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Патент USA US3067219

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United States Patent O?tice
I 3,067,209
Patented Dec. 4, 1962
2
1
tected hyydroxyl- and/or protected carboxyl substituents
3,067,209
I
.
with a compound having the formula
‘
9-(0MEGA-AMINOALKYL)-XANTHENOLS AND 9
(OMEGA-AMINOALKYLIDENE)-XANTHENES
Karl Doebel, Gerald Rey-Bellet, Reinhard Schliipfer and
Hans Spiegelberg, all of Basel, Switzerland, assignors to
wherein A represents a metal-organic group containing
more than two carbon atoms and B represents a mono;
Hotfmann-La Roche Inc., Nutley, N .J ., a corporation of
New Jersey
valent tertiary amine radical, hydrolyzing the metallo
I
condensation'product obtained, splitting be any protect
No Drawing. Filed June 6, 1957, Ser. No. 663,881
ing group which maybe present and, if desired, subjecting
Claims priority, application Switzerland June 12, 1956
11 Claims. (Cl. 260-335)
10 the 9-substituted xanthene-9-ol or thioxanthene-9-ol thus
obtained to dehydration. By “protectedr amino sub
This invention relates to novel-chemical compounds and
stituent”
ismeant e.g. the reaction product of the amino
to novel intermediates and novel processes useful in pro
vgroup with one mole of Grignard reactant. For vthe
ducing the same. More particularly, it relates to com
purpose of protecting the hydroxyl substituent', this group
pounds which can be broadly characterized as being
may be transformed e.g. into a tetrahydropyranyl-ether
15
derived from xanthene or thioxanthene and which carry
group. The keto group of-theacyl substituent may be
a basically substituted side chain attached to the 9-posi
protected e.g. by ketalisation with glycol.
tion thereof; and to intermediates and processes for mak
The preparation of the heterocyclic starting materials
ing said substituted xanthenes and thioxanthenes.
required for the practice'of the invention can be effected
In the following disclosure, the numbering system used
according to procedures known per se. Thus, the thio
for xanthene derivatives is that indicated under System 20
xanthones can be prepared, for example, by condensation
No. 2000 in “The Ring Index” by Patterson and Capell
of thiosalicylic acid or appropriately substituted thio
(New York, 1940), i.e.
salicylic acids with benzene 0r appropriately substituted
benzenes. Alternatively, the thioxanthones can be pre
25 pared by condensation of diazo-anthranilic acid crepe
propriately substituted anthranilic acids with thiophenol
or appropriately substituted thiophenols and subsequent
cyclisation. The preparation of some new compounds
of this class is more elaborately described in the ex
For the sake of uniformity, the numbering system used 30
herein for derivatives of thioxanthene is the alternate
numbering system shown under “Ring Index” System No.
2019, i.e.
amples. The xanthones can be similarly preparedhfor
example, by condensation of orthochlorobenzoic acid or
appropriately substituted orthochlorobenzoic acids with
alkali metal phenolates or appropriately substituted alkali
metal phenolates. The preparation of the non-aromatic
35 metal-organic compounds containing one or more basic
substituents can likewise be prepared by methods known
per se. In a preferred mode of execution, magnesium
compounds of dialkylaminoalkyl halides are employed as
the basically substituted non-aromatic metal organic com
From a broad product point of view, the invention 40 pounds, and these can be prepared, for‘ example, by direct
provides novel compounds selected from the group con
reaction of magnesium with an‘ ethereal solution of a
sisting of: bases constituted by 9-Xanthenols and 9-thio
dialkylaminoalkyl halide. _, In such case, an especially
Xanthenols each of which carries a basically substituted
active form of metal is employed, e.g. _a ?nely divided
non-aromatic radical in the 9-position, and their respec
‘ copper-‘magnesium alloy such as that of Gilman (Reeueil
tive nuclear all<yl-, aralkyl-, aryl-, alkoXy-, aralkyloxy-,
aryloxy-, alkylthio-, aralkylthio-, arylthio-, halo-, acyl-,
amino-, hydroxyl- and carboxyl-substitution products;
bases constituted by dehydration products of the fore{
going and stereoisomeric forms thereof; and acid addition
45
des Travaux Chimiques des Pays-Bas, 47 [1928], 19),
and the reaction is initiated by addition of a‘ suitable alkyl
halide, e.g. methyl iodide, ethyl bromide and the like.
In the ?rst stage,_reierred toyabove, of a process accord
' ing to the invention, magnesium-,_ lithium- and zinc or
salts and quaternary salts of all of the foregoing bases. 50 ganometal compounds can be employed. In a preferred
The basically substituted non-aromatic radical is preferi
procedure, the xanthonesror thioxanthones are employed
ably a lower alkyl radical substituted by a tertiary amino
either in solid, ?nely divided foi‘rn,,or in solution in an
group, e.g. a di-(lower alkyl)amino(lower alkyl) radical.
inert organic solvent such as absolute ether, benzene,
The N,N-lower alkyl radicals can be joined in a ?ve- or
six-membered ring, if desired with an additional oxygen
or sulfur atom, e.g. as in the radicals w-(N-piperidino)
propyl, w-(N-morpholino)-propyl, w-(N-thiarnorpholin'o)
pentyl and the like.
The process provided by the present invention corn
tetrahydrofuran andthe like. To this heterocyclic re;
actant' is added a solution in an inert organic solvent of
the magnesium compound of a dialkylarnin-oalkyl halide.
When the reaction is completed, the metal-containing con
densation product is hydrolyzed. It is especially advan
tageous to e?fect the‘ decomposition of the metal-con}
prises condensing a compound selected from the group 60 taining condensation product in neutral or slightly alka
line medium, e.g. by hydrolysis in aqueous ammonium
consisting of Xanthones and thioxanthones each of which
chloride solution. In this manner, the basicallyv sub
may carry one or more nuclear alkyl-, aralkyl-, aryl-,
alkoxy-, ar'alkyloxy-, aryloXy-,' alkylthio-, aralkylthid;
arylthio-, halo-, protected acy1-, protected amino-, pro
stituted' ithioxanthene or -xa’nthene' compounds are ob
tained in the form of the free base, and can be separated
3,067,209
0
o:
-
from the byproducts of the reaction and isolated by treat
ment with suitable organic water immiscible solvents, e.g.
