Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
The present appli.cation is a divisional oE
Appli.cation Seri.al No. 389,082, filed October 30, 1981.
This invention relates to new intermediates for
5the preparation of certain phthalimidines and phthalazinones.
The intermediates are more particularly concerned with the
preparation of 3-aryl-3-hydroxyphthalimidines which are use-
ful as therapeutic agents.
The 3-aryl-3-hydroxyphthalimidines produced in
accordance with the present invention are compounds of the
formula:
15 ~ OH
~}S02X'
wherein,
Y and Z are each H, alkyl, halo, alkoxy, ~ri-
fluoromethyl, hydroxy, alkanoyloxy, or alkanoyl-
amin~;
X is F, Cl, Br or NRlR2 in which Rl and R2 are
each hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, aryl or
aralkyl; and
R is H, alkyl, cycloalkyl, or aralkyl.
3o
Specifically, the present invention relates to com-
pounds of the formula
~ IV
5~}so2x
y
wherein,
Z is ~, CI-C~O alkyl, halo, CI-ClO alkoxy, trifluoromethyl,
hydroxy, C,-CIO alkanoyloxy, or CI-ClO alkanoylamino;
Y is H, CI-C~o alkyl, halo, CI-ClO alkoxy, trifluoromethyl,
hydroxy, C,-C,O alkanoyloxy, or C,-CIO alkanoylamino;
X is F, Cl, Br or NR,R2 in which RI and R2 are independently
H, CI-Clo alkyl, C2-CIo alkenyl, C2-CIO alkynyl, C3-C~o
cycloalkyl, C6-CIO aryl or C,-CIO aralkyl;
and pharmaceutically acceptable salts tlIereof,
which are prepared by reacting a compound of the formula
~
. z f~l
COOH
C = O VIll
~J
wherein,
Y and Z are`as defined above; and
y2 is H or SO2X wherein X is as defined above;
with an hydroxylamine compound to effect nucleophllic addition
and subsequent ring closure;
and, in those compounds where Y2 is H, thereafter
reacting by substitution to introduce substituent SO2X in
lieu of H;
and optionally forming a pharmaceutically acceptable
salt of the product so formed.
The preferred compounds are those wherein Y is
halo or CF3 and X is NRlR2
as previously def ined.
1 Some of the said compounds are known and are
characterized by valuable therapeutic activit~. For example,
chlorthalidone, 3-hydroxy-3-(3'-sulfamyl-~-chlorophenyl)-
phthalimidine, is widely used as an anti-hypertensive and
5 diuretic, and Eor treatment of renal or cardiovascular
disorders. A substantial number of the said compounds ar~
also useful as therapeutic agents for the same purposes.
The compounds of formula I are prepared in accordance
with the present process by oxiaation of the corresponding
10 desoxy compounds represented by the formula:
,P
Z ~ ~R
~ II
~-S02X
Y
20 wherein X, Y, Z and R are each as previously described.
The total number of carbon atoms in each hydrocarbyl
substituent deseribed in Formulae I and II can range up to
about 10, and these substituents ean be branehed or straight-
ehained. The preferred compounds are those in which the
25 hydroearbyl radicals eontain up to about 7 earbon atoms when
aliphatic and up to about 10 carbon atoms when aromatie, e.g.
phenyl, tolyl and naphthyl.
The particularly preferred compounds of Formula I
are those prepared from compounds of the formula:
3o
$ III
~S02Xl -
Y
10 wherein,
R and Z are as hereinbefore described;
Yl is halo or CF3; and
Xl is Cl, Br or NRlR2 wherein each of Rl and R2 is
hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, aryl or aralkyl.
The desoxy compounds of Formula II, and Formula III,
are converted to corresponding compounds of Formula I by
oxygenation at the 3-position of the phthalimide ring. Such
oxidation can be accomplished by the usual methods employed
in benzylic oxidation, e.g., Helv. Chem. Acta, a2, 1085 ~19~9)
and Chem Ber., 103, 3783 (1970) wherein oxidation of 3-(4'-
chlorophenyl)phthalimidine to the corresponding 3-hydroxy
compound is described employing chromic acid-acetic acid as
the oxidizing agent.
The oxidation can also be accomplished by simple
contact with oxygen or an oxygen-containing gas with or
without catalyst present. The catalysts include ferrous
ammonium sulfate, cupric sulfate, cobalt naphthenate,
3o
--5--
1 cuprous chloride and zinc chloride, all of which ga~e
varying yields, in part predicated on varying time of
reaction. ~sually, reaction times can range from as little
as about 8 hours up to about 2~ hours and even longer.
