. _ _ . .. . ... .. _ . ,.. _ ... _ . . . .
~ 13 ~ 20
Example 7
~ solution of 2.0 g of 10,11-dihydro-10--oxodibenz-
[b,f]oxepin, ?..96 ~ of y-dimethylaminopropylthiol hydro-
chloride and ~ ml of boron trifluoride etherate in 8 ml of
glacia]. acetic acid which was permitted to stand for 16 hours
is refluxed on a stream bath for 30 minutes, cooled and poured
into a 6~1sodium hydroxide solution. The reactioa~ ture is extracted with
ether and the combined ether extracts are washed successively
~ith a 25% sodium hydroxide solution and water and dried.
The dried solution is filtered and the filtrate concentrated
' leaving an oil. The oil is chromatographed through a silic~
gel column with an eluant of 10C/~ methanol in chloroform. The
chromatographed oil is converted to its oxalic acid salt,
mp 151-152C, which is 10-[y-~dimethylamino)propylthio]-
dibenz[b,f]oxepin oxalate.
Analysis:
Calculated for ClgH21NOS C2H2O4: 62.82%C; 5.77C/uH; 3.49C/~N.
Found: 62.71%C; 5.7~a/OH; 3~43V/
Example 8
A miY~ture of 1.2 g of lO,ll-dihydro-10-oxodibenz-
tb,f]oxepin, 2.l~ g of ~-dimethylaminoethylthiol hydrochloride
and 2 ml of boron trifluoride etherate in 10 ml of glacial
acetic acid which was stirred at ambient temperature for 16
hours is warmed on a steam bath for 30 minutes. The warm
mixture is poured onto 200 g of ice-water and the diluted
mixture basified with a 40% sodium hydroxide solution liberating
an oil which is dissolved ln ether. The ether solution is
,
- 19 ~ zo
d~ied and concentrated leaving a thick oil which is
converted in ether to a crystalline oxaiic acid salt.
The salt is recrystallized from a methanol-ether mixture
to give granules, 147-148C of 10-[~-(dimethylamino)-
- 5 ethylthio]dibenæ~b,f]oxepin oxalate.
Analysis:
Calculated for C18HlgNOS-C2H204: 62.00~/~; 5.~:6/~1; 3.61%II; 8.28C/~S.
Found: 61.88~/2C; 5.46%H;3.55%~; 8.22%S.
Examp]e 9
To a stirrin~ solu~ion o 0.36 g o cyanogen bromlde,
2.28 g of potassium carbonate in 10 ml of chloroform is added
dropwise a solution of 1.0 g of 10-[~-(dimethylamino)ethylthio]-
dibenz[b,f]oxepin, Example 8, in chloroform. After total
addition the reaction mixture is refluxed for 2 hours and the
solvent removed leaving an oil. The oil is dissolved in 10 ml
of methanol and the methanolic solution refluxed for 10 mi.nutes
and again concentrated to recover the oil. The oil is chroma-
tographed through a silica ~,el column with an eluant of ether.
The top fraction is collected and concentrated leaving a white
solid, mp 106-107C of lO- [~-(bromo)ethylthlo~dibenz[b,f]oxepin.
Analysis:
Calculated for C16H13BrOS: 57.66%C; 3.93%H; 9.62%S; 23.98~/,Br.
Found: 58.38%C; 3. 89~ 1; 9.34%S; 24.12%Br.
. . ~ .
- 20 - 11~1~20
Example 10
To a stirring solution of d. 36 g of cyanogen
bromide, 2.28 g of potassium carbonate in lO ml of chloroform
is added dropwise a solution of 1.0 g of lO-[~-(dimethylami.no)~
ethylthio]dibenzEb,f~oxepin, Example &, in 20 ml of chloroform.
After total addition the reaction mixture is treated according
to Example 9. Following column chromato~raphy the middle
fraction is collected and concentrated leaving the whlte
product, mp 54-56 DC, ol~ 10-[,B-(N-Cyano-N-methylamino)el~hylthio]-
dibenz[b,f]oxepin.
~ - .
:Analysis:
ted ~or C1~16N2CS: 70.10%C; 5.23/.H.
Found: 69.99%C; 5.28%H.
~11
A solution of 2.0 g of 10,11-dihydro-lO-oxodibenz-
lb,f]oxepin, 3.76 g of ~- diisopropylaminoethy~thiol hydro-
chloride, and 8 ml of boron trifluoride etherate in ].0 ml of
glacial acetic acid is treated according to Example 7 to pro-
duce a yellow oil. The oil is chro~atographed through a silica
20 gel column with an eluant of 5% methanol in chloroform. The
chromatographed oil soli.difie.s upon scratching to a pale ye].low
powder, mp 65-66C, of 10-[~-(diisopropylamino)ethylthio]-
dibenz[b,f]oxepin.
Analysis:
.25 C~lculated for C22H27NOS: 74.74%C; 7.70%H; 3.96%~.
Found: 74.95%C; 7.71%H; 4.06%N.
- 21 ~ 1420
.. Example 12
A mixture of 1.14 g of 10~ (bromo)ethylthio]-
dibenz~b,f3oXepin, Example 9, 0.36 g of morpholine, 0.92 g
of sodium bicarbonate and 0.93 ~ of potassium iodide in ].5
ml of dimethylformamide is stirred for 16 hours while main-
taining the mixture between 60 and 65C. Thereafter the
mixture is poured into 150 ml of water, the biphasic mixture
extracted with ether and the ether extracts combined and
dried. The dried ether solution is filtered and the filtrate lO concentrated leaving an oil which is chromatographed through
a silica gel column with an eluant of 5% methanol in chloroform.
