U.S. patent application number 10/318900 was filed with the patent office on 2003-06-12 for process for preparing zolpidem.
This patent application is currently assigned to Boehringer Ingelheim Pharma KG. Invention is credited to Sauter, Markus, Wohlleben, Wolfgang.
Application Number | 20030109707 10/318900 |
Document ID | / |
Family ID | 27214417 |
Filed Date | 2003-06-12 |
United States Patent
Application |
20030109707 |
Kind Code |
A1 |
Sauter, Markus ; et
al. |
June 12, 2003 |
PROCESS FOR PREPARING ZOLPIDEM
Abstract
The invention relates to a process for preparing a compound of
formula (I) 1 wherein a compound of formula (II), 2 wherein R.sup.1
denotes chlorine, bromine, iodine, --O--COCH.sub.3, tosylate or
mesylate, is reacted with a compound of formula (III), 3 optionally
in a suitable diluent and/or in the presence of a suitable added
reagent or catalyst, the reaction being carried out in a
temperature range from 20 to 80.degree. C.
Inventors: |
Sauter, Markus; (Gensingen,
DE) ; Wohlleben, Wolfgang; (Hueffelsheim,
DE) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877
US
|
Assignee: |
Boehringer Ingelheim Pharma
KG
Ingelheim
DE
|
Family ID: |
27214417 |
Appl. No.: |
10/318900 |
Filed: |
December 13, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10318900 |
Dec 13, 2002 |
|
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10133830 |
Apr 26, 2002 |
|
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60290747 |
May 14, 2001 |
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Current U.S.
Class: |
546/113 |
Current CPC
Class: |
C07D 471/04 20130101;
C07C 235/78 20130101; C07C 235/74 20130101 |
Class at
Publication: |
546/113 |
International
Class: |
C07D 471/02 |
Foreign Application Data
Date |
Code |
Application Number |
May 3, 2001 |
DE |
101 21 638.6 |
Claims
What is claimed is:
1. A process for preparing a compound of formula (I) 10wherein a
compound of formula (II) 11wherein R.sup.1 denotes chlorine,
bromine, iodine, --O--COCH.sub.3, tosylate or mesylate, is reacted
with a compound of formula (III), 12optionally in a suitable
diluent and/or in the presence of a suitable added reagent or
catalyst, wherein the reaction is carried out in a temperature
range from 20 to 80.degree. C.
2. The process according to claim 1, wherein a diluent is used
which is selected from the group consisting of acetonitrile,
N-methylpyrrolidinone, tetrahydrofuran, acetone, ethanol and
dichloromethane.
3. The process according to claim 1, wherein acetonitrile is used
as diluent.
4. The process according to claim 1, wherein the reaction is
carried out at a temperature of about 60 to 75.degree. C.
5. The process according to claim 1, wherein the compound of
formula (II) is used in a molar ratio of 1:1 to 1:3 to the compound
of formula (III).
6. The process according to claim 1, wherein the compound of
formula (II) is used in a molar ratio of about 1:2 to the compound
of formula (III).
7. The process according to claim 1, wherein an added reagent
and/or catalyst is used, selected from the group consisting of
p-toluenesulphonic acid monohydrate, sodium hydrogen carbonate,
sodium acetate, pyridine, dimethylaminopyridine, magnesium
sulphate, triethylamine, trimethylorthoformate and
tetrabutylammonium bromide.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
10/133,830, filed on Apr. 26, 2002, which claims benefit of U.S.
Provisional Application Serial No. 60/290,747, filed on May 14,
2001 is hereby claimed.
FIELD OF THE INVENTION
[0002] The invention relates to a process for preparing
zolpidem.
BACKGROUND OF THE INVENTION
[0003] Zolpidem is a known sedative which has the following
structure: 4
[0004] EP 0 251 859 describes a process for preparing zolpidem. The
six-step synthesis starting with a bromoacetophenone is a generally
laborious method.
[0005] A process for preparing compounds analogous to zolpidem in
which 2-aminopyridines and corresponding bromoketoamides are
reacted is described in the literature (J. of Med. Chem.,1999, Vol.
42, No. 19,3934-3941).
[0006] The problem of the present invention is therefore to provide
an improved, economical process for preparing zolpidem which can be
used on an industrial scale.
DETAILED DESCRIPTION OF THE INVENTION
[0007] The present invention solves the problem outlined above by
the method of synthesis described hereinafter.
[0008] The invention thus relates to a process for preparing a
compound of formula (I) 5
[0009] wherein
[0010] a compound of formula (II) 6
[0011] wherein
[0012] R.sup.1 denotes chlorine, bromine, iodine, --O--COCH.sub.3,
tosylate or mesylate,
[0013] is reacted with a compound of formula (III), 7
[0014] optionally in a suitable diluent and/or in the presence of a
suitable added reagent or catalyst,
[0015] characterised in that the reaction is carried out in a
temperature range from 20 to 80.degree. C.