5 Significant yields of product are obtained when the reaction
time ranges from about 15 to about 20 hours which is
preferred when a catalyst is employed. Without added
catalyst, the reaction times are considerably longer ranging
from about ~8 up to 72 hours for significant yields to be
10 obtained. When oxygen is employed as the oxidant, the
reaction is conveniently effected at room temperature as a
matter of convenience, since temperature does not play a
critical role in the reaction.
As an alternative to the foregoing oxidative methods,
15 there may be employed the usual oxidizing agents alone or in
combination to accomplish the desired oxygenation. For example,
oxidants such as permanganates, peroxides, chromates, hypochlo-
rites, such as t-butyl and sodium hypochlorite, manganese diox-
ide, periodates, ferric ammonium sulfate, bromine and the like
20 can be used. The time of reaction is usually within the range
of 0.5 hour to about 60 hours depending on the reagent selected
and the yield of product sought. For example with manganese
dioxide, as little as one hour is sufficient to obtain high
yields of the oxygenated product, whereas reaction times of
25up to 100 hours may be required with reagents such as ferric
ammonium sulfate-cupric sulfate in water at room temperature.
In most cases, aqueous reaction media are employed
and can be comprised of water alone or in mixtures with
water-miscible polar solvents such as dimethyformaide,
3 tetrahydrofuran, acetone, dioxane, and the like. In addition~
glacial acetic acid can be used as solvent, or in mixtures
with water as co-solvent. Conveniently, the deoxy
phthalimidine can react with alkali to form water-soluble
1 salts and, for more efficient oxidation, the substrate
compounds are usually dissolved in water, or the aqueous
solvent, by use of suitable alkali, such as sodium hydroxide,
potassium hydroxide, sodium carbonate and potassium carbonate.
5 The oxygenated products can be recovered from the aqueouC
reaction medi~ by merely acidifying and thereafter extracting
the mixture with suitable organic solvents from which the
product can be separated using known techniquesO
In the desoxy compounds used as starting materials
10 for the oxygenation, it is preferred to avoid the presence of
substituents (X, Y and Z) which would be reactive with oxidants
under the reaction conditions. Thus, reactive groups suc'n as
amino groups, where present, should be blocked as by acylation
and the blocking group removed after oxidation is completed.
15 Alternatively, the reactive group, such as amino, can be
formed after oxygenation, e.g by reducing nitro to amino,
and as necessary, con~rerting amino to other substituents.
The desoxy compounds of Formula II can be prepared
by conversion of the corresponding benzoxazinones of the
20 formula
Z ~ ~
¦ IV
[~-502X
3o wherein X, Y and Z are as hereinbefore definedO
1 The preferred compounds are those of formula IV
wherein Y is halo or CF3 and X is NRlR2 as previously
described.
The conversion of formula IV compounds to those of
5 formula III is accomplished by deoxygenation, i.e., removal
of the hetero oxygen atom from the oxazinone ring. This
reduction can be accomplished by art-recognized procedures
such as using zinc metal, conveniently zinc dust and acid.
The starting compound is dissolved in a suitable solvent
10 system, usually a polar solvent, preferably water-miscible,
as previously described. The water-Tniscible solvent is
convenient since it permits ready precipitation of th~ product
by dilution with water. The solvent, star~ing compound, acid
and zinc dust are hea~ed conveniently at the reflux temperature
15 of the solvent system for reaction periods of about one to
about four hours~ For efficient reaction, the zinc dust is
used in excess, usually about 10--20 fold molar excess, and the
dust is added portionwise to the refluxing reaction mixture.
After completion, the reaction mixture is diluted with cold
water after removal of the zinc dust and the product separates.
Compounds of Formula II can be preparea by substitu-
tion of compounds of the following formula:
~
Z + ¦ NR
~/ ~~ V
~Y
3o
wherein Y, Z and R are each as pre~iously described to
introduce substitutent S02X, e.g. by halosulfonation to
form the sulfonyl halide followed by reaction with basic
2~
1 nitrogen compounds to form the sulfamyl group, e.g. reaction
with ammonia to form the sulfonamide group.