The chromatographed oil is converted to its white oxalic acid
. .
salt, mp 181-183C, of lO-[ ~tmorpholino)ethylt}lio~dihe;lz-
[b,f]oxepin oxalate.
.
Analysis:
Calculated for C20H2lNO~S C2~2 4
Found: 61.33%C; 5.35%H; 3.34','N.
. . .
Example 13
To a sti.rred solution of 2.08 g of 10-[~-(di.methyl-
amino)ethylthio]dibenz[b,f~oxepin, free base of Example 8,
in 10 ml of methylene chloride is added dropwise ~ solution of
1.26 g of phenyl chloroformate in 10 ml of methylene chloride.
After total addition the reaction mixture is permitted to stir
at ambient temperature for 16 hours and then concen~rated
leaving an oily residue. The residue is triturated ~ith hexane
and then chllled at -20C F ~fect a solid. The solid is
.
.
- 22 - 11~20
recrystallized from an ether-hexane mixture to gi.ve ~hite
needles, mp 103-103.5C, of 10-[~-(N-methyl-ll-phenoxy-
carbonyl)aminCethylthio]dibenz[b~f]oxepin.
Analysis:
Calculated for C24H21NO3S: 71.42/,C; 5.24~1~H; 3.47%N.
Found: 71.37%C; 5.31C/~H; 3 51%N.
Example 14
A stirring suspension of 1.6 g of 10-[~ -methyl-
N-phenoxycarbonylamino)ethyl~hio~dibenz[b,f}oxepin, ~xample 13,
and 3.4 g of potassium hydroxide pellets in 40 ml of ethylene
glycol is heated to between 150 and 160C over a 60 minu~e
span. Sti.rring is continued at this temperature for an
additional 30 minutes. The mixture is cooled, diluted ~ith
water and the biphasic mixture extracted with an excess of
ether. The ether extracts are combined, washed with ~a~er and
dried and the solvent removed leavin~ a clear, mobi.le oil.
The oil is converted to its oxalic acid salt and recrys~alli.zed
from methanol to give shiny needles, mp 207-208C(dec),
of 10-~(methylamino)ethylthio]dibenz[b,f]oxepin oxalate.
Analysis:
. .
Calculated for C17H17NS C2~12~4
Found: 60.8S7,C; 5.14%H, 3.78';'~.
Example 15
A mixture of 1.82 g of : 10-[~-~me~hylamino)-
ethylthlo]dibenz[b,f]oxepill, free base of Example 14, 0.72
g of cyclopropylmetltyl chloride~ 1.93 g of sodium bica~bonate
.
,
- 23 ~ 20
- and a few crystals o potassium iodide in 50 ml of
dillletllylformamide is stirred at 80C for 16 hours. The
reaction mixture is permitted to cool and filtered and the
~iltrate concentrated leaving an oil which is converted to ttle
oxalic acid salt,mp 137-139C., of 10-[~-(M-cyclopropyl-
~ethyl-N-methylamino)eLhylthio~dibenz[b,f]oxepin oxaiate.
Analysis: ~
Calculated for C21H23NOS C2H204. 64.61%C; 5.89~H; 3.2g%N
Found: 64.80%C; 5.96/u~l; 3.24%N.
rxample 16
A mi~ture of l.S g of 10 [~-(methy].~mino)-
ethylthio]di~enz[b,f]oxepin, free base of Example 14, 1.1 g
of ethyl iodide, 1.48 g of sodium ~icarbonate and 1.46 g
of potassium iodide in 20 ml of dimethylformamide is stirred
at 80-85~C for 16 hours. The reaction miY~ture is permltted
to cool and diluted with 75 ml of water and then extracted
thrice with 75 ml portions of ether. The ether extracts are
combined, washed with 75 ml of a saturated sodium chloride
solution and then dried. The dried solution is filtered and
the filtrate concentrated leaving an oil. The oil is chroma-
tographed through an alumina column with an eluant o ether.
The chromatographed oil is converted to its oxalic acid salt
which is recrystallized from an acetone-ether nixture to gi~e
the white product, mp 126-128~C, of 10-[B~ -e~hyl-ll-methyl-
amino)ethylthio]dibenz[b,f]oxepin oxalate.
Analysis:
Calculated for ClgH2lNOS C2H204: 62.82r,~C; 5.77r/'H; 3.4g%N.
Found: 62.39%C; 5.69%H; 3.56%N
_
- 24 - ~ zo
Example 17
The substitution of propargyl bromide for ethy].
i.odide into the procedure of ~xample 16 provides the ~Jhite
solid, mp 140-142C, of 10-[~-(N-methyl-~-propargyl)-
aminoethylthio]dibenz[b,f]oxepin oxalate.
Analysis:
Calculated for C20H19MS C2~24 64-21/~C; 5-
Found: 64.49~; 5.22%1~; 3.41%N.
~ .
E_ample 1~
To a mixture at a temperature OI O C of 2.~ g of
~-diethylaminoethylthiol hydrochloride in 5 m]. of acetic
acid and S ml of boron trifluoride etherate is added drop-
wise a solution of 2.0 g of 2-chloro-10,11-dihydro-11~
hydroxydiben?.[b,f]oxepin in 6 ml of ~lacial acetic acid.