4
(
FLOW SHEET
I)
ether, ethyl acetate, chloroform, methylene chloride and
?
the like.
The second stage of the general process, referred to
above, comprises splitting out water from the 9-basically
substituted-9-Xanthenol or -9-thioxanthenol by treatment
with reagents ordinarily employed for such purposes, e.g.
Z
X-(CHa) n-B
/
sulfuric acid, iodine in benzene, potassium bisulfate, zinc
chloride and the like. In the case of the 9-basically sub
stituted-9-thioxanthenols, this dehydration step is prefer
ably effected by treatment with phosphorus oxychloride,
preferably by heating at the re?ux temperature. In the
t/ condense
(in presence of condensing metal)
10
(IIIa)
(II)
MO
case of the 9-basically substituted -9-xanthenols, the de
hydration is preferably effected by treatment with a hy 15
drogen halide, preferably in solution in an inert organic
solvent and at room temperature.
l (hydrolyze)
When applied to asymmetrically substituted starting
materials, the process of the present invention leads to
stereoisomeric mixtures of 9-xanthenes and 9-thi0xanth 20 (III)
enes. The particular isomers may be isolated by known
HO
\
(CH)1.—B
2
processes, i.e. by fractional crystallization.
In one of its comprehensive aspects, the invention
provides a process which comprises condensing a com
pound having the formula
P
Q
Z
25
l (dehydrate)
(I)
(IV)
CH—(CH2)m-B
H
30
Z
P
wherein Z represents a divalent chalkogen selected from
the group consisting of oxygen and sulfur, P represents
a monovalent radical selected from the group consisting 35
of hydrogen, halogen, lower alkyl and lower alkoxy and
Q
\z
Preferred novel compounds of the invention are those
selected from the group consistingn of: bases constituted
Q represents a monovalent radical selected from the
by 9-w-di(lower alkyl)amino-propylidene-thioxanathene,
group consisting of hydrogen, halogen, lower alkyl and
9-w-di(lower alkyl)-amino-propylidene-xanthene, 9-w-di
(lower alkyl)aminopropyl-thioxanthen-9~01, 9-w-di(lower
alkyl)amino-propyl-xanthen-9-ol, and their respective
nuclear (especially in 2-position) halo-, lower alkyl- and
lower alkoxy attached to anyone of carbon atoms 1-8,
by means of a metal-organic reaction with a basically 40
substituted lower alkyl halide having the formula
lower alkoxy-substitution products; acid addition salts of
said bases with pharmacologically acceptable acids; and
quaternary salts of said bases with pharmacologically
wherein X represents a halogen, n represents an integer
from 3 to 7, inclusive, and B represents a monovalent
acceptable quaternizing agents.
Exemplary of pharma~
tertiary amino radical, and hydrolyzing the metallo con 45 cologically acceptable acids that are suitable for the
densation product obtained, thereby producing an inter—
practice of the invention are common mineral acids such
mediate compound having the formula
(III)
HO\ (cunt-B
.UQ
as hydrochloric acid, hydrobromic acid, phosphoric acid,
sulfuric acid and the like, and common organic acids
such
as acetic acid, tartaric acid, maleic acid, citric acid,
50
ethanesulfonic acid and the like. Exemplary of phar
macologically acceptable quaternizing agents that are
suitable for the practice of the invention are common
quaternizing agents such as methyl bromide, ethyl bro
mide, ethyl iodide, dimethyl sulfate, ethyl paratoluene
wherein each of the symbols Z, P, Q, B and n has the 55 sulfonate
and the like.
[same meaning set forth above; and, if desired, dehy
The novel products of the invention (as exempli?ed,
drating said intermediate compound thereby producing
for instance, by the products of Formula III and of For
a compound having the formula
mula IV shown above) exhibit manifold pharmacologic
(IV)
CH- (CH2) m—B
activity, especially upon the nervous system. These com
60
ll
- pounds are accordingly useful as medicinals, and particu
larly they are useful as adrenolytic, sedative, antihista
Q
minic, antipyretic, hypothermic and narcotic-potentiating
agents.
The invention is further disclosed in the following ex
wherein each of the symbols Z, P, Q and B has the same 65 amples, which are illustrative but not limitative there
of. Temperatures are stated in degrees centigrade, un
meaning set forth above, and m is a number equal to n
corrected.
minus one, i.e. a Whole number from 2 to 6, inclusive.
Example 1
This comprehensive process of the invention can be il
lustrated by the following flow sheet, wherein each of 70
In a 1-liter, 3-neck ?ask ?tted with stirrer, dropping
the symbols Z, P, Q, B, n and m has the meaning set
funnel and condenser were placed 2.5 g. of activated ?nely
forth above, and the symbol M represents a monovalent
divided copper-magnesium alloy (Gilmann, op. cit. supra).
metallo radical useful in facilitating metal-organic con
This was covered with 10 cc. of dry ether and 0.5 cc.
densations, e.g. a lithium or magnesium halide or zinc
of methyl iodide were added. As soon as the vigorous
salide rest.
75 reaction subsided somewhat, 7.5 g. of magnesium shav
2
3,067,209
5
6
crystallized from ethanol-ether.
ings were added in a single portion, and a solution of 40
The 2-chloro-9'-(w-di
methylaminop'ropylidene)-xanthene hydrochloride thus
g. of freshly distilled o-dimethyl-aminopropyl chloride
obtained formed colorless, water-soluble crystals; M.P.
in 180 cc. of dry ether was dropped in during a period
of one hour. The reaction mixture was then boiled for
?ve hours at 40° under a re?ux condenser, and then was
stirred overnight at room temperature. On the follow
ing day, a suspension of 20 g. of ?nely pulverized xan
thone in 400 cc. of dry ether was added portionwise
while continuing the stirring. The whole mixture was
then stirred for an additional period of 20 hours at
120225". Thereupon the reaction mixture was cooled
with ice water and mixed with a cold saturated ammo
nium chloride solution. The organic layer was sepa
rated, the aqueous layer was extracted twice, each time
with 100 cc. of ether, and the combined ethereal por
tions were dried over sodium sulfate and evaporated.