Further, compounds of Formula I~ can be obtained
by reduction of compounds of the formula:
H
VI
~
~S02X
wherein X, Y and Z are as hereinbefore described, using
15 reduction processes known for this reaction, such as zinc
metal reduction. The starting compound dissolved in
organic solvent, preferably water-miscible as herein
previously described, and the 2inc metal is added along with
a mineral acid such as sulfuric or hydrochloric acids. The
20 reaction is usually carried out at elevated temperature
although room temperature will suffice. Convenientlyt the
reflux temperature of the reaction mixture can be used as
reaction temperature. The reaction proceeds quite rapidly
and is usually complete in relatively short periods of time.
25 Heating for about 1-2 hours is desirable to assure maximum
yields, particularly at temperatures between 50 and 100C.
- The product is obtained by pouring the reaction mix-
ture into water and thereafter filtering or extracting with suit-
able organic solvent, e.g. ethylacetate, to remove the product.
30 The organic solvent can then be removed to obtain the product
as residue.
9~
1 The compounds of formula II herein can also be
prepared from the corresponding phthalides of the following
formula:
~ VII
~--S02X2
y
wherein~
Z and Y are as previously described; and
X2 is fluoro, chloro or bromoO
The preferred compounds are those in which Y is halo
or trifluoromethyl. A useful class of the phthalide inter-
mediates are those in which Y is in the 4-position and S02X
20 is in the 3-position of the phenyl group to which they are
attached.
The aforesaid phthalide compounds can be converted
to the corresponding phthalimidines by treatment with ammonia
or an ammonium derivative by known procedures, e.g. as
25 described in U~S. Patent 3,055,904.
Intermediate compounds of the Formulae V and VI
are known and can be prepared by art-recognized procedures.
For example, compounds of Formula V can be prepared from the
corresponding phthalazinones or the corresponding benzoxa-
30 zinones, usually by treatment with zinc dust by the methodhereinbefore described. The phthalazinone compounds of
Formula VI can be prepared by substitution reactions of the
corresponding compounds wherein substituent Y is H, by
substitution methods hereinbefore described.
--10--
2~
1 Employlng the procedures described herein, a variety
of compounds of formulae II, III, IV, V and VI can be prepared
with various substituent as hereinafter illustrated:
R Z ~ X Y
~ . . . . ... _ .
CH3 H NH2 CF3
CH3 H NH2 CF3
CH3 H Cl C~3
C2H5 H C]. Cl
3 NH2 CF3
CH3 H NHCH3 OC4Hg
CH3 H NH2 Cl
C3H7 H N 6 5 CF3
C4~9 H N (CH3) 2 CF3
C6Hl3 H N 2 6 5 Cl
i-C4Hg OCH 3 NH2 CF3
H H NH2 OCH 3
6 5 2 N2 CEI 3 CH ~
C6Hll H Cl C 2C6 5
H H NH2 C(CH3) 3
C~H5 OC3H 7 NH2 C6H5
EI H Cl Cl
E~ Cl Cl Cl
H Cl Br Cl
H Cl NH Cl
H OCH3 NH~2 C5H
H H N~2 H
H H NH2 H
H H NH2 OH
H H Br Cl
3 CH30 Br Br
H H Cl CH3
H H Cl Cl
H H NH2 Cl
3 7 Cl Cl
~. 'Z X Y
H H NH2 Cl
H H NHC6Hll OH
H C~I3COO N(CH3)2 OOCCH3
H H NHC4Hg H
H ~ H NH2 Cl
H H Cl CF3
H H NH2 H
H OCH3 Cl H
H H NH2 OCH3
H H Cl OCH3
H OCH3 Cl - CF3
H H NH~ CF3
H OCH3 NH2 CF3
H H NH2 Cl
H . H NH~ Bx
H H NH~ NHCOCH3
Formula IV compounds include the following: -
R Z X Y Z'
.
CH3 H NH2 CF3 O
C 3 H NH2 CF3 O
CH~ H Cl CF3 NH
C2H5 H Cl Cl NCH3
C~3 H NH2 CF3 N 6 11
CH3 H NHCH3 OC4H9 N CH2C4H5
C~3 H NH2 Cl NC4H9
C3H7 H NHC6H5 CF3 O
C4Hg ~ H N~CH3)2 CF3 O
C6H13 H NHCH2C6H5 Cl o
i-C4Hg OCH3 ~IH2 CF3 NCH3
H H NH2 OCH3 6 13
6 5 2 No2 CH3 CH3
6 11 H Cl CH2~6H5
H H NH~ C(CH3)3
-12-
1 The desoxy compounds of Formulae II and III and the
benzoxazinones of Formula IV are new compounds and are useful
as intermediates in the present process. The said desoxy com-
pounds also possess therapeutic activity useful in the treatment
5 of renal or cardiovascular disorders, or as anti-allergic agents.