After total addition the reaction mixture at 0 C is stirred
for 20 minutes and thereafter at ambient temperature or 16
hours. The well stirred mixture is added slow to 50 ml of
a 20% sodiul~ hydroxide solution at 0 C. After this addition
ether is added and the biphasic mixture filtered and permitted
to form separate layers. The aqueous layer is extracted
twice with 50 ml portions of ether and the e~her extracts com-
bined with the organic (ethereal) phase. The combined solutions
are washed successively with one portion each of 40 ml of 20%
sodium hydroxide solution, 30 ml of 10% sodiu~ hydroxide, SO ml
of water and 30 ml of a saturated sodium chloride solution and
then dried over potassium carbonate and potassium hydroxidc
' ,' , ~ .
- 25 -
- pellets ].eavin~ an oil. The oil is chrornatographe~ through
a silica gel column with a 5~,~ methanol chloroforrn mixture
to obta~n a purified oil ~7hich is disso].ved in ether and treated
with an ethereal oxalic acid solution to obtain ~he correspond-
ing oxalic acid salt which is recrystallized frorn acetone to
give a white powder, mp 1~6.5-128.5C, of 2-chloro-
ll-[,B(diethylami.no)ethylthio]-10,11-dihydrodibenz[b,f]oxepin
oxalate.
~nalysis: ,
Calculated for C20H23ClMOS C2H2~ 58-60%C; 5.59%~i; 3.11%~l;
7.~6%Cl.
Found: . 58.68%C; 5.7~%II; 2.95%I~I;
- . ~.27~Cl.
' Example 19
To a stirred solution of ~.. 5 g of 10,11-dih~dro-
10-hydroxydibenz[b,fJoxepin, 3.7 g oE y dimethylaminopropylthio
h~drochloride in 13 ml of glacial acetic acid ~re added ~ ml
of boron trifluoride etherate. The reaction mixture is pe~itted
to s~and for 2~ hours before being poured into 50 m]. of a
chilled 25% sodium hydroxide solution. The basic mix~ure is
extrac,,ed with ether, the ether extracts combined ~hich are
was,hed succ,essively with a 20% sodium hyclroxide solu~ion and
water, dried and filtered and the filtrate evaporated leaving
an oil. The oil is chromatographed through a silica gel column
with a 5% me~hanol in chloroform eluant an~ thc eluate is
- 26 - ~ zo
evaporated leavin~, a purified oil which is converted t:o a
white ~,ranular oxalic acid sal " mp 179-181C, of 10,-
~ dihydro-10-[~-(dimethylamino)p~opylthio]dibenz[~,f]oxe~in.
Analysis:
Calculated for ClgH22~0S C2~20~
Found: 62.60C/~C; 6.26%H; 3.64%N.
~xample 20
A mixture of 1.5 g of 10-[~-bromoethyl)thio]-
, 10,11-dihydrodibenz[b,f]oxepin, Example 3, and 1.0 g of
potassium iodide in 15 ml of dimethylformami.de is bubbled for
five minutes with ethylamine. The reaction mixture is per-
mitted to cool to ambient temperature and then stirred for ]6
hours. Ice-water is added and the biphasic rnixture is extracted
thrice with ben~ene and the combined ~en~e~le extrac~s are dried
audevaporated to dryness leaving a crude l?roduct ~hich is con-
verted in acetone to it:s oxalic acid salt. The sal.t is re-
crystallized from 90% ethanol to give cvlorless prisms, mp
205-207C, dec, of 10-[~ -(ethylamino)e~hylthio]-10,].1-dlhydro-
,
debenz~b,f~oxepin oxalate.
.
~nalysis:
Calculated for C]~T21~0S C2ll204: 61.67~J; 5.95%1~; 3.60%1~.
61.68~/~; 5.97%~1; 3.39%N.
Found:
EY.amp].e 21
To a solution of 2.5 g of 10,11-dihydro-2-
methylthio-ll-oxodibenz[b,f]oxepin, 2.8~of ~-dimethyl-
aminoethylthiol hydrochloride and 24 ml of glacial acetic scid
27 ~ 1420
which was s~irred at am~ient ~emperature for 30 minutes
is added,with additional stirring,8 ml of boron trifluoride
etherate. After total addition,stirring is discontinued and
the reaction mixture is permitted to stand for 72 hour5 before bein~
added to 50 ml of ice-water. The diluted mixture is rnade
strongly alkaline with a 10% sodium hydroxide solution and
the strongly alkaline mixture is extracted ~ith ether. The
combined ether extracts are dried and evaporated ~o dryness
leaving an oil. The oil is chromatograplled through a silica
gel column with a 5% methanol in chloroorm eluant and the
desired fractions were collected and concentrated leaving
a purifi.ed oil. The oil was converted to a white granular oxalic
acid salt of ll-[~-(dimethylamino)e~hylthio~2~methylthio-
dibenz[b,f]oxepin oxalate.
Analysis: -
Calculated for C19}121NOS2 C2H24 5~ ;
~otl~lcl: 57.99/~C; 5. 26D/~H;
xample 22
To a solution of 1.0 g of 2-fluoro-10,11-clihydl:o~
ll-oxodibenzrb,f]oxepin and 1.2 g of dimethylaminoethanthiol
hydrochloride in 11 ml of glacial acetic acid is added 3.3 ml
of boron trifluoride etherate. After total addition the
reaction mixture is stirred at ambient te~lperature ~or 6~ hours
and them poured into 25 ml of solution at 0C of 20% sodium
hydroxide and the aqueous mixture extract~d ~Jith ether. The
combined ether extracts are ~7ashed successively with two porti.ons
of 20% sodiu~ hydroxide, one portion of water and one portion of
.
.
.
