U.S. patent application number 11/074198 was filed with the patent office on 2005-07-07 for process for preparing 6-aryl-4h-s-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazep- ines.
This patent application is currently assigned to Boehringer Ingelheim Pharma KG. Invention is credited to Belzer, Werner, Lock, Ralf.
Application Number | 20050148579 11/074198 |
Document ID | / |
Family ID | 27214382 |
Filed Date | 2005-07-07 |
United States Patent
Application |
20050148579 |
Kind Code |
A1 |
Belzer, Werner ; et
al. |
July 7, 2005 |
Process for preparing
6-aryl-4H-S-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazep- ines
Abstract
An improved process for preparing
6-aryl-4H-s-triazolo[3,4-c]-thieno[2,3-e- ]-1,4-diazepines of
formula I, 1 wherein: R.sup.1 is a hydrogen or halogen atom or a
C.sub.1-C.sub.6 alkyl group, R.sup.2 is a hydrogen or halogen atom
or a C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 hydroxyalkyl,
C.sub.3-C.sub.6 cycloalkyl group or a 5- or 6-membered oxygen-,
sulphur- or nitrogen-containing heterocyclic group which may
optionally be substituted at the nitrogen atom by a C.sub.1-C.sub.3
alkyl group, and R.sup.3 is a hydrogen or halogen atom,
Inventors: |
Belzer, Werner; (St. Goar,
DE) ; Lock, Ralf; (Mainz, DE) |
Correspondence
Address: |
MICHAEL P. MORRIS
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
Boehringer Ingelheim Pharma
KG
Ingelheim
DE
|
Family ID: |
27214382 |
Appl. No.: |
11/074198 |
Filed: |
March 7, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11074198 |
Mar 7, 2005 |
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10096809 |
Mar 13, 2002 |
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6884886 |
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60289880 |
May 9, 2001 |
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Current U.S.
Class: |
514/220 ;
540/499 |
Current CPC
Class: |
C07D 495/04 20130101;
C07D 495/14 20130101 |
Class at
Publication: |
514/220 ;
540/499 |
International
Class: |
A61K 031/551; C07D
498/14 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 4, 2001 |
DE |
101 16 378.9-43 |
Claims
1-9. (canceled)
10. A 5-aryl-2-chlorothieno[2,3-e]-1,4-diazepine of the formula IlI
7wherein: R.sup.1 is a hydrogen or halogen atom or a
C.sub.1-C.sub.6 alkyl group, and R.sup.3 is a hydrogen or halogen
atom.
11. The process according to claim 10, wherein R.sup.1 denotes a
bromine atom and R.sup.3 denotes a chlorine atom.
Description
RELATED APPLICATIONS
[0001] Benefit of U.S. Provisional Application Ser. No. 60/289,880,
filed on May 9, 2001, is hereby claimed.
FIELD OF THE INVENTION
[0002] The invention relates to a process for preparing
6-aryl-4H-s-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines of formula
I, 2
[0003] wherein R.sup.1, R.sup.2 and R.sup.3 have the meanings
given, from a 5-aryl-1,3-dihydrothieno[2,3-e]-1,4-diazepin-2-one of
formula II 3
BACKGROUND TO THE INVENTION
[0004] 6-Aryl-4H-s-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines,
particularly brotizolam (R.sup.1=Br, R.sup.2=methyl, R.sup.3=Cl),
are known for example from U.S. Pat. No. 4,094,984 and are valuable
medicaments which have sedative properties, in particular, and may
be used for treating sleep disorders.
[0005] However, the preparation described therein, starting from a
5-aryl-1,3-dihydrothieno[2,3-e]-1,4-diazepin-2-one of formula II,
is unsuitable for production on an industrial scale, as the
intermediate products involved, such as for example
5-aryl-1,3-dihydrothieno[2,3-e]-1,- 4-diazepin-2-thiones, have to
be isolated, and when reacted give off foul-smelling and in some
cases toxic thiols which may lead to contamination of the
products.
[0006] The aim of the present invention is therefore to provide a
process which makes it possible to synthesise, work up, purify and
isolate 6-aryl-4H-s-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines of
formula I on an industrial scale while overcoming the disadvantages
mentioned above.