In therapeutic usage, the compounds themselves can ~e employed
or, as desired, salts thereof with alkali or alkaline earth
metals. The al~ali metal, e.g., Na, K and Li, salts in
particular are especially useful in view of their water
10 solubility especially in the formation of aqueous therapeutic
compositions. The alkaline earth metal, e.g., Ca, Mg, Ba,
Sr, are especially useful in the purification and/or isolation
of the desoxy compounds in view of their more limited water
solubility. The Ca and Mg salts are also useful in
15 therapeutic formulations where only limited water solubility
of the active ingredient is desired.
Of course, where basic suhstituents are present in
the desoxy compounds, such compounds can form salts with a
wide variety of acids, inorganic and organic, including
20 therapeutically-acceptable acids. The salts with thera-
peutically-acceptable acids are, of course, useful in the
preparation of formulations where water solubility is desired.
The salts with therapeutically-unacceptable acids are
particularly useful in the isolation and purification of the
25 present new compoundsO Therefore, all acid salts of the
present new basic compounds are contemplated by the present
invention.
The pharmaceutically-acceptable acid addition
salts are of particular value in therapy. These include
30 salts of mineral acids such as hydrochloric, phosphoric,
metaphosphoric, nitric, sulfuric acids, as well as
salts of organic acids such as tartaric, acetic, citric
-~3-
1 e.g., p-toluenesulfonic acids, and the like. The
pharmaceutically-unacceptable acid addition salts, while not
useful for therapy, are valuable for isolation and purification
of the new substances. Further, they are useful for the
5 preparation of pharmaceutically-acceptable salts. Of this
group, the more common salts include those form~d with hydro-
fluoric and perchloric acids. Hydrofluoride salts are
particularly useful for the preparation of the pharmaceutically-
acceptable salts, e.g., the hydrochlorides, by solution in
10 hydrochloric acid and crystallization of the hydrochloride
salt formed. The perchloric acid salts are useful for
purification and crystalli~ation of the new productsO
As therapeutic agents, the present new deoxy compounds
of Formulae II and III are useful as anti-hypertensive agents
15 and diuretic agents. The therapeutic agents of this invention
may be administered alone or in combination with pharmaceuti-
cally-acceptable carriers, the proportion of which is
determined by the solubility and chemical nature of the
compound, chosen route of administration and standard
20 pharmaceutical practice. For example, they may be administered
orally in the form of tablets or capsules containing such
excipients as starch, milk sugar, certain types of clay and so
forth. They may be administered orally in the form of
solutions which may contain coloring and flavoring agents or
25 they may be injected parenterally, that is, intramuscularly,
intravenously or subcutaneously. For parenteral administration,
they may be used in the form of a sterile solution containing
other solutes, for example, enough saline or glucose to make
the solution isotonic.
The physician will determine the dosage of the
present therapeutic agents which will be most suitable and it
will vary with the form of administration and the particular
-14-
~2~
1 compound chosen, and furthermore, it will vary with the
particular patient under treatment. He will generally wish to
initiate treatment with small dosages substantially less than
the optimum dose of the compound and increase the dosage by
5 small increments until the optimum effect under the circum-
tances is reached~ It will generally be found that when the
composition is administered orally, larger quantities of the
active agent will be required -to produce the same effect as a
smaller guanti-ty given parenterally. The compounds are useful
10 in the same manner as comparable therapeutic agents and the
dosage level is of the same order of magnitude cas is generally
employed with these other therapeutic agents. The therapeutic
dosage will generally be from 10 to 750 milligrams per day and
higher although it may be administered in several different
~5 dosage units. Tablets containing from 10 to 250 mg. of active
agent are particularly useful.