[0016] In a particularly preferred process a diluent is used which
is selected from among acetonitrile, N-methylpyrrolidinone,
tetrahydrofuran, acetone, ethanol and dichloromethane. In another
preferred process, acetonitrile is used as the diluent.
[0017] According to the invention, a process in which the reaction
is carried out at a temperature of about 60 to 75.degree. C.,
preferably 70.degree. C., is particularly important.
[0018] Also preferred is a process in which the compound of formula
(II) is used in a molar ratio of 1:1 to 1:3 to the compound of
formula (III).
[0019] Particularly preferred is a process in which the compound of
formula (II) is used in a molar ratio of about 1:1.3 to the
compound of formula (III).
[0020] Most particularly preferred is a process in which an added
reagent and/or catalyst is used which is selected from among
p-toluenesulphonic acid monohydrate, sodium hydrogen carbonate,
sodium acetate, pyridine, dimethylaminopyridine, magnesium
sulphate, triethylamine, trimethylorthoformate and
tetrabutylammonium bromide.
[0021] The invention further relates to the compound of formula
(II) 8
[0022] wherein
[0023] R.sup.1 denotes bromine.
[0024] The present invention also relates to a process for
preparing a compound of formula (II), wherein a compound of formula
(IV) 9
[0025] is reacted with elemental bromine in a diluent, preferably
dichloromethane.
[0026] The reaction of a compound of formula (IV) with elemental
bromine is generally carried out at a temperature of 10 to
50.degree. C., preferably 15 to 35.degree. C., more preferably 18
to 30.degree. C., most preferably about 20 or 25.degree. C.
[0027] The compound of formula IV is generally used in a molar
ratio of 1.5:1 to 1:1.5, preferably about 1:1.2, to elemental
bromine.
[0028] The invention also relates to the use of compounds of
formula (II) for preparing pharmaceutically active compounds.
[0029] Preferably, the compound of formula (II) is used to prepare
zolpidem.
[0030] The invention further relates to a process for preparing a
compound of formula (I), this process comprising the following
steps:
[0031] a) reacting the compound of formula (IV) in an organic
diluent at a temperature of 30 to 50.degree. C., preferably about
40.degree. C., with elemental bromine.
[0032] b) washing the reaction mixture with water,
[0033] c) after phase separation, concentrating the organic phase
by evaporation and optionally diluting it with another organic
diluent, and
[0034] d) reacting the concentrated organic phase of a) to c) with
the compound of formula (III) at 20 to 80.degree. C., preferably 60
to 75.degree. C., preferably about 70.degree. C., without isolating
the intermediate product.
[0035] The present invention further relates to the use of the
compound of formula (I) for preparing the pharmaceutically
acceptable salts thereof.
[0036] The compound of formula (I) is preferably used to prepare
zolpidem semitartrate.
[0037] Acids suitable for forming a salt of the compounds according
to the invention include, for example, hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid,
oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric
acid, citric acid, ascorbic acid and methanesulphonic acid,
particularly tartaric acid.
[0038] In a preferred embodiment of the process according to the
invention for preparing the compound of formula II, one equivalent
of the compound of formula IV is dissolved in a diluent, preferably
glacial acetic acid, ethyl acetate, n-butyl acetate or
diethylether, most preferably ethyl acetate. A solution of usually
1 to 1.5 equivalents, preferably one equivalent, of bromine is
added dropwise in a diluent, preferably ethyl acetate, at a
temperature of 40 to 70.degree. C., preferably about 45.degree. C.,
and stirred for 2 to 24 h, preferably 5 to 15 h, most preferably 12
h, at a temperature of 10 to 50.degree. C., preferably 15 to
35.degree. C., more preferably 18 to 30.degree. C., most preferably
about 20 or 25.degree. C. The suspension obtained is filtered, the
residue is added to a little water and stirred for about 0.5 to 2
h, preferably about 1 h. The suspension is filtered again and the
residue is washed with water. The crystals obtained are dried,
preferably in a vacuum drying cupboard at 40 to 80.degree. C.,
preferably at about 70.degree. C.
[0039] In a preferred embodiment of the process according to the
invention for preparing the compound of formula I, about 1
equivalent of the compound of formula (II) is placed in a diluent,
for example acetonitrile, and a solution of generally 2 equivalents
of the compound of general formula (III) and a diluent, for example
acetonitrile, is added dropwise at 20 to 80.degree. C., more
preferably at 40 to 75.degree. C., most preferably at a temperature
of about 70.degree. C. within 0.5 to 3 h, preferably 1 to 2 h, more
preferably about 1.5 or 1.75 h. After it has all been added, the
mixture is stirred for 2 to 6 h, preferably 2 to 5 h, more
preferably about 2.5 to 3 h.