196°'-197°. The free base is an oil.
Example 3
In a 2-liter, round-bottom ?ask ?tted with stirrer, drop
ping funnel and condenser, 5 g. of activated ?nely divided
Gilman copper-magnesium alloy were covered with, 20
cc. of dry ‘ether and 1.0 cc. of methyl iodide was added.
As soon as the vigorous reaction subsided somewhat, 15 g.
of magnesium shavings were added in a single portion,
and a solution of 70 g. of freshly distilled w-(N-pi'pe'ri
dino)-pr0pyl chloride in 360 cc. of dry ether was dropped
in during a period of one hour. The reaction vmixture
was then boiled for six hours at 40° under ar'e?ux con
denser and then was stirred overnight at room tempera
ture. On the following day a suspension of 40 g; "of ?nely
pulverized xanthone in 800 cc. of dry ether was added
The residue, upon recrystallization from high boiling pe~
troleum ether, yielded colorless crystals of 9-(w-dimethyl
aminopropyl)-xanthen-9-ol; M.P. l09°-ll0°.
25 g. of 9-(w-dimethylaminopropyl)ixanth'en-9-ol, were 20 portionwise, while stirring. The whole mixture was stirred
for an additional 20 hours at 20°. Then, the reaction
mixture was cooled with ice water and mixed with a cold
dissolved in 250 cc. of absolute ethanol, and the solu
tion was mixed with 25 cc. of ethanolic hydrogen chlo
saturated ammonium chloride solution. , The organic
ride solution (30% HCl by weight). The reaction mix
ture was allowed to stand for three hours at room tem
perature, then the alcohol was removed under diminished 25
pressure at 30°—40°, and the residue was recrystalilzed
from ethanol-ether. The product thus obtained, 9-(w
dimethylamino - propylidene) - xanthene hydrochloride,
30
9~(w-dimethylarninopropylidene)~xanthene which sepa
rated was extracted with methylene chloride, the methyl
ished pressure at 30°—40°, and the residue was recrystal
lized from ethanol~ether. The 9-[w-(N-piperidino)-pror
pylidene]-xanthene hydrochloride thus obtained formed
colorless, water soluble crystals; M.P. 210°'—211° (with
ene chloride solution was dried over sodium sulfate and
evaporated. The residue was dissolved in 40 cc. of dry
of 9-(w-dimethylaminopropylidene)-xanthene precipitated
_ _
chloride solution (30% HQ by weight). The reaction
mixture was allowed to stand for three hoursat roorri
temperature, then the alcohol was removed under dimin
The oily
acetone and the solution was saturated with methyl bro
mide at room temperature. Thereby, the bromomethylate
,
25 g. of 9-[w-(N-piperidino)-propyl]-xarithen-9-o1, were
dissolved in 250cc. of absolute ethanol. The solution
obtained was mixed with 25 cc. of ethanolic hydrogen
6.0 g. of 9-(w-dimethylaminopropylidene)-xanthene hy
drochloride were dissolved in 50 cc. of Water and treated
with an excess of sodium hydroxide solution.
The residue, upon recrystallization from ethyl acetate,
yielded colorless crystals of 9-[w-(N-piperidino)-propyl]
xanthen~9-ol; M.P. l44°—~145°.
formed colorless, water-soluble ‘crystals; M.P. 201°-202°.
The free base is an oil.
layer was separated, the aqueous layer was extracted twice
with 200 cc. portions of ether, and the combined ethereal
layers were dried over sodium sulfate and evaporated,
40 decomposition).
immediately and, upon recrystallization from alcohol
ether, melted at 215-216“.
Example 2
In a 1-liter, round bottom ?ask ?tted with stirrer, drop
ping funnel and condenser, 2.5 g. of activated ?nely
divided Gilman copper-magnesium alloy were covered
with 20 cc. of dry ether and 0.5 cc. of methyl iodide was
The free base is an oil.
Example 4
2.0 g. of activated ?nely divided Gilman copper-mag
nesium alloy and 1.6 g. of unactivated copper-magnesium
alloy were placed in a 250 cc., 3-neck ?ask, which was
equipped with stirrer, condenser and dropping funnel,
and were covered with 20 cc. of absolute ether and a
trace of iodine. Then, _10—12 drops of ethyl bromide
were added. After vigorous reaction had developed, a‘
added. As soon as the vigorous reaction subsided some
solution of 16 g. of w~dimethylaminopropyl chloride in
what, there was added 7.5 g. of magnesium shavings in a
30 cc. of absolute ether was slowly dropped in during
single portion, and a solution of 40 g. of freshly distilled
which
time the stirrer was operated only occasionally. As
w~dimethylaminopropyl chloride in 180 cc. of dry ether
soon as the reaction subsided, the reaction vessel was
was dropped in during a period of 1 hour. The reaction
dipped into a heating bath having a temperature of 50°,
mixture was boiled for ?ve hours at 40° under a re?ux
the stirrer was started and stirring was continued for
condenser and then stirred overnight at room tempera 55
four
of thioxanthone
hours in order
in tosolid
complete
form the
were
reaction.