DETAILED DESCRIPTION OF THE INVENTION
[0007] Surprisingly, it has been found that
6-aryl-4H-s-triazolo[3,4-c]-th- ieno[2,3-e]-1,4-diazepines of
formula I, wherein
[0008] R.sup.1 denotes a hydrogen or halogen atom or a
C.sub.1-C.sub.6 alkyl group,
[0009] R.sup.2 denotes a hydrogen or halogen atom or a
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 hydroxyalkyl,
C.sub.3-C.sub.6 cycloalkyl group or a 5- or 6-membered oxygen-,
sulphur- or nitrogen-containing heterocyclic group which may
optionally be substituted at the nitrogen atom by a C.sub.1-C.sub.3
alkyl group, and
[0010] R.sup.3 denotes a hydrogen or halogen atom,
[0011] can be produced on an industrial scale if a
5-aryl-1,3-dihydrothien- o[2,3-e]-1,4-diazepin-2-one of formula
II,
[0012] wherein R.sup.1 and R.sup.3 are as herein defined,
[0013] (a) is treated with a chlorinating agent,
[0014] (b) the resulting 5-aryl-2-chlorothieno[2,3-e]-1,4-diazepine
of formula III, 4
[0015] wherein R.sup.1 and R.sup.3 are as herein defined, is
reacted with an acylhydrazine of formula IV
R.sup.2--CO--NH--NH.sub.2
[0016] wherein R.sup.2 is as hereinbefore defined, and
[0017] (c) the product thus obtained is treated with a base.
[0018] The invention thus relates to a process for preparing the
compounds of formula I from compounds of formula II according to
steps (a), (b) and (c) mentioned above.
[0019] The invention also relates to a process for preparing a
compound of formula I wherein R.sup.1 denotes bromine, in which a
compound of formula V, 5
[0020] wherein R.sup.3 is as hereinbefore defined,
[0021] is subjected to the following reactions one after
another:
[0022] (d) cyclisation under water-cleaving conditions;
[0023] (e) reacting the product obtained in step d) with a
brominating agent;
[0024] (f) converting the compound of formula II thus obtained
wherein R.sup.1 denotes bromine into the compound of formula I
according to steps (a) to (c),
[0025] characterised in that steps (d) and (e) are carried out in a
one-pot process.
[0026] The invention also relates to
5-aryl-2-chlorothieno[2,3-e]-1,4-diaz- epines of formula III, 6
[0027] wherein R.sup.1 and R.sup.3 have the meanings given,
particularly
7-bromo-5-(2-chlorophenyl)-2-chlorothieno[2,3-e]-1,4-diazepine.
[0028] The term "alkyl" as used hereinbefore and hereinafter with
regard to the groups R.sup.1 and/or R.sup.2 denotes a
straight-chain or branched alkyl group with up to 6 C atoms,
preferably 1 to 4 C atoms. Particularly preferred are methyl,
ethyl, n-propyl, i-propyl, n-butyl and tert-butyl, particularly
methyl.
[0029] The term "hydroxyalkyl" as used hereinbefore and hereinafter
with regard to the group R.sup.2 denotes a straight-chain or
branched alkyl group with up to 6 C atoms, preferably 1 to 4 C
atoms, which is substituted by a hydroxy group.
.omega.-Hydroxyalkyl groups with 1 to 3 C atoms, particularly
hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl are
preferred.
[0030] The term "cycloalkyl" as used hereinbefore and hereinafter
with regard to the group R.sup.2 denotes a cyclic alkyl group with
3 to 6 C atoms, preferably 5 or 6 C atoms, particularly cyclopentyl
and cyclohexyl.
[0031] The term "heterocyclic group" as used hereinbefore and
hereinafter with regard to the group R.sup.2 denotes a saturated or
unsaturated 5- or 6-membered heterocyclyl group, which contains in
addition to carbon atoms and at least one heteroatom selected from
among nitrogen, oxygen and sulphur. The following heterocyclyl
groups are preferred:
[0032] saturated or aromatic 5- or 6-membered heterocyclyl groups
which
[0033] contain one or two nitrogen atoms, particularly pyrrolidyl,
pyrazolyl, imidazolyl, pyridyl, pyrimidyl, piperidyl and piperazyl,
or
[0034] a nitrogen atom and an oxygen or sulphur atom, particularly
morpholino and thiomorpholino,
[0035] contain an oxygen atom, particularly tetrahydropyranyl and
tetrahydrofuranyl.