, '
- 23,-
ZO
a saturated sodium chloride solution and then dried to
give an oil. The oil is chromatographed through a si].ica
gel column wit:h a 5~/J methanol in chloroform solution to
give a purified oil which is treated with ethereal hydrogen
S bromide solution efecting ~ white precipitate. The pre-
cipitate is washed with ether and recrystallized from
acetone to give a white powder, mp 197-198.5C of 2-fluoro-
ll-[~-(dimethylamino)ethylthio]dibellz[b,f]oxepin hy~ro-
bromide.
Analysis:
Calculated for C18H17F~OS H~r: 54.55%C; 4. ~3C/"H; 3 5~CioM; 20 . ].7/OBr~
Found: ' 54.49%C; 4,30C~ ; 3.50~ 1; 20,1~%Br.
The 2-fluoro-10,11-dihydro-11-oxodibellz[b,f]oxepin,
starting material for Example 22, can be prepared by the following
se~uence of reactions:
a. l'o 147 g of iodobenzoic acid and 45.5 g of votassium
carbonate are added 57 ml of nitroben~ene. The mixture is heated
with stirring at 160C for 40 minutes. To the heated ~lixture
is added an additionai 46.5 g o~ potassium carbona~e and then
successively 73.1 g of 4-fl.uorophenol, anot~her (~6.5 g of potassium
carbonate and 0.3 g of copper powder. After these additions,
the mixture is stirred at 160~C for 45 minutes and the result,ing
solid is cooled to 0~C. The cooled solid is mixed with 100 ml
of water and 220 ml of 6M hydrochloric acid. The acidic mix-
ture is diluted with water to a volume of one liter and then
mixed with 450 ml of chloroform. The white soli.d is filtered
- 29 11~14Z~
o~f and washed tlitll chloroform and ~ater. The solid is
dissolved in hot acetone cooled and filered to leave a
white crystalline product mp 1~ 147C of 2-(4-fluoro-
phenoxy)bcnzoic acid.
b. To 3.28 g of 2-(4-fluorophenoxy)benzoic
acid is added 5.6 ml of 97% thionyl chloride. The reaction
mixture is heated on a steam bath for 10 minutes and any
excess thionyl chloride is then removed under reduced
pressure. The residual liquid is dissolved in 30 m]. of
1 2~dichloroethane and added dropwise over a 30 minute span
to a ~ixture of 1.9 g of aluminum chloride in 5 ml of 1 2-
dichloroethane. -After total addition the reaction.mixture
is stirred at re~lux for 2 hours and allowed to s~ancl at
ambient temperature ~or 64 hours. Thc mix~ure is poured on~o
i5 a mixture of 150 ml of ice and water and 125 ml of ether. The
biphasic n~ixture is filtered through paper and separate~. The
aqueous layer is collected and extracted twice wiLh two portions
(50 Inl) of ether. The combined ether extracts are ~ashec~
successively with two 25 ml portions o~ a sa~urated sodium
bicarbonate soltuion and one 25 ml portion of saturated sodium
chloride solution and then dried to give an oil. The oil is
treated with hexane and the resulting solution clecanted off
and evaporated leaving a bright yellow crystalline solid. The
solid is chromotographed ~hrough a silica-ge] column with a
chloroform eluant and is recrystallized from cyclohexalle to ~ive a
yello~ hite.crystalline so]id mp 85.5-87.5C of 2-fluoro-10,].1
dihydro-ll oxodibenztb ~]oxepin.
~he ~etones of which are starting materials of other
examples may be prepared in a fashion similar to the procedure
- outlined above.
zo
- 30 - -
Example 2_
To a solution which was stirred at amhient
temperature for 30 minutes, 2.5 g of 2~chloro-10,]1-dihydro-
ll-oxodibenz[b,f]oxepin, 2.9 g of ~-dimethylaminoethylthiol
S hydrochloride in 25 ml of glacial acetic acid is added with
continuous stirring 5 ml of boron trifluoride etherate.
After total addition the stirring is discontinued and the
reaction mixture is permitted to stand or 24 hours. The re-
action is basified with 10~/~ sodium hydroxide solution and
extract~ed ~ith ether. The combined e~her extracts are dried
and filtered and then the solvent removed leaving an oil.
The oil is chromatographed tlll-ough a silica gel column ~7ith
a 5% methanol in chloroform eluant to obtain a purified oil
which is converted to a white oxa]ic acid salt, mp 183-184C
of 2-chloro-11-[~-(dimethylamino)ethylthio]dibenz[b,f]oxepin
oxalate.
~nalysis:
Calculated for C]8Hl8cll~os c2~l2o4 56.93%C; 4 78%H-
Found: 56.67%C; 4.70%~1.
~xample 24
To a solution of 2.5 g of 10,11-dihydro-2-(methyl-
thio)-ll-oxodibenz[b,fJoxepin, 3.33 g of ~-die~hylamino-
ethylthiol hydrochloride and 24 ml of glacial acetic acid
whicll was stirred for 30 minutes is added 8 ml of boron
trifluoride etherate. After this addition the reaction mix-
ture is permitted to stand for 72 hours bcfore its addition
- 31 - 11~1420
to 50 ml of ice water. The diluted mixture is made strongly
alkalinc with a 10% sodium hydroxide solution and then ex-
tracted with ether. The combined ether extracts are dried,
filtered and the ether evaporated off ],eaving a yello~i oil.
The oil is chromatographed through a silica gel in chloroform
colu~n with an eluant of 5~/~ m.ethanol in chloroform to purify
the oil which is converted to its hydrogen bromide acid sal~
hich is rec-rystallized fro~ acetone to give t'he salt, mp 184-
186~C, of ll-[~-(dimethylamino)ethy].thio]-2-(methyltllio)-
di~enz[b,f]oxepin hydrobromide.
, .