added Then,
portionwise
6.0
ture. On the following day a suspension of 23.5 g. of
?nely pulverized 2-chloro-xanthone in 400 cc. of dry'
and
the
reaction
mixture
was
stirred
at
50°
until
the
yelé
ether was added portionwise while stirring. The whole
low
color
of
the
thioxanthone
disappeared
and
the
re
mixture was then stirred for an additional 20 hours at
action mixture took on a grayish-white color. The mixture
20-25“. The reaction mixture was cooled with ice water 60 was cooled ‘down to room temperature and was poured
and was mixed with a cold saturated ammonium chloride
into a well cooled solution of 20" g. of ammonium chloride
solution. The organic layer was separated, the aqueous
in 300 cc. of water. 200 cc. of ethyl acetate were added
layer was extracted twice with 100 cc. portions of ether,
andv the mixture was stirred well. The mixture was freed
andv the combined ethereal layers were dried over sodium
by ?ltration of a little undissolved sludge, the organic
sulfate and’ evaporated. The residue, upon recrystalliza
layer was separated in a separatory funnel, dried with
tion from ethyl acetate-petroleumv ether, yielded colorless
sodium sulfate and freed of solvent in vacuo. The residue
crystals of 2-chloro-9-(w-dirnethylaminopropyl)~xanthen
9-01; M.P. l29°-130°.
20 g. of 2-chloro-9-(w-dimethylaminopropyl')'-xanthenj
9-01 were dissolved in 200 cc. of absolute ethanol, and the 70
resulting solution was mixed’ with 20 cc. of ethanolic hy
drogen chloride solution (30% I-lCl by weight). The
reaction mixture was allowed to stand for two hours at
room temperature, then the alcohol was removed under
diminished pressure at 30°—40°, and the residue was re
was recrystallized from high boiling petroleum ether;
Thus, 7.2 g. of compact yellowish-white crystals of 9-(w
dimethylaminopropyl)-thioxanthen-9-o1, were obtained;
M.P. 147°-148°.
,
7.2 g. of 9-(w-dimethylaminopropyl)-thioxanthen-9-ol,
were covered with 40v cc. of phosphorus oxychloride'.
The reaction mixture was re?uxed for one hour at 110°,
cooled, and dropped into ice. Upon completion of the
3,067,209
7
8
hydrolysis, the reaction mixture was made strongly al
kaline with sodium hydroxide solution, and was then ex
tracted well with ethyl acetate. The organic extract
ing point 95°, the remaining petroleum ether solution
was dried over sodium sulfate, freed of solvent in
vacuo, and the residue was distilled in high vacuum.
residue from aqueous methanol (90%). A preferred
mode of execution consisted in ?rst allowing the evapora~
was cautiously evaporated in vacuo. The lower melting
isomer was isolated direct by recrystallization of the
Thus, 6.9 g. of 9-(w-dimethylaminopropylidene)-thio
tion residue to crystallize in the ice-box in absence of
solvent. The separated crystals were sucked off and
washed with little ice-cooled low boiling petroleum ether.
Then the crystals were dissolved in methanol, the solu—
xanthene were obtained as a yellowish oil; B.P. 153°
154°/0.05 mm.
Example 5
1.0 g. of activated ?nely divided Gilman copper-mag
nesium alloy and 1.0 g. of unactivated copper-magnesium
10 tion was cautiously mixed with Water until constant
alloy were placed in a 5 cc., 3-neck ?ask, which was
equipped with stirrer, condenser and dropping funnel,
turbidity and the latter was straight away removed by
dropwise addition of methanol. The mixture was allowed
to stand in the ice-box for at least 12 hours, the yellow
crystals that separated were sucked off, washed with a
and were covered with 10 cc. of absolute ether and a trace 15 little portion of cold aqueous methanol (90%) and ?nally
of iodine. Then, 5 drops of ethyl bromide were added.
dried over phosphorus pentoxide in a vacuum desiccator.
After vigorous reaction had developed, a solution of 9 g.
The low melting stereoisomer of 2-chloro-9—(w-dimethyl
of w-dimethylaminopropyl chloride in 20 cc. of absolute
aminopropylidene)-thioxanthene melted at 43° and was
ether, was slowly dropped in during which time the stirrer
easily soluble in the usual organic solvents.
was operated only occasionally. As soon as the reaction 20
The 2-chloro‘thioxanthone used as starting material
slowed down somewhat, the reaction vessel was dipped
was obtained as follows:
into a heating bath having a temperature of 5 0", the stirrer
A diazo solution of anthranilic acid (prepared from
was started and stirring was continued for four hours in
300 g. of anthranilic acid) was added dropwise to a
order to complete the reaction. Then, 4.0 g. of 2-chloro
stirred suspension containing 225 g. of sodium hydroxide,
thioxanthone in solid form were added portionwise and 25 1000 cc. of water, 500 g. of ice, 300 g. of p-chloro-thio
the reaction mixture Was stirred at 50° until the yellow
phenol and 15 g. of copper. The mixture was stirred
_ color of the 2-chloro-thioxanthone disappeared and the
overnight, then the precipitate was sucked OE and redis
reaction mixture took on a grayish-white color. Then
solved in much warm water. By ?ltration the solution
the mixture was cooled down to room temperature, poured
was freed of the insoluble copper. The light yellow
into a well cooled solution of 15 g. of ammonium chlo 30 ?ltrate was treated with hydrochloric acid. Thereby, the
ride in 200 cc. of water, 150 cc. of ethyl acetate were
4’-chloro-2-carboxy-diphenylsul?de precipitated; M.P.
added and the mixture was stirred well. The mixture was
232—233°.
freed by ?ltration of a little undissolved sludge. The or
347 g. of this acid were stirred for 2 hours at 110°
ganic layer was separated in a separatory funnel and was
with 3470 cc. of concentrated sulfuric acid. The reac
dried with sodium sulfate and freed of solvent in vacuo. 35 tion mixture was then poured into 14 liters of water. The
The residue was recrystallized from high boiling petroleum
ether. Thus, 4 g. of prismatic needles of 2-chloro-9-(w
dimethylaminopropyl)-thioxanthen-9-ol were obtained;
light yellow crystals of 2-chloro-thioxanthone which
formed thereby Were sucked o?; M.P. 149°.