The following examples further illustrate the
invention,
3o
-15-
~9~2
1 EXP~LE 1
Preparation of 3-(3'-sulfamyl-4'-chlorophenyl)phthalimicline
from 3-(4'-chlorophenyl)phthalimidine
To a stirred suspension of 3-(4'-chlorophenyl)-
5 phthalimidine (5.00 g., 20.5 mmol) in dry (via 3A molecular
sieves) chloroform (25 ml.) is added dropwise chlorosulfonic
acid (6.0 equiv., 8.0 ml., 120 mmol) and the solution is
heated under reflux for 3 hours. Additional chlorosulEonic
acid (6.0 equiv., 8.0 ml., 120 mmol) is added and reflux
10 continued for 0.5 hours. The solution is then added dropwise
to crushed ice (400 ml.). Ammonia gas is bubbled into the
suspension until pH = 10.0 and reaction as evidenced by
solution occurs. The entire reactio~ mixture is concentrated
in vacuo to remove the chloroform and the resulting aqueous
15 solution is adjusted to pH ~7.0 with glacial acetic acid to
yield a precipltate. The precipitate is collected hy vacuum '
filtration and dried under vacuum to yield the crude product:
4.68 g. This crude product is recrystallized from aqueous
dimethyl formamide to yield a first crop of product having a
20 melting point of 249-250C. and weighing 2.61 g. Anal.
calculated for Cl~HllN2O3SCl: C, 52.26; H, 3.13; N, S.71.
Found~ C, 52.24; H, 3.3S; N, 8.45.
.
3o
1 EXAMPLE 2
Preparation of 3-hydroxy-3-~3'-sulfamyl-4'-chlorophenyl)-
phthalimidine from 3-(3'-sulfam 1-4'-chlorophenyl)Phthalimidine
Y
Method A
To a stirred solution of 3-(3'-sulfamyl-4'-chloro-
phenyl)phthalimidine (1.00 g., 3.09 mmol) in glacial acetic
acid (25 ml.) is added 8~0 ml. of a 1 M solution of chromic
acid in aqueous a~etic acid (16.56 mmol of chromic acid),
made by dissolving,21.0 g. (0 D 2,1 mol) of chromic anhydride in
lO 190 ml. of glacial acetic acid followed by the addition of
10 r 0 ml (0.5S mo,l) of water, via an addition funnel over a
four hour period. After o,ne hour additional reaction time the
p^oduct is isolated by dilution of the reaction mixture with
water and extraction into ethyl acetate. The ethyl acetate
layer is dried over calcium chloride, filtered and the
filtrate concentrated in vacuo to yield 900 mg. of the crude
product. Recrystalli~ation from ethyl ace~ate/toluene ga~-e
~h~ product ha~Jillg a melt,jng point of 230~240Co and weighin~
600 mg.
~o Method B
3-(3'-sulfamyl-~.'-chlorophenyl~phthalimidine is
suspended in distilled water (500 mg., 1.55 mmol in 20 mlO)
and with stirring 50% aqueous sodium hydroxide is added
dropwise until solution is complete (requires 1 ml.). Air is
~5 pdssed through a pre-saturation cham~er of wa!er and then
dixectly into the reaction mixture for a period of 65 hours.
The solution is acidified to pH = 3.0 with concentrated hydro-
chloric acid, diluted with water (100 mlO) and the product
isolated by partitioning with ethyl ace~ate (~00 ml.). ;rhe
~0
1 ethyl acetate extract is drled over sodium sulfate, filtered
to remove the drying agent and the filtrate concentrated in
vacuo to yield 590 mg. o~ crude product. The crude product
is dissolved in ethyl acetate, diluted with an equal volume
5 of toluene and the solution concentrated in vacuo at room
temperature to remove the ethyl acetate. The resulting toluene
insoluble precipitate is collected by vacuum filtration to
yeild 230 mgO of product having a melting point greater than
240 C
10 Method C
In a 25 ml round bottom reacti-on vessel is pl,aced
50 mgO deoxycompound (0.155 mmol); then ~ ml~ o~ 1 normal
sodium hydroxide solution is added; the reactants are soluble
at room temperature. Then 1 ml. of 30~ hydrogen peroxide
5 solution is addedO After 24 hours the reaction is worked up
by adding 15 ml. of 2 molar citric acid and transferred to a
separatory f~mnel where the reactioll mi~ture is extracted
with ethyl acetate. The ethyl acetate is cross washed with
water, sodium bicarbonate solution, and brineO The ethyl
20 acetate is separated, dried with magnesium sulfate, clarified
and evaporated. An infrared spect,rum of the product along
with an NMR spectrum and TLC indicated the formation of
3-hydroxy-3 (3'-sulfam~ '-chlorophenyl)-phthalimidine.