Analysis:
Calculated for C21}125NOS2-l~Br: 55.74%C; 5-79%H; 3-10%N-
~ound: 55.83/,C; 5.85/,~1; 3.05%~.
Example 25
To a stirring solution of 11.3 g of ll~ (dimethyl-
alllino)ethylthio]-2-(methylthio)dibenz[b,f]oxepill, free base
of Example 21, and 10.0 g of potassium carbonate in 50 m] of
~ethylene chloride is added drop~ise a solution o~ 5.7 g of
phenylchloroformate in 50 ml of methylene chloride. ~fter
total addition the reaction mixture is stirred at,ambient
temperature for 24 hours and then evaporated to dryness. The
residue is trlturated with ether and the ethercal solution is
sequentially washed successively with a 10% sodium hydroxide
solution and ~ater, dried and filtered and the filtra~e evap-
orated to dryness leaving a yellow oil. The oil is chromato-
' graphed throu~h a silica gel column with a methylene chloride
- 32- ~ 4;~0
eluant to obt~ain the pu~ ied orange oil of 11- [~ etl~yl-
N-pheno~ycar~onylamino)ethylthio]-2~ ethyltllio)-dibenz[b,f]-
oxepin.
~nalysis:
Calculated for C25H231~03S2: 66.79%C; 5.16%1~; 3.12C~N.
Foun~: 66.~41~/.C; ~.93C/,~; 3.06C/,Il.
Example 26
mixture of 8.3 g of ll-~ methyl-N-phenoxy-
c~rbonyl)a~inoethylthio]-2-(methyl~hio)-dibenz[b,f]oxepin,
Example 25, 190 ml of ethylene glycol C~dl6 ~ of potassium
hydroxide is stirred at 155C for 30 minutes. The reaction
mixture is cooled and then poured onto 500 ml of ice wa~er.
The biphasic mi~ture is extracted ~;~ith a 1:1 ether benzene
~ixture and the combi.ned extracts are washed with ~ater and
dried. The c~ri.ed soiution is iltered and the filtrate evapo
rated to dryness leaving an oil. The oil is converted ~o i~s
maleic acid salt ~hich is recrys~al3.ized from ace~onc leaving
the salt, mp 160-162C of ll-~-(methylamino)ethylthio~-2-
(methylthio)dibenz[b,f]oxepin maleate.
Analysis:
Calculated for C18Hlg~OS2-C4H404 59.30%C; 5.20~ ; 3.1/l%N.
Found: 59.40~/~C; 5.23%H; 3.08C/~N.
Exa~ple 27
A reaction solution of 1.9 g of ll-[~-(methyl-
amino)ethyltllio]-2-(methyltbio)dibenz[b,f]oxepin, free base
,
, .
33 ~ 4Z~
of Example 26, 1.2 g of ethyl iodide and 1.60 g of sodium
bicarbonate in 25 ml of di~ethylforn.amide is stirred with
heating for 72 hours. The solution is diluted wi~h 100 ml
of water and the ~iphasic mixture extracted with eLher. The
combined ether extracts are wa~hed ~ith ~ater, ~ried and then
iltered and ~he filtrate evaporated to dryness leaving an
oil. 'rhe oil is converted to a ~hite salt, mp 112-114C
of ll-[~-ethylmethylamino)ethylthio]-2-(me~hylthio)dibenz[b,f~-
oxepin maleate.
Analysis:
for C20I~23NOS2-C4~404: 60.~6%C; 5.75C,/,~I; 2 96%~
Found: 6].11%C; 5.74%I~; 2.87%N.
Examples 28 and 29
By following the procedure of F.xample 25, 2-fluoro-
ll-[~-(d~.~.ethylamino)ethylthi.o]dibcnz[b,f]oxepin, free base of
Example 22, and 2-chloro-10,11-dihydro-11-[~-(dimethylamino~-
ethy3.~.hio]dibenz~b,f]oxepin, free based of Example 6, are ~reated
respectively to obtain 2-f].uoro-ll-[~ -methy]-~-pl~en
carbonylami.no)ethylthio]dibenz[ D, f]oxepin, Example 28, and
2-chloro-11-[~ -methy]-Id-phenoxycarbonyl~mino)ethylthio~-
dibenz[b,f]oxepin, Example 29.
Ana]ysis: [~xample 28]
Calculated for C24H20F~IO3S: 68.40%C; 4.78%1-l; 3.32%~; 4.51%F.
Found: 6S.25%C; 4.85C/vH; 3.28%~1; 4.80%F.
.
- 34 ~ 20
~,xample 30
A reaction solution of 5.1 g of 2-fluoro-
ll-[~-(M-methyl-N-phenoxycarbonylamino)ethylthio]dibenz[b,f]-
oxepin and 10.6 g of potassium hydroxide in 125 ml of ethylene
-glycol is stirred ~ith heating at fro~ 80 to 155C for 30
minutes and then at 155C for 30 minutes. Then the reaction
is permitted to stand a~ 0C for 16 hours before being poured
onto 350 ml of ice water. The biphasic mixture is extracted
thrice ~7ith 125 ml portions of 1 1 e~her-benzene mixture.
The combined orgallic l~yers are washed successively with three
portions of water and one portion of a saturated sodi~m
chloride solution and then dried ].eaving a clear orange oil.
The oil is swirled with a 50 ml portion and 0.25 ml portion
- of boiling hexane and decanted from any residue effecting a
yellow oil. The oil is treated in ether ~ith ethereal maleic
acid effecting a salt which is recrys~alli.zed from a methanol-
acetone-ether mix~ure to give a white po-7der, mp 135.5--~36C,
of 2-~luoro-11-[~-(methylamino)ethylthio]dibcnz[b,f]oxepin
maleate.