Example 6
M.P. 148°-150°.
Upon shaking and cooling, 117 g. of 2-Cl'1lO1‘0-9-(a-dl 40
methylaminopropyl)-thioxanthen-9-ol were introduced
into 700 cc. of phosphorus oxychloride. The red solu
tion thus obtained was boiled for 2 hours under re?ux
4.66 g. of activated ?nely divided Gilman copper-mag
nesium alloy and 1.0 g. of unactivated copper-mag
nesium alloy were reacted with w-dimethylaminopropyl
chloride and 4-chloro-thioxanthone according to the pro
at a bath temperature of 130", then the solvent was re
cedure described in Example 5. The 4-Cl1l0I‘0-9-(w-dl
moved under diminished pressure. The residue was cooled 45 methylaminopropyl)-thioxanthen - 9 - 01 thus obtained
and shaken overnight with 3500 cc. of water, a light brown
melted at 129°, after recrystallization from benzene-high
clear solution being thus produced. The solution was
made alkaline to phenolphthalein with about 400 cc. of
boiling petroleum ether.
at 60°. The petroleum ether extract was Washed with
water and dried over sodium sulfate. Then, the solvent
rated in vacuo. the remaining oil was digested at 50° with
12 g. of 4-chloro~9-(w-dimethylaminopropyl)thioxan
30% sodium hydroxide solution, ?ltered and extracted
then-9-ol were boiled for 4 hours under re?ux with 100
well with petroleum ether (boiling interval of 80—l05°) 50 cc. of formic acid. An excess of formic acid was evapo
was carefully removed on the water bath under water
1 N sodium hydroxide solution and, after cooling, the
alkaline solution was extracted With methylene chloride.
pump vacuum. The remaining oil was puri?ed by distilla
The methylene chloride extract was dried over sodium
tion at low pressure. Thus, 103 g. of a mixture of stereo 55 sulfate, the solvent was evaporated and the remaining oil
isomers of 2-chlor0-9-(w-dimethylaminopropylidene)
thioxanthene was obtained as a light yellow oil (B.P.
was distilled in high vacuo. Thus, 10 g. of 4-chloro-9-(w
dimethylaminopropylidene)-thioxanthene were obtained
160-—162°/0.05 mm.), which was almost colorless after
B.P. 180°/0.02 mm.
a
redistillation.
The 4-chloro-thioxanthone used as starting material was
100 g. of a mixture of stereoisomers of Z-ChlOX‘O-9-(w 60 produced according to Example 5 by condensation of
dimethylaminopropylidene)-thioxanthene were dissolved
diazotized anthranilic acid with o-chlorothiophenol and
at 35° in 300 cc. of low boiling petroleum ether and the
subsequent cyclisation by means of concentrated sulfuric
solution was allowed to stand in the ice-box for 48 hours.
acid; M.P. 178-179".
The higher melting isomer that precipitated was separated
Example 7
from the mother-liquor by ?ltration. The rough crystals 65
4.66 g. of activated ?nely divided Gilman copper-mag
thus obtained were recrystallized from high boiling pe
nesium alloy and 3.75 g. of unactivated copper-magnesium
troleum ether (boiling interval 80—105°). Thus 28-—30
alloy were reacted with w-dimethylaminopropyl chloride
g. of light yellow crystals of melting point 95° were ob
and 3-chlorothioxanthone according to the procedure de
tained. With acids and quaternizing agents this substance
formed well crystallized salts which were easily soluble 70 scribed in Example 5. The S-chloro-9-(w-dimethylamino
propyl)-thioxanthen-9-ol was thus obtained; M.P. 104".
in alcohol, but dif?cultly soluble in water. The solu
This product was treated with phosphorus oxychloride
bility of the hydrochloride (M.P. 193494") and of the
neutral sulfate (M.P. 139-l40°) of the high melting
in the same manner as in Example 5. By splitting out
stereoisomer was less than 1%.
water, there was obtained 3-chloro-9-(w-dirnethylamino
After separation of the higher melting isomer of melt 75 propylidene)-thioxanthene; B.P. 150°/0.01 mm.
5,067,209
9
10
This product was treated with phosphorus oxychloride
The 3-chloro-thioxanthone used as starting material was
in the same manner as in Example 5. By splitting out
water, there was obtained 4-rnethoxy-9-(w-dimethylamino
propylidene)-thioxanthene; B.P. 194-196°/0.06 mm.
The 4-methoxy-thioxanthone used as starting material
produced according to Example 5 by condensation of
diazotized 4-chloro anthraniiic acid with thiophenol and
subsequent cyclisation by means of concentrated sulfuric
acid. M.P. 168°-169°.
was produced as follows:
Example 8
A mixture containing 14.7 g. of thiosalicyclic acid,
22.5 g. of o-iodo-anisol, 13.5 g. of ?nely pulverised potas
sium carbonate, 51 cc.‘of isoamyl alcohol and a trace of
4.66 g. of activated ?nely divided Gilman copper-mag
nesium alloy and 3.75 g. of unactivated copper-magnesium
alloy were reacted with 37.5 g. of w-dimethylaminopropyl 10 copper acetate was boiled for 16 hours under re?ux. The
reaction mixture was treated with 3 N sodium hydroxide
chloride and 15 g. of 2-bromo-thioxanthone according to
and the amyl alcohol was removed by steam distillation.
the procedure described in Example 5. The 2-br0mo-9
The remaining solution was ?ltered and treated with 3 N
(w-dimethylaminopropyl)-thioxanthen-9-ol was thus ob
hydrochloric acid; thereby, the 6-methoxy-2’-carboxy-di
tained; M.P. 139-140".
This product was treated with phosphorus oxychloride I
in the same manner as in Example 5. By splitting out
water, there was obtained 2-bromo-9-(w-dimethylarnino
phenyl sul?de precipitated; M.P. l89-191°.
10 g. of this acid were boiled for 1 hour under re?ux
with thionyl chloride.