[0036] The term "one-pot process" as used hereinbefore and
hereinafter for the sequence of certain reaction steps denotes the
succession of two or more synthesis steps occurring one after
another, with the intermediate product obtained in a first or
second synthesis step being used in the next synthesis step without
any isolation or purification. Preferably, the subsequent reaction
step is carried out in the same reaction vessel and optionally in
the presence of the reaction medium in which the previous reaction
step was carried out.
[0037] In a preferred embodiment the groups R.sup.1 to R.sup.3 have
the following meanings:
[0038] R.sup.1 denotes halogen or methyl, particularly bromine,
[0039] R.sup.2 denotes hydrogen or methyl, particularly methyl,
and
[0040] R.sup.3 denotes halogen, particularly chlorine.
[0041] In a preferred embodiment of the process according to the
invention for preparing the compound of formula I:
[0042] in step (a) the compound of formula (II) is reacted with
phosphorus pentachloride in the presence of an inert diluent and a
tertiary amine;
[0043] in step (b) the compound of formula (III) is reacted at a
temperature below 100.degree. C. with acetic acid hydrazide in the
presence of an inert diluent.
[0044] in step (c) the compound obtained in step (b) is treated
with aqueous sodium hydroxide solution at a temperature of
0.degree. C. to 50.degree. C.;
[0045] the reaction sequence of steps (a) to (c) is carried out in
a one-pot process.
[0046] Stage II.fwdarw.III
[0047] Step (a)
[0048] The reaction of the compound of formula II with the
chlorinating agent is generally carried out in the presence of an
inert diluent.
[0049] Preferably the compound of formula II is reacted with a
chlorinating agent selected from among thionyl chloride, sulphuryl
chloride, titanium tetrachloride, oxalyl chloride, phosgene, di-
and triphosgene, phosphorus trichloride, phosphorus oxychloride,
phosphorus pentachloride and antimony pentachloride, conveniently
in a diluent such as tetrahydrofuran, dioxane, toluene,
dichloromethane, chloroform or chlorobenzene, or mixtures of these
diluents, optionally in the presence of an organic base, e.g.
triethylamine, N-ethyldiisopropylamine, pyridine or
4-dimethylaminopyridine, at temperatures from -20 to +60.degree.
C., preferably -10 to +20.degree. C. The reaction is generally
carried out at normal pressure, using 0.9 to 2.0, preferably 1.1 to
1.9, particularly 1.2 to 1.4 mol of a chlorinating agent based on 1
mol of the compound of formula II. The reaction is generally
complete, under the conditions specified, after 15 to 600 minutes,
preferably 30 to 180 minutes. The crude product obtained is
generally further processed in the next step without any other
purification.
[0050] In a particularly preferred embodiment of the process
according to the invention a suspension of the compound of formula
II in pyridine and dichloromethane is added dropwise to a
suspension of 1.1 to 1.5 mol of phosphorus pentachloride based on 1
mol of the compound of formula II in dichloromethane at 0 to
20.degree. C. with cooling. The mixture is stirred for 30 to 120
minutes at about 10.degree. C.
[0051] Stage III.fwdarw.I
[0052] Step (b)
[0053] The reaction of the compound of formula III with the
compound of formula IV generally takes place in an inert
solvent.
[0054] Preferably, the compound of formula III is reacted with a
compound of formula IV, particularly acetic acid hydrazide,
conveniently in a diluent such as tetrahydrofuran, dioxane,
toluene, dichloromethane, chloroform or chlorobenzene, or mixtures
of these diluents, particularly in a mixture of dichloromethane and
tetrahydrofuran, optionally in the presence of an organic base,
e.g. triethylamine, N-ethyldiisopropylamine, pyridine or
4-dimethylaminopyridine, and the other reaction products formed in
step (a), e.g. phosphorus oxychloride, at temperatures from 0 to
100.degree. C., preferably 10 to +90.degree. C. The reaction is
generally carried out at normal pressure, using 0.9 to 3.0,
preferably 1.5 to 2.5, particularly 1.8 to 2.2 mol of a compound of
formula IV based on 1 mol of the compound of formula III. The
reaction is generally complete, under the conditions specified,
after 1 to 48 hours, preferably 5 to 24 hours. The crude product
obtained is generally further processed in the next step without
any other purification.
[0055] In a particularly preferred embodiment of the process
according to the invention, a heated solution of about 2
equivalents of acetic acid hydrazide in tetrahydrofuran based on 1
equivalent of formula III is added dropwise with cooling at
0-30.degree. C. to the reaction mixture obtained in step (a). The
resulting mixture is then stirred for a further 0.5 to 2 hours at
ambient temperature and then refluxed for 5-20 hours. The
brotizolam is obtained as the hydrochloride/phosphate, and the
brotizolam is liberated by the subsequent addition of a base.