' ' . .
Analysis: ~
Calculated for C17H16F~lOS C411404: 60.43~1~C; 4.83%H; 3.36%N; 4.5S%~.
Found: 60.42%C; 4.86~/~H; 3.26%N; 4.85%F.
.
- . Example 31
A reaction mixture of 4.0 g of 2-chloro-11-[~-(N-
methyl-N-phenoxycarbonylamino)ethylthio~iben7.[b,f~0xepi.n,
Example 29, and 8.5 g of po~assium-hydroxide in 80 ml of ethylene
~ ~ 35 ~ 1 1~ 14 ~0
glycol is s~irred at 155C for 30 minutes. The mixture
is permitted to cool and ice is added. The mixture is
extracted with ether and the combined ether extracts are
dried and ~he ethe~ evaporated o~f leaving an oil.. The oil
is ~reated in ether with ethereal maleic acid and the resulting
salt recrystallized from a methanol-ether mixture to give
colorless prisms, mp 153-]54C, of 2-chloro-11-[~-(methyl-
amino)ethylthio]dibenz[b,f]oxepin maleate.
Analysis: -
,.
Calculated for C17lll6Cl/lOS C4H404: 58.12~/.C; 4.64/,11; 3.22%~1; 8.17%C~
Found: 58.15%C; 4.77%H; 3.~4%i~; 8.33~/oCl
Example 32
To a mixture of 1.1 g of ~-dimetllylaminoethanethiol
hydrochloride and 2.8 ml of boron tri1uori.cle etllerate in 5 ml
of glacial a.cetic acid is added dropwise a solution of 0.9
of 2~fluoro-10,11-dihydro-11-hydroxydibenz[b,f]oxepin in ~
ml of glacial ace~ic acid. After total addition the reaction
mixture is permitted to stir for 16 hours before being poured
onto a mixture of 30 ml of.a 20% sodium hydroxide solution and
ice. The mixture is extracted with ether and the combined
ether extracts are washed successively with two-portions of
a 20% sodium hydroxide solution, one portion of wa~er and one
portion of a saturated sodium chloride solution. The washed
extracts are dried producin~ an oil which is chroma~ographed
throu~h a silica gel column with an eluant of 5V/~ methanol
in chlorofo-rm to obtain a purified oil.. The oil is converted
- 36 ~ 20
to its o~alic acid sal~ which is recrystallized from acetone
to ~ive a white po~der, mp 169-170.5~C, of 2-f].uoro-10>-
ll-dihy~o-ll-[~-(dim~thylamino)ethylthio]dibenz[b,f]oxepi
oxalate.
Analysis:
Calculated for C18~20F~S-C21124
Found: 59.17%C; 5.1~4%H. 3.51%~; 4.~1%F.
- ~xample 33
-. To a mixture of 2.3 g of cyanogen bromide and 5.0 g
of potassium carbollate in 40 ml of chloroform is added portlon-
wise over a 50 minutes span a solu~ion o~ 4.8 of 2-fluoro-10,-
ll-dihy~-o~ [~-(dimethylamiIIo)ethylthlo]dibenz[b,f]oxepin, free
base of Example 32, in 85 ml of ch~o]^oform. After total addition,
the mixture is stirred for 20 minutes before being filtere~.
The filt~ate is evaporated to leave an oil which is treated
with three portions of boiling hexane. The combined hexane
portions are eva?orated leaving an oi.l ~hich is chromatographed
throu~h a silica gel column ~ith an eluant of l~ethylene chloride
and is recrystalli.zed from cold hexanc to ~ive a white powder, m~
46-48C of ll-~-(bromo)eth~lthio]-2-fluoro-10,11-dihvdrodibenz-
[b,']oxe~in.
Analysis:
Calculated for C16H14BrFOS: 54.41C/~C; 4.00/~H; 22.63V~r; 5.3~%~.
Found: 54.36%C; ~Oi~/o~i; 22.91%Br; 5.69~.F.
~ 37 ~ 1;4z~
~xa~ le 34
Methylamine is bubbled into 10 ml of dimethylsulfoxide
for 5 minutes. To this solution is added dropwise a SO].U~iOII
of 2.2 g of ll [B-(bromoethyl)thi~}2-fluoro-]-olll-dih~drodiben
[b,f)oxepin in 11 ml of dimethylsul.fo~ide. Sufficient methyl-
amine is bubbled into the reaction mixture to complete the
reaction. Thereafter the reac,ion mix~ure is permitted to stand
or 64 ilours. The reaction mixture is poured onto 125 rlll of
ice ~ater, and the biphasic mixture is extracted with three
portions of ether. The combined ether extracts are washed
.
successively ~ith two ~0 ml portions of ~7ater and one 10 ml
portion of saturated sodium chloride solu~ion and dried to
produce an oil. The oil is dissoved in ether and treated with
ethereal ma]elc acid ~hich precipita~.es a salt which is re-
crystallized from an acetone-ether mixture to gi.ve a whi.te
solid, mp 11~-119.5 C, of 2-fluoro-10,].1-dihydro-ll-[~-(methyl-
amino)ethylthio]di.benz[b,f]oxepin maleate.
Analysis:
, ~"
C17~.18FNOS C4H404: 60.14%C; 5.29%H; 3 34%N; 4 53%F
Found: 60.11%C; 5.19%H; 3.19%N; ~.80'~F.
rxample 35
To a stirring solu~ion of 2.8 g of ~-dimethylamino-
ethylthioi hydrochloride and 7 ml of boron trifluorine etherate
in lO ml of glacial acetic acid is added dropwise a solution
of 2.5 g of 10,11-dihydro-11-hydroxy-2-methylthiodiben~[b,f]--
oxepin in 10 ml of glacial acetic acid. After to~al addition
,
.