Method ~
In a 25 ml round bottom reaction vessel is placed
deoxycompound 50 mg (0.155 mmol) and 2 ml of l'normal sodium
hydroxide solution~ The reactants are soluble in
this medium. At room temperature add,,~ ml of O o l normal
30 potassium permanganate solution~ As permanganate is added
the blue color of the reagent discharges and a brown precipi
tate forms. The last ml of reagent resulted in a permanent
pT~rple tint to the reaction mixture, Thin layer'chromatoqraphy
-18-
of the reaction mixture at -this time revealed rapid conversion
of the deoxycompound to 3-hydroxy-3-(3'-sulfamyl-4'-chlorophenyl)-
phthalimidine. The reaction mixture was allowed to stir
overnight~ Workup consisted of acidification of the reaction
mixture with 2N HCl and addition of aqueous sodiurn bisulfite
10 ml. The reaction mixture was extracted with ethyl acetate,
cross washed with water and sodium bicarbonate solution and
finally brine. The ethyl acetate was separated, dried with
magnes:ium sulfate, clarified and evaporated to dryness, to
obtain the product.
Additional Methods
These processes were carried out in a manner as described
in Method B except for variations in solvents and temperatures
and the presence of inorganic catalysts as noted in Table
I.
--19--
r-l ~ ~C~~r or~
r~ ~ # O1~
o~o
o~
~1 a).,.
u-,l ,~ ~r ~r ~ ~D~ CO Ct~
~ E~ ~Ln
~ x x
~ ~-l
E~ ~ ~ ~`
a) a
h
O O ~:
o h h ~~:: O ~ o
o o ~ o æ z ~
~o a a æ Z Z Z z
U~ . . .
~
~ o~ d~
0~O 0~O O~o u~ In o~o
O O 0~00~o 0 0\o . . ,~,
,~ ~r ~r ~ u~ ~ ~ ~ ~ ~
W
n
.
. ~ O
~ ~ ~ O
.,, O
.
~ _, a,
_
o ~ o
.~ O O O
U~ ~ ~ ~ ~ ,~ -- . .
~ ~ O O ~ ~ ~ ,~
~ ~ o ~ Z ~1 o ~
o ~
o
1 al O h O C) t~
ra
a~ -
U~ O
s~ ~
~ O
-,1
~0 ~ ~ O
~J ~ ~ I', H 1~ ~ ~ ~I M
~1
--20--
. ~
1 In all cases of Methods E-M, the appropriate
3~hydroxy-3-aryl-phthalimidine was identified by TLC
techniques against known standards. The TLC technique used
was one based on a solvent system composed of 1,2-dichloro-
5 ethane/ethanol/ammonium hydroxide (28%~ (80/20/5).
3o
EX~PLE 3
Preparation of 4-(3'-sulfamyl-4'~chlorophenyl)phthalazin-1-
one from 4-(4'-chlorophenyl)phthalazin-1-one
4-(4'-Ch]orophenyl)phthalazin~l-one (3.99 g., 15.54
mmol) is added to chlorosulfonic acid (10.0 ml., 150.45
mmol, 9.7 equiv.) and the solution stirred for 24 hours at
room temperature. The reaction is heated at 120C. for 18
hours to give complete conversion of starting material
to product. The reaction mixture is cooled to room temperature
and added dropwise to an ice cold stirred solution of concentrated
ammonium hydroxide (100 ml.)~ The suspension is stirred for
0.5 hour and made strongly alkaline with 50~ aqueous sodium
hydroxide. Insoluble material (320 mg.) is removed by
vacuum filtration, the filtrate adjusted to pH = 2.0 with
concentrated hydrochloric acid and the precipitate is collected
by vacuum filtration. The product weighs 3.40 g. after
drying under vacuum (20 mm.Hg/60~C.) for 16 hours. The
product was identified against a known standard by TLC using
two different solvent systems: ethyl acetate/glacial acetic
acid (99/1) and methanol/toluene (40/60).