The excess of thionyl chloride
was removed in vacuo. 10.6 g. of the acid chloride thus
obtained was dissolved in 50 cc. of absolute benzene.
The 2-bromo-thioxanthone used as starting material was
prepared according to Example 5 by condensation of 20 After addition of 5 g. of aluminium chloride at room
pr-opylidene)-thioxanthene; B.P. 180°/0.05 mm.
diazotized anthranilic acid was p-bromo-thiophenol and
subsequent cyclisation by means of concentrated sulfuric
acid. M.P. 154“.
Example 9
temperature the reaction mixture was stirred overnight
and then extracted well with ethyl acetate. The organic
extract was washed with 3 N sodium hydroxide solution
and with water. Then, it was dried over sodium sulfate,
25 freed of solvent in vacuo, and the residue was recrystal
4.66 g. of activated ?nely divided Gilman copper mag
lized from acetic acid. Thus, yellow needles of 4-meth
nesium alloy and 3.75 g. of unactivated copper-magnesium
oxy-thioxanthone were obtained; M.P. 163-164”.
alloy were reacted with 37.5 g. of w-dimethylaminopropyl
Example 13
chloride and 17 g. of 2-?uoro-thioxanthone according to
the procedure described in Example 5. The 2-?uoro-9
4.66 g. ‘of activated ?nely divided Gilman copper-mag
(w-dimethylaminopropyl)-thioxanthen-9-ol was thus ob 30 nesium alloy and 3.75 g. of unactivated copper-magnesium
tained; M.P. 171-172".
alloy were reacted with 37.5 g. of w-dimethylaminopropyl
This product was treated with phosphorus oxychloride
chloride and 18 g. of 3-methoxy-thioxanthone according
in the same manner as described in Example 5. By split
to the procedure described in Example 5. The 3-meth
ting out water, there was obtained 2-‘luoro-9-(w—dimethyl
35 oxy-9-( w-dimethylaminopropyl)-thioxanthen-9-ol was thus
aminopropylidene)-thioxanthene; B.P. l62°/0.05 mm.
obtained; M.P. 108—110°.
The 2-?uoro-thioxanthone used as starting material was
This product was treated with phosphorus oxychlo
prepared according to Example 5 by condensation of di
ride in the same manner as in Example 5. By splitting
azotized anthranilic acid with p-?uoro-thiophenol and
there was obtained 3-methoxy-9-(w-dimethyl
subsequent cyclisation by means of concentrated sulfuric 40 outwater,
aminopropylidene‘) -thioxanthene; B.P. 176-178°/0-.02
acid; M.P. 171°.
mm.
Example 10
The 3-methoxy-thioxanthene used as starting material
4.66 g. of activated ?nely divided Gilman copper-mag
was prepared as follows:
nesium alloy and 3.75 g. of unactivated copper-mag
A diazo solution of 4-methoxy-anthranilic acid was
nesium alloy were reacted with 37.5 g. of w-dimethyl 45 added‘ dropwise- to a solution of 12 g. of thiophenol and
aminopropyl chloride and 20 g. of Z-methyl-thioxanthone
30 g. of sodium hydroxide in 50 cc. of water, which was
according to the procedure described in Example 5. The
warmed up to 70°. Then, the reaction temperature was
2-methyl-9-(w-dimethylaminopropyl) - thioxanthen - 9-ol
was thus obtained; M.P. 118-119°.
held for one more hour at 70°. The reaction mixture
was ?ltered and the ?ltrate was treated with hydrochloric
This product was treated with phosphorus oxychloride 50 acid. The precipitate thereby formed was sucked off and
in the same manner as in Example 5. By splitting out
water, there was‘ obtained 2-methyl-9-(w-dimethylamino
propylidene)-thioxanthene; B.P. l63°/ 0.02 mm.
Example 11
Washed with water. The brown-red crystals were ‘then
dissolved in sodium carbonate solution, the latter was
boiled for 1% hours under re?ux. After cooling, the
solution was ?ltered and treated again with hydrochloric
acid. The precipitate was ?ltered off and dried. 26 g.
of the 5-rnethoxy-2-carboxy-diphenyl sul?de thus obtained
were mixedv with 30 cc. of obsolute benzene. Then, 50
cc. of thionyl chloride were added dropwise. The reac
tion mixture Was boiled for 1/2 hour under re?ux and
4.66 g. of activated ?nely divided Gilman copper-mag
nesium alloy and 3.75 g. of unactivated copper-magnesium
alloy were reacted with 37.5 g. of w-dimethylaminopropyl
chloride and 14 g. of Z-methoxy-thioxanthoue according
to the procedure described in Example 5. The 2-meth 60 the solvent was removed in vacuo. The acid chloride
oxy-9-( w-dimethylaminopropyl ) -thioxanthen-9-ol was thus
thus obtained was dissolved in 100 cc. of absolute benzene;
After addition of 11 g. of aluminium trichloride at room
obtained; M.P. 117-118“.
This product was treated with phosphorus oxychloride
temperature, the mixture was stirred overnight and poured
in the same manner as in Example 5. By splitting out
into dilute hydrochloric acid. The aqueous phase was
water, there was obtained 2-methoxy-9-(w-dimethylamino
. extracted well with ethyl acetate. The combined ex
tracts Were washed with 3 N hydrochloric acid, 3 N
propylidene)-thioxanthene; B.P. 180-l83°/0.02 mm.
sodium hydroxide and‘ water. Then, it was dried over
Example 12
sodium sulfate and freed of solvent. The residuewas
4.66 g. of activated ?nely divided Gilman copper-mag
snblimated in high vacuo. The S-methoxy-thibx-anthone
nesium alloy and 3.75 g. of unactivated copper-mag 70 wasthus obtained; M.P. 118-120".
nesium alloy were reacted with 37.5 g. of w-dimethyl
Example 14
aminopropyl. chloride and 20 g. of 4-methoxy-thioxan
thone according to the procedure described in Example
5.