[0056] Step (c)
[0057] The reaction of the compound obtained in step (b) with the
base generally takes place in the presence of an inert solvent.
[0058] Preferably, the compound obtained in step (b) is reacted
with an aqueous base, particularly sodium hydroxide, conveniently
in a diluent such as water, methanol, ethanol, tetrahydrofuran,
dioxane, toluene, dichloromethane, chloroform, acetone,
methylethylketone or chlorobenzene, or mixtures of these diluents,
particularly in a mixture of dichloromethane, tetrahydrofuran and
water, optionally in the presence of an organic base, e.g.
triethylamine, N-ethyldiisopropylamine, pyridine or
4-dimethylaminopyridine and the other reaction products obtained in
steps (a) and (b), e.g. phosphorus oxychloride, at temperatures
from 0 to 120.degree. C., preferably 10 to 100.degree. C. The
reaction is generally carried out at normal pressure using 1.0 to
10, preferably 6 to 9 mol of a base, based on 1 mol of the
chlorinating reagent. The reaction is generally complete, under the
conditions specified, after a few minutes to several hours, 0.1 to
24 hours, preferably 0.1-2 h. The crude product obtained is
generally isolated by extraction and/or crystallisation and
optionally purified by recrystallisation.
[0059] In a particularly preferred embodiment of the process
according to the invention water is added to the reaction mixture
obtained in step (b), with cooling, and the pH is adjusted with
sodium hydroxide solution to an alkaline level of 7.5-13,
particularly 9-11. The phases are separated and the aqueous phase
is extracted with dichloromethane. The combined organic phases are
preferably decolorised with activated charcoal, filtered and
evaporated to dryness in vacuo. The residue is taken up in boiling
methylethylketone, decolorised again, filtered and then evaporated
down. The mixture is cooled to 0 to 10.degree. C. and stirred for a
further 2 hours at this temperature. The product that crystallises
out is filtered off, washed with methylethylketone and ethyl
acetate and dried.
[0060] In a preferred embodiment of the process according to the
invention for preparing the compound of formula II:
[0061] the compound of formula V is heated in step (d) with an acid
in a high-boiling solvent;
[0062] the compound obtained in step (d) is reacted with bromine in
the presence of a tertiary amine.
[0063] Stage V.fwdarw.II
[0064] Step (d)
[0065] The cyclising of the compound of formula V generally takes
place in the presence of an inert diluent.
[0066] Preferably, the compound of formula V is reacted with an
acid selected from among hydrochloric acid, sulphuric acid,
p-toluenesulphonic acid, phosphoric acid, a carboxylic acid such as
acetic acid, propionic acid, pivalic acid, trifluoroacetic acid and
silica gel, optionally in the presence of a base such as pyridine,
conveniently in a high-boiling diluent such as n-butanol,
amylalcohol, toluene, xylene, chlorobenzene, or mixtures of these
diluents at temperatures from 20 to 160.degree. C., preferably 60
to 140.degree. C. The reaction is generally carried out at normal
pressure using 1.5 to 6.0, preferably 1.9 to 4.0, particularly 3.2
to 3.8 mol of an acid, based on 1 mol of the compound of formula V.
The reaction is generally complete, under the conditions specified,
after 15 to 600 minutes, preferably 30 to 180 minutes. The crude
product obtained is generally further processed in the next step
without any other purification.
[0067] In a particularly preferred embodiment of the process
according to the invention, one part of
2-amino-N-[3-(2-chlorobenzoyl)thiophen-2-yl]ac- etamide is added to
a mixture of 4 to 12 parts of n-butanol and 0.4 to 1.2 parts of
glacial acetic acid at 80-110.degree. C. and refluxed for 0.5 to 2
hours.
[0068] Step (e)
[0069] The reaction of the compound obtained in step (d) with a
brominating agent generally takes place in the presence of an inert
solvent.