-22-
1 EXAMPLE 4
_
Preparation of 3-(3'-sulfamyl-4'-chlorophenyl)phthalimidine
4-(3'-Sulfamyl-4'-chlorophenyl)phthalazin-l-one
5 (3.36 g., 10.07 mmol) is added to 2D0 ml. of a solution of
dry dimethyl formamide / glacial acetic acid (l:l v/v) and
the resulting suspensi.on heated at 95 to 100C. Zinc dust
(5000 g., 76.49 mmol) .is added portionwise over a twenty
minute interval. After ~.5 hours the solution is filtered
lO through Celite in order to remove the excess zinc and the
filtrate ~oncentrated in acuo to ca, 50 ml. and diluted with
waterO ~he product crystal].izes from solution after
standing overnight at 5Co 1O05 gr.ams of product are
recovered having the same retention time as a k~own standard
15 of 4-(3'-sulfamyl-4'-chlorophenyl)phthalimidine (using an
ethyl acetate solvent system)0
* Trade Mark
3o
3~
-23-
1 EX~MPLE 5
Preparation of 3-(3'-chlorosulfonyl-4'-chlorophenyl)-
phthalimidine :Erom 3-(4'-chlorophenyl)phthalimidine
3-(4'-Chlorophenyl)phthalimidine (2.4 g., 10 mmol)
5 is added to 13.2 ml. of chlorosulfon;.c acid (200 mmol) and
stirred for 0~5 hour at ambient te~ erature followed by
0.5 hour at 90~ C. The product was isolated by pouring the
cooled reaction mixtu.re over a mi.xture of 200 ml. water and
200 g~ ice, washing with 400 ml. of methylene chloride,
lO drying the methylene chloride with magensium sulfate and
evaporating off the solvent unde.r vacuumO The residue was
taken up in carbon tetrachloxide from which crystallized,
the product, 3-(3'-chlorosulfonyl-4'-chlorophenyl)--
phthalimidine.
3o
--24-
EXA~PLE 6
Preparation of 4-(3'-ch:Lorosulfonyl-4'-chlorophenyl)-
phthalazin~1-one from 4-(4'-chlorophenyl)phthalazin-1-one
4-(4'-chlorophenyl)phthalazin-1-one (2.00 g., 7.79
mmol) was added to chlorosulfonic acid 10.0 ml., 17.53 g.,
150.45 mmol) and the solution was heated at 140C. for 3.5
hours. The solution was then cooled to room temperature and
quenched by pouring onto crushed ice (100 g.)O The precipitated
product was collected by suction filtration and dried under
vaeuum at 45C. for 18 hours. The dried product weighed
2.70 g. (98~ yield) and melted at 187-195C. Mass spectral
analysis confirmed the product as 4-(3l-chlorosulfonyl-4'-
chlorophenyl)phthalazin-l-one (M+ at 354, M+ + 2 at 356
chlorine isotope peak). IR and NMR analyses were also
consistent with the product.
~L~
EXAMPLE 7
Preparation of 3-(3'-sulfamyl-4'-chlorophenyl)-3H-phthalide
o-(3'-sulfamyl-4'-chlorobenzoyl) benzoic acid (6.5 g,
19.17 mmol) is added to a solution of methyl amine (20.0 ml,
300 mmol~ in acetonitrile (150 ml). After 15 minutes of
stirring the resulting solution, methyl amine hydrochloride
(3.4 g, 50.3 mmol) and sodium borohydride (1.14 g, 30.11
mmol) are added. The mixture is stirred for 5 hours at room
temperature.
The solvent is removed in vacuo and the resulting solid
is partitioned between ethyl acetate and dilute aqueous
hydrochloric acid. The organic extract is washed with water
until neutral, then brine.
The organic extract is concentrated to dryness to
yield the crude product, 6.13 g. An analytical sample is
obtained by recrystallization from aqueous glacial acetic
acid; m.p. = 232-234. The product is characterized by
micro-analysis and spectral data.
-26-
EXAMPLE 8
Preparation of 3-(4'-chlorophenyl)-3H-phthallde
o-(~'-chlorobenzoyl) benzoic acid (25.0 g, 95.9 rnmol)
is aclded -to a solution of methyl amine (20.0 ml, 800 mmol)
in acetonitrile (250 rnl). After 15 minutes of stirring the
resulting solution, methyl amine hydrochloride (17.0 g. 150
mmol) and sodium borohydride (1.14 gms, 30.11 mmol) are
added. The mixture is stirred for 63 hours at room temperature.
The solvent is removed in vacuo and the resul-ting solid is
partitioned between ethyl acetate and dilute aqueous hydrochloric
acid. The organic extract is washed with 10% aqueous sodium
hydroxide, then brine.
The organic extract is concentrated to about 1/3 volume
in vacuo, heated to reflux and diluted with hexane to induce
crystallization. A 1st crop of crystals weighs 7.1 g. An
analytical sample is obtained by recrystallization from
aqueous glacial acetic acid, m.p. = 124-125. The product
is characterized by microanalysis and spectral data.
This product is converted to the corresponding 3'-
sulfamyl compound by chlorosulfonation and ammonolysis as inthe preceding examples.