The 4 - methox-y - 9 - (w-dimethylaminopropyl) - thio
xanthen-9-ol was thus obtained; M.P. 119-121".
4.66 g. of activated ?nelyidivided Gilman copper-‘mag
nesium alloy and 3.75 g. of unactivated copper-mag
35 nesium alloy were reacted with 37.5 g. of w-dimethyl
3,067,209
ll
l2.
aminopropyl chloride and 19 g. of l-methoxy-thioxanthone
according to the procedure described in Example 5. The
oxy-9-(w-dimethylaminopropyl) - thioxanthen - 9 - 01
was
thus obtained, M.P. 162-164".
This product was treated with phosphorus oxychloride
1-methoxy-9-(w-dimethylaminopropyl) - thioxanthen-9-ol
was thus obtained; M.P. 126—128°.
This product was treated with phosphorus oxychloride
in the same manner as in Example 5. By splitting out
water, there was obtained l-methoxy-9-(Lu-dimethylamino
proplidene)-thioxanthone; B.P. 166—168°/0.004 mm.
The l-methoxy-thioxanthone used as starting material
in the same manner as in Example 5. By splitting out
water, there was obtained 2-chloro-7-methoxy-9-(w-di
methylaminopropylidene) -thioxanthene; B.P. 198 ° / 0.05
mm.
The 2~chloro-7-methoxy-thioxanthone used as starting
material was prepared as follows:
was prepared according to Example 13 by condensation
of diazotized 6-methoxy-anthranilic acid with thiophenol
and subsequent cyclization. M.P. 125-126“.
A mixture containing 4.5 g. of S-chloro-thiosalicyclic
acid, 5.6 g. of p-iodo-anisol, 3.33 g. of ?nely pulverised
potassium carbonate and a trace of copper acetate was
heated for 16 hours under reflux. The reaction mixture
Example 15
was treated with 3 N sodium hydroxide and the amyl
4.66 g. of activated ?nely divided Gilman copper-mag 15 alcohol was removed by steam distillation. The remain
nesium alloy and 3.75 g. of unactivated copper-mag
ing hot solution was ?ltered and, after cooling, treated
nesium alloy were reacted with 37.5 g. of w-dimethyl
with 3 N hydrochloric acid. Then, the solution was
aminopropyl chloride and an absolute benzenic solution
extracted well with chloroform. The organic extract
of l-chloro~4-methoxy-thioxanthone according to the pro
was dried over sodium sulfate, and the solvent was re
cedure described in Example 5. The 1-chloro-4-methoxy
moved in vacuo. 3.3 g. of 4-meth0xy-4'-chloro-2'-car
9-(w-dimethylaminopropyl)-thi0xanthen-9-ol was thus ob
boxy-diphenyl sul?de was thus obtained, M.P. 170-172".
tained; M.P. 96—98°.
20 g. of this acid were boiled for 1/2 hour under re
This product was treated with phosphorus oxychloride
?ux with 100 cc. of thionyl chloride. The excess of
in the same manner as in Example 5. By splitting out
thionyl chloride was removed in vacuo. The acid chlo
Water, there was obtained l-chloro-4-methoxy-9-(w-di 25 ride thus obtained (20.1 g.) was dissolved in 200 cc. of
methylaminopropylidene) -thioxanthene; B.P. 206-208 ‘’ /
absolute benzene. After addition of 5 g. of aluminium
0.09 mm.
trichloride at room temperature, the reaction mixture
Example 16
4.66 g. of activated ?nely divided Gilman copper-mag
nesium alloy and 3.75 g. of unactivated copper-mag
nesium alloy were reacted with 37.5 g. of w-dimethyl
aminopropyl chloride and an absolute benzenic solu
tion of 20 g. of 1~methyl-4-methoxythioxanthone accord
ing to the procedure described in Example 5. The 1
methyl-4-methoxy-9-(w-dimethylaminopropyl) - thioxan
was stirred overnight and poured into 3 N hydrochloric
acid. The aqueous phase was well extracted with ethyl
30 acetate.
The combined extracts were dried over sodium
sulfate and freed of the solvent. The residue was mixed
with 3 N sodium hydroxide, ?ltered and washed with
Water. After sublimation in high vacuo yellow needles
of 2-chloro-7-thioxanthone were obtained; M.P. 164
35 166°.
Example 20
then-9-ol was thus obtained; M.P. 133-134“.
This product was treated with phosphorus oxychloride
in the same manner as in Example 5. By splitting out
water, there was obtained 1-methyl-4-methoxy-9-(w-di
4.66 g. of activated ?nely divided Gilman copper-mag
nesium alloy and 3.75 g. of unactivated copper-magne
sium alloy were reacted with 37.5 g. of w-dimethylamino
40
methylaminopropylidene)-thioxanthene; B.P. 177—180°/
propyl chloride and 20 g. of 2,7-dibromo-thioxanthone
according to the procedure described in Example 5. The
0.03 mm.
Example 17
2,7-dibromo-9-(w-dirnethylaminopropyl)-thioxanthen-9-ol
4.66 g. of activated ?nely divided Gilman copper-mag
nesium alloy and 3.75 g. of unactivated copper-magne
sium alloy were reacted with 37.5 g. of w-dimethylamino
propyl chloride and 19 g. of 1-methyl-4-chloro-thioxan
was thus obtained; M.P. 209-210“.
10 g. of this product were heated for 4 hours under
re?ux with 80 cc. of acetic anhydride. The acetic an
hydride was distilled off in vacuo, the residue was digested
thone according to the procedure described in Example
5. The 1-methyl-4-chloro-9-(w-dimethylaminopropyl)
thioxanthen-9-ol was ?rst obtained; M.P. 150°.
50
This product was treated with phosphorus oxychloride
in the same manner as in Example 5.
fate and the solvent ‘evaporated. After recrystallization
from petroleum ether, there was obtained 8 g. of 2,7-di
By splitting out
bromo-9 - (w - dimethylaminopropylidene) - thioxanthene;
water, there was obtained l-methyl-4-chloro-9-(ax-dimeth
ylaminopropylidene)-thioxanthene; B.P. 174°/0.009 mm.