': ~
~ 3g ~ ~ 20
the reaction mixture was permitted to stand for 2l~ hours
before bein~ added to 50 ml of a cold 25% sodium hydroxide
solution. The reaction mixture is extracted with ether and
the combined ether eY~tracts are successively washed witll a
20% sodium hydroxide solution and water and~dried. The dried
solution is ~iltered and the filtrate is e~Taporated to dr~ness
leaving an oil ~;~hich is dissolved in chloroform. The chloroform
solution is chromatographed through a silica gel column ~ith an
- eluant of 5~ methanol in chloroform to obtain a purified oil.
The purified product lS conver~ed to its maleic acid salt, a
white powder, mp 100-102C of 10,11-dihydro-11-[~-(dimethyl-
amino)ethylthio]-2-(methylthio~dibenz[b,f]oxepin maleate.
Analysis:
. ClgH23NOS2-C4l-1404: 59.84%C,; 5.90%1I; 3 0~l%N
Found: 59.92%C; 5.93%H; 3.00%N.
; Example 36
By the procedure of Example 35, ~-diethylamino-
ethylthiol hydrochloride is treated with 10,11-dihydro 11-
hydroxy-2-1Ilethylthiodibenz[b,f]oxepill to obtain an oil of
ll-[~-diethylamino)ethylthio] 10,11-dihydro-2 (me~hylthio)-
~; dibenz[b,f]oxepin. The oil is chromatographed throu~h a silica
gel methylene chloride column ~ith an eluant of a 5~/, me~hanol
in methylene chloride to purify the oil. The purified oil is
converted to its white oxalate salt, mp 118-120C.
Analysis:
' ~ Calculated for C21~12?NOS2 C2~124
Found: ~ 59.30%C; 6.32%11; 2.93%N.
.
. '
.
.
.. ~. ' . :
~ 39 11~420
Exam~le 37
A sample of 10,11-dihydro~ [R-(dimethylamino)-
ethylthio]-2-(methylthio)di~enz[b,f]oxepin, free base of
Example 35, is treated according to the procedure of Example
33, to obtain 11-(~-bromoethylthio)-10,11-dihydro-2-(methyl-
thio)dibenz[b,f]oxepin. The oil is. dissolved in hexane and
cooled in a dry/acetone bath to effect crystallization of the
oil to a white solid, mp 64-66C.
Analysis: .
.~;~ ' .
Calculated for Cl7H17~rOS2: 53.54%C; ~.49%H; 20.9~%Br.
Found: 53.72%C; 4~47C/oH; 21.0~%Br.
Example 38
To a mi.xture of 2.0 g of 2-fluoro-11-[~-dimethyl-
amino)ethylthio]dibenz[b,f]oxepin, free base of Example 22, in
62 ml of methanol are added 6.1 g of magnesium shavings. l'he
reaction is stirred for 90 minutes with sufficient coolin~ to
maintain the reaction at a~bient temperature. The methanolic
3 mixture is decanted off and then cooled. The cooled mixture
is then treated with careful addition of 60 ml of 6N hydro-
chloric acid. The acidi~ied mixture is permitted to reach
ambient tcmperature before being diluted with 60 ml of water
and the diluted mixture is extracted wi'~h chloroform. The
combined chloroform extracts are successively washed wlth 80 ml
of a 10% sodium hydroxide solution, 100 ml of water and 25 ml
of saturated sodium chloride solution and dried to effect a yellow oil
~ The oil is extracted thrice with 30 ml portions of hot pentane
. .
? . .
~ o 1~ 20
and the com~ined pentane extracts are e~aporated le~ving
purer oil 17hich is treated in ether with ethereal ox~lic acid
to precipitate out a salt. The salt is ~ashed well with
.
ether leaving a white solid, mp 167-169G of 2-fluoro-10,-
ll-dihydro-ll-~-(dimethylamino)ethylthio]dibenz[b,f]oxepin
oxalate identical to the product described in r,xample 32.
- Example 39
A solution of 1.5 g of ll-[~-(bromo)etl~ylthio]-
10,11-dihydro-2-(methylthio)diben7[b,f]oxepin, F,xample 37,~ 10 and 0.9 g of potassium iodide in 15 ml of dimethylformamide
is stirred a~ ambient temperature ~hile methylamine is
bubbled into the solution over a 5 minut:e span. ~fter ~otal
addition,the solution is permitted to stir for 16 hours before
being successively poured into 100 mi of ice water, extrac.ed
with benzene,and the combined benzene extracts dried. The
dried solution is filtered and then evaporated to dryness
leaving a yellow oil ~hich is converted to its maleic acid
salt as a granular powder ~hich is recrystallized from a
methanoi-e~her mixture to provide the product, mp 138-140~C,
of 10,11-dihydro-ll-[~-(methylamino)ethylthio]-2-methyl-
thiodibenz[b,f]oxepin maleate.
Analysis:
Calculated for C18H2ll~0S2 4 4 4
Found: 58.~3%C; 5.43%1-1; 2.90%M.