-27-
1 EXA~PL~ 9
The starting compound of Method B of Example 2 is
prepared by the following method:
A stirred solution of 4-(3'-sulfamyl-4'chlorophenyl)-
5,6-benz-2,3-oxazine-1-one (10.0 g, 29.7 mmol) in a 1:1 mix-
ture (v/v) of dimethyl formamide/glacial acetic acid (250ml/
250/ml) at 85-90 is treated with zinc dust ~15~0 g, 0023 mol)
portionwise over a 25 minute interval. After two hours
lQ of heating the solution is vacuum filtered through a celite
filter pad to remove excess zinc. The filter pad is not
allowed to go to dryness until it is xinsed with a small
volume of water. The filtrate is added to 500 ml of ice
water, and the precipitate collected by vacuum filtration,
15 and recrystallized from aqueous methanol to yield a first
crop; 5.5 g, m.pO = 261.5-262.5 + 0~3O
.,
28-
EXAMPLE 10
The starting compound for Example 9 is prepared by the
following method:
o-(3l-Sulamyl-4'-chlorobenzoyl)-benzoic acid (25.0 y,
73.7 mmol) and hydroxylamine hydrochloride (20.0 g, 287.6
mmol) are dissolved in a 1:1 solution (v/v) of pyridine (100
ml) and absolute ethanol (100 ml) and the solution is heated
for 6 hours. The reaction mixture is poured into ice water
(400 ml), the precipitate collected by vacuum filtra-tion and
dried under vacuum to give the crude product; 22.33 g, m.p.
= 275-280. Recrystallization of the crude product from
a~ueous dimethyl formamide gives a first crop of pure
product, 10.13 g, m.p. = 277-278.
-29-
EXP~LE 11
The starting compound for Example 1 is prepared by
the following methods:
Method A
To a stirred solution of formic acid (167 ml, 4.43
mol) and formamide (100 ml, 2.50 mol) is added 0-(4'-chloro-
benzoyl)~benzoic acid (50.00 g, 0.19 mol) and the solution is
heated immediately to reflux. The solution is stirred at
relux for 24 hours, during which time crystals precipitate
10 from the solution. The solution is cooled to room temperature
and placed into an ice bath for one hourO The produ~t is
collected by ~acuum filtration and washed with water until
neutral to litmus paper. The crude product is drie~ under
vacuum to yield 48.73 g of material. The crude product is
15 recrystallized from a solution of dimethyl formamide/toluene
(125 ml/400 ml) to yield a first crop of the product: 21~4-l g,
m.pO = 199O1~205~4o -A second crop is reco~ered from t~e
mother liquo~ .0~ ~O
Method s
4-(4'-chlorophenyl)-5,6-benz 2,3-oxazine-1-one (57.0 g,
0.22 mol) is dissolved in glacial acetic acid (500 ml) at
100-105 and zinc dust (31012 g, 0.48 mol) is added portionwis~
over a 40 minute intervalO The solution is heated and stirred
for 1 hourO An additional portion of zine (5~0 g, 0.076 mol)
25 is added and heating and stirring continued at 110 for 30 min-
utes. The reaetion is completed by addition of excess zinc
(11.3 g, 0 17 mmol) with heating continued for 1 hourn The
hot solution is filtered through a celite filter pad to remove
excess zincO The filtrate is diluted with water until turbid
30 (250 ml of water is required)n The crystalli2ed product is
then collected by vacuum filtration to give a first crop;
73.04 g, m.p. = 199.7-203.2, A second crop of product is
recovered from the mother liquor; 9.66 gO --
-
-3~-
EXAMPLE 12
The starting compound of Example 9 can also be prepared
as follows:
o-(4'-Chlorobenzoyl) benzoic acid ~30.0 g, 11.5 ~ol)
and hydroxylamine hydrochloride (30.0 g, 43.1 mml) are
dissolved in a solution of pyridine (125 ml) and absolute
ethanol (100 ml). The solution is heated under reflux for
5~ hours. The reaction mixture is then poured over 2 liters
of crushed ice and the precipitate collec-ted by vacuum
filtration. The mother liquor is cooled to yield additional
precipitate which is combined with the first precipitate.
The total combined crude precipitate after drying under
vacuum weighs 28.2 gO The crude precipitate is recrystallized
from a solution of e-thyl acetate/dimethyl formamide/heptane
to yield a first crop of the product; 21.9 g, m.p. = 185-
186. A second crop of discolored product is obtained from
the mother liquor, 6.0 g. Then, the product is chlorosulfonated
and treated with ammonia to introduce the requisite 3'-
sulfamyl group.
-31-