Example 18
with 1 N sodium hydroxide solution and the alcaline
suspension was extracted with methylene chloride. The
methylene chloride extracts were dried over sodium sul
M.P. 109—110°.
55
A mixture of 21.2 g. of thioxanthone, 100 cc. of acetic
acid, 12 cc. of bromine and a trace of iodine was boiled
under a reflux condenser. After the development of hy
4.66 g. of activated ?nely divided Gilman copper-mag
drogen bromide had subsided the reaction mixture was
nesium alloy and 3.75 g. of unactivated copper-magne~
cooled and treated with 200 cc. of water. The precipi
sium alloy were reacted with 37.5 g. of til-dimethylamino
propyl chloride and 19 g. of 1-chloro-4-methyl-thioxan 60 tate which formed was separated, washed with dilute
thiosulfate solution, dried and recrystallized from ben
thone according to the procedure described in Example
zene, 2,7-dibromo-thioxanthone was thus obtained, M.P.
5. The 1-chloro-4-methyl-9-(w-dimethylaminopropyl)
263—264°.
thioxanthen-9-ol was ?rst obtained; M.P. 137".
We claim:
This product Was treated with phosphorus oxychloride
1. A compound selected from the group consisting of
in the same manner as in Example 5. By splitting out 65
compounds of the formula
water, there was obtained 1-chloro-4-methyl-9-(ta-dimeth
ylaminopropylidene)-thioxanthene; B.P. 172°/0.05 mm.
Example 19
4.66 g. of activated ?nely divided Gilman copper-mag 70
nesium alloy and 3.75 g. of unactivated copper-magne
sium alloy were reacted with 37.5 g. of iii-dimethylamino
propyl chloride and an absolute benzenic solution of 18
g. of 2-ch10ro-7-methoxy-thioxanthone according to the
procedure described in Example 5. The 2-chloro-7-meth 75
P
Q
0
wherein B is a tertiary amino radical containing up to
?ve carbon atoms selected from the group consist
ing of di~lower alkyl-amino, piperidino, morpholino
3,067,209
13
ing of di-lower alkyl-amino, piperidino, morpholino
alkyl and lower alkoxy; and n is an integer from 3
to 7 inclusive
and thiamorpholino; P and Q are each selected from
the group consisting of hydrogen, halogen, lower
alkyl and lower alkoxy; and m represents an integer
pharmaceutically acceptable acid addition salts thereof,
and pharmaceutically acceptable quaternary ammonium
from 2 to 6
salts thereof wherein the quaternizing radical is lower
which comprises dehydrating a compound of the for
mula
alkyl.
2. 2-halo-9-(w-dimethylaminopropyl)-xanthen-9-ol.
3. 2-lower alkyl-9-(w-dimethylaminopropyl) -xanthen
14
wherein B is a tertiary amino radical containing up to
?ve carbon atoms selected from the group consist
and thiamorpholino; P and Q are each selected from
the group consisting of hydrogen, halogen, lower
10
HO
Orton-B
9-01.
4. 2-lower alkoxy-9-(w-dimethylaminopropyl)-xanthen
9-01.
5. A compound selected from the group consisting
15
of compounds of the formula
P
Q
0
wherein B, P and Q have the same meaning as above
and n is an integer from 3 to 7 inclusive.
11. A process which comprises condensing a com
20 pound of the formula
0
0
wherein B is a tertiary amino radical containing up to
?ve carbon atoms selected from the group consist
l
ing of di-lower alkyl-amino, piperidino, morpholino
and thiamorpholino; P and Q are each selected from 25
P
the group consisting of hydrogen, halogen, lower
alkyl and lower alkoxy; and m is an integer from 2
to 6 inclusive
pharmaceutically acceptacle acid addition salts thereof, 30
and pharmaceutically ‘acceptable quaternary ammonium
salts thereof wherein the quaternizing radical is lower
thene.
8. 2-lower
35
consisting of hydrogen, halogen, lower alkyl and
lower alkoxy
wherein X is halogen; B is a tertiary amino radical
containing up to ?ve carbon atoms selected from the
group consisting of di-lower alkyl-amino, piperi
alkoxy - 9 - (w-dimethylaminopropylidene)
xanthene.
9. A process of preparing a compound of the formula
wherein P and Q are each selected from the group
with a compound of the formula
alkyl.
6. 2-halo-9-(w-dimethylaminopropylidene)-xanthene.
7. 2-lower alkyl-9-(w-dimethylaminopropylidene)-xan
Q
\o
dino, morpholino and thiamorpholino, (and n is an
integer from 3 to 7
‘
40 in the presence of a metal selected from the group con
sisting of magnesium, lithium, and zinc and hydrolyzing
the metallo condensation product obtained, thereby pro
ducing an intermediate compound of the formula
0
45
HO
0 Ha) w-B
wherein B is a tertiary amino radical containing up to
?ve carbon atoms selected from the group consist
ring of di-lower alkyl-amino, piperidino, morpholino
and thiamorpholino; P and Q are each selected from
the group consisting of hydrogen, halogen, lower
50
alkyl and lower 'alkoxy; and n is an integer from
0
wherein B, P, Q and n have the same meaning as
3 to 7
above and dehydrating said intermediate compound
which comprises reacting a corresponding nuclearly sub
thereby producing a compound of the formula
stituted Xanthone with a compound of the formula
55
(I'IJH—(CH:)m—B
wherein X represents halogen, and B and n have the
same meaning as above
in the presence of a metal selected from the group con
sisting of magnesium, lithium, and zinc.
10. A process of preparing a compound of the for
P
60
mula
Q
0
wherein B, P and Q have the same meaning as above
and m is a number equal to n minus one.
65
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,951,082
Sprague et al. ________ _- Aug. 30, 1960
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