' .:
,
4ZO
Example 40
Into a solution of 2.6 g of 10~ bro~oethylthio)-
10,11-dihydrodibenz~b,f]oxepirl, F.xample 3, in 15 ml of dimethyl-
- formamide is bubbled methylamine over a 20 ~inu~e span. After
tota~ addition the reaction m-ixture is permitted to stand at
ambient temperature for 16 hours. Tllereafter, ice water is
added and the biphasic mixture is extrac~ed thrice with ether
and the combined ether extracts are ~ashed ~ith ~ater. The
ethereal solution is dried and the resulting product is con-
verted to its maleic acid salt. The salt is recrystal]ized froman acetone-ether mixture to provide prisms "np 102-104C
of 10,11-dihydro-10-[(~-methylamino)etllylthio]dibcnz[b,f]oxepin
maleate.
Analysis:
'"" - ~ . .
Calculated for C17HlgNOS-C4H4O~: 62.82%C; 5.77%H; 3.49%M; 7.99%S.
Yound: 62.30~/,C; 5.77%~1; 3. 36~/oM; ~ . 1S%S .
le 41
A mixture of 2-chloro-10,11-dihydro-11 [~-(dimethyl~
amino)ethylthio]dibenz[b,f]oxepin, free base of Example 6, 0.7 g
of cyanogen bromide, and 0.8 g of potassium carbonate in 20 ml
of methylene chloride is stirred at ambient temperature
or ~ hours. Thereafter the mixture is filtered and the filtrate
concentrated under vacuum,leaving a viscous oil. The oil is
chromatographed over silica gel, leaving a pale yellowish oil,
Rf of 0.8, of 11-(~-bromoethylthio~2-chloro 10,11-dihydrodibenz-
lb.f]oxepin.
. .
Analysis:
' '. ' .
.
.
,~ :
- ~2 - 1~420
Calc~llated ~or C16Hl~BrClOS: 51.98~/~C; 3.82C/oH; 8.67%S.
Found: 52.26/,C; 3.76/,EI; 8. 61~oS.
Example 42
Into a solution of 1.5 g of ll-[~-(bromo)ethyl~hio~-
2-chloro-10,11-dihydrodibenz[b,f]oxepin, E~ample 41, in 20
ml of dimeth~lformamide is bubbled methylamine over a 10
- minute span. Thereafte~, the solution is permit~ed to stand
at ambient temperature for 16 hours. Then the solutiorl is
evaporated to dryness leaving a yellowish oily residue which
is equilibrated with sodium bicarbonate and ether. The ethereal
phase is collected and then dried before being concentrated
under vacuum leaving a clear oil which is converted to a
crystalline ~naleic acid salt. The.sal.t is recrys~allized fro~n
an acetone-etller mixture to provide white prisms, mp 13~-140C
of 2-chloro-]0,11-dihydro-11-[~-(methylamino)ethylthio~dibenz-
[b,f~oxepin ~aleate.
Analysis:
.~
Calculated ior C17H18ClNOS C4H404: 57.86%C; 5-09/~11; 3-21%M; ~ 13%Cl
~ound: 57.62%C; 5.00%~1; 3.0S%N; 8~33~/oCl
Example 43
_
a. A solution of 28.4 g of 2-(4-methylsulfonyl-
phenoxy)benzyl nitrile, 99 ml of 95% ethanol, 15.2 g of 85%
potassium hYdroxide and 25 ml of water is stirred at 115C
for 24 hours. Thereafter, the reaction mixture is concentrated
to an oil. The oil is dissolved in water and the aqueous
.
- 43 -
solution is washed with ether, acidified with dilute hydrochloric
acid providing an oil. This oil is dissolved in methylene
chloride and the solution, successively, is dried, filtered and
concentrated to dryness leaving a light yellow solid. The
solid is chromatographed through a silica ge]/ether column with
a 10% methancl in ether eluant to provide the product 2-(4-
methylsulfonylphenoxy)phenylacetic acid, mp 1~5-127C.
b. A mixture of 1.0 g of 2-(4-methylsulfonylphenoxy~-
phenylacetic acid and lO ml of polyphosophoric acid under nitrogen
is stirred at 90-100C for 2 hours. The reaction mixture is
permitted to cool and then poured into 100 ml of an ice-water
slurry. The aqueous solution is basified with 20% sodium
hydroxide before being extracted with methylene chloride. 'rhe
combined extracts are dried and then evaporated ~o dryness
leaving an oil. The oil is chromatographed through a silica
gel/methy]ene chloride column with 2% methanol in methylene
chloride. The chromatographed solution is evapora~ed
to dryness leaving an oil which solidifies on s~anding. The
solid is triturated with pentane to provide 10,11-dihydro-2-
methylsulfonyl-ll-oxodibenz[b,f]oxepin, mp 105-106~C.
c. A stirring solution of 4.4 g of 10,11-dihydro-
2-methylsulfonyl-11-oxodibenz[b,f]oxepin, 4.3 g of dimethyl-
aminoethylthlol hydrochloride and 37 ml of glacial acetic acid
is treated with 15 ml of boron trifluoride etherate. Thereafter
the reaction mixture is poured into 300 ml of a cold lOC,'
- sodium hydroxide solution and the resulting solution is extracted
witb methylello hlor de. The combined ~xtracts Ire washed w,th
,
- 44 ~ 1420
t~7ater and dried before being filtered. The filtrate is evapor-
ated to d~yness leaving an oil which is chromatographed through
silica gel/methylene chloride ~ith a 2-4C' meth~lol chloride
- eluant. The chromatographed solution is evaporated to dryness
and the resulting oil is converted to a white maleic acid salt,
mp 137-139C of ll-[(~-dimethylamino)ethylthio]-2-methyl-
- sulfonyldibenz[b,~]oxepln maleate.
Analysis:
or Cl9H21~13S2 C~ 44 56 19%C; 5.13%17; 2.85%1~
Found: 56 . ~4//oC; 5 . lSV/oH, 2 . 36~oN.
.
'