[0070] Preferably, the compound obtained in step (d) is reacted
with a brominating agent selected from among bromine,
N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin,
conveniently in a diluent such as n-butanol, amylalcohol, toluene,
xylene, chlorobenzene, or mixtures of these diluents, optionally in
the presence of an organic base, e.g. triethylamine,
N-ethyldiisopropylamine or pyridine, at temperatures from -20 to
+60.degree. C., preferably -10 to +20.degree. C. The reaction is
generally carried out at normal pressure, using 0.9 to 2.0,
preferably 1.1 to 1.9, particularly 1.2 to 1.8 mol of a brominating
agent based on 1 mol of the compound of formula V. The reaction is
generally complete, under the conditions specified, after 15 to 600
minutes, preferably 30 to 240 minutes. The crude product obtained
is generally isolated by crystallisation and optionally purified by
recrystallisation.
[0071] In a particularly preferred embodiment of the process
according to the invention the reaction mixture obtained in step
(d) is cooled to ambient temperature, and pyridine and about 1.2 to
1.8 mol bromine based on 1 mol of the compound of formula V used
are added. The resulting mixture is then stirred for a further 0.1
to 4 hours, cooled to 0-20.degree. C. and stirred for another 1 to
3 hours at this temperature. The product that crystallises out is
isolated by filtration, washed with aqueous ethanol and dried.
[0072] The compound of formula V needed as a starting material is
known, for example, from published German application DE 22 17 157
or U.S. Pat. No. 4,094,984 and can be prepared in a manner known
per se by reacting a 2-amino-3-arylthiophene with
bromoacetylbromide and ammonia.
[0073] Other advantageous aspects of the method according to the
invention are the high space/time yields of the present process and
the high yield and purity of the associated intermediate products,
which can be further processed without being purified by
chromatography.
[0074] The Examples that follow serve to illustrate the processes
carried out by way of example for preparing the compound of formula
I. They are to be understood as being possible methods given solely
as examples without restricting the invention to their content.
EXAMPLE 1
7-Bromo-5-(2-chlorophenyl)-1,3-dihydrothieno[2,3-e]-1,4-diazepine-2-one,
(1)
[0075] 220 g (0.746 mol) of
2-amino-N-[3-(2-chlorobenzoyl)thiophen-2-yl]ac- etamide (prepared
by reacting 2-amino-3-(2-chlorobenzoyl)thiophene with
bromoacetylbromide and subsequently piping in gaseous ammonia) are
added at 110.degree. C. to a mixture of 1.8 l of n-butanol and 150
ml of glacial acetic acid. The mixture is refluxed for 1 hour,
cooled to ambient temperature and 330 ml of pyridine and 57 ml
(178.8 g, 1.12 mol) of bromine are added with cooling. Then the
mixture is stirred for another 0.5 to 2 hours, cooled to 5 to
10.degree. C. and stirred for a further 2 hours at this
temperature. The product that crystallises out is isolated by
filtration, washed with 50% ethanol and dried overnight in vacuo at
60.degree. C. Yield: 152 g (57.3%).
EXAMPLE 2
Brotizolam
[0076] A suspension of 50 g (0.14 mol) of (1) in 2.5 ml of pyridine
and 200 ml of dichloromethane is added dropwise to a suspension of
36 g (0.183 mol) of phosphorus pentachloride in 250 ml of
dichloromethane at 5-10.degree. C. with cooling. The mixture is
stirred for 1 hour at 10.degree. C. and a solution of 17 g (0.28
mol) of acetic acid hydrazide in 170 ml of tetrahydrofuran, heated
to 40-50 .degree. C., is added dropwise with cooling at
10-20.degree. C. The mixture is then stirred for 1 hour at ambient
temperature and then refluxed for 5 to 18 hours. It is then cooled
to ambient temperature, 380 ml water are added with cooling and the
mixture is adjusted to an alkaline pH with 45% sodium hydroxide
solution. The phases are separated and the aqueous phase is
extracted with 100 ml of dichloromethane. 5 g of activated charcoal
are added to the combined organic phases which are then stirred for
10 minutes, filtered and evaporated to dryness in vacuo. The
residue is taken up in 750 ml of boiling methylethylketone, 5 g of
activated charcoal are added and the resulting mixture is refluxed
for another 10 min. The suspension is filtered, then 570 ml of
solvent are distilled off. The mixture is allowed to cool slowly to
ambient temperature and then cooled to 5.degree. C. and stirred for
2 hours at this temperature. The product that crystallises out is
filtered off, washed with 30 ml of cold methylethylketone and 50 ml
of cold ethyl acetate and dried overnight at 60.degree. C. in
vacuo. Yield: 36.6 g (66%) of brotizolam.
* * * * *