[0040] The reaction mixture is then diluted with a diluent,
preferably dichloromethane, and washed one to five times,
preferably three times, with water. The organic phase is extracted
one to five times with hydrochloric acid, preferably 2 N
hydrochloric acid. The combined acid phases are adjusted to a pH of
between about 7 and 9, preferably to a pH of about 8, using a base,
preferably sodium hydroxide solution, more preferably 20% sodium
hydroxide solution. After the reaction mixture has been cooled it
is extracted one to five times with an organic diluent, selected
from among dichloromethane, toluene, ethyl acetate, n-butyl acetate
and methyl-tert.-butylether, preferably dichloromethane and ethyl
acetate, more preferably ethyl acetate. The combined organic phases
are dried, preferably with magnesium sulphate, and concentrated by
evaporation. The product which crystallises out is mixed with a
little water and stirred for 5 to 20 h, preferably 15 h, and the
crystals are filtered off, washed with water and dried, preferably
at 30 to 80.degree. C., preferably at 60.degree. C., for 1 to 10 h,
preferably 5 h.
[0041] In a preferred embodiment of the process according to the
invention for preparing the semitartrate salt of the compound of
general formula I, generally 2 equivalents of the compound of
formula I are placed in a diluent, preferably methanol, ethyl
acetate, Isopropanol or ethanol, more preferably methanol, and a
solution of 1 equivalent of (2R, 3R)-(+)-tartaric acid in a
diluent, preferably methanol, ethanol or isopropanol, more
preferably methanol, is added.
[0042] A precipitation agent, preferably tert.butylmethylether, an
isopropanol/methanol-mixture or a methanol/ether mixture,
preferably tert.butylmethylether, is optionally added. The mixture
is stirred for 1 to 24 h, preferably 12 h, at a temperature of 15
to 30.degree. C., preferably at about 20 or 25.degree. C. The
suspension formed is stirred for a further 0.5 to 3 h, preferably
about 1 hour at a temperature of 0 to 20.degree. C., preferably 3
to 10.degree. C., most preferably at about 5.degree. C. The
crystals obtained are filtered, optionally washed with a solvent,
preferably with tert.butylmethylether, and the crystals are dried,
preferably for 1 to 10 h, more preferably for 5 hours at a
temperature of 20 to 70.degree. C., preferably about 50.degree.
C.
[0043] In a particularly preferred embodiment of the process
according to the invention, about 1 equivalent of the compound of
formula (IV) is placed in a diluent, for example ethyl acetate,
butyl acetate or dichloromethane, preferably dichloromethane, and
heated to 30 to 50.degree. C., preferably 40.degree. C. Preferably,
catalytic amounts, preferably 5 to 6 mol-%, of HBr are added to the
reaction mixture. Then 1.2 equivalents of bromine are added
dropwise. The reaction mixture is stirred for another 60 min,
preferably 30 min. The mixture is cooled to about 20 to 25.degree.
C. and extracted with water. The organic phase is evaporated down
to about 10% (v/v) and then diluted with another diluent,
preferably tetrahydrofuran, N-methylpyrrolidinone or acetonitrile,
preferably acetonitrile. The mixture is added dropwise to a
solution of 1.3 equivalents of 6-amino-3-picoline and a diluent,
preferably tetrahydrofuran, N-methylpyrrolidinone or acetonitrile,
preferably acetonitrile. The resulting mixture is then stirred for
about 2 h at 50 to 80.degree. C., preferably 70.degree. C. The
reaction mixture is combined with an organic diluent, preferably
toluene, extracted with an aqueous solution, for example 2N
hydrochloric acid, and the organic phase is discarded. The aqueous
phase is again mixed with an organic diluent, adjusted to a pH of
about 4, and the organic phase is discarded again. The extraction
step is repeated at a pH of about 8 to 9. After the aqueous phase
has been separated off the organic phase is evaporated down to
about 10%. The residue is combined with diisopropylether,
diethylether or methyl-tert.butylether, preferably
methyl-tert.butylether, and stirred for about 30 to 60 minutes at
about 0 to 15.degree. C., preferably 5.degree. C. The crystals
formed are washed and dried.
[0044] The procedure according to the invention leads to an
economical process with a high space-time yield with regard to the
compound of formula I or the pharmacologically acceptable salts
thereof and a high yield and purity of the intermediate product of
formula II, which can be further processed without being isolated
or purified by chromatography. The Examples that follow serve to
illustrate the processes for preparing the compound of formula I.
carried out by way of example. They are to be understood as
examples of possible procedures without restricting the invention
to their contents.
EXAMPLE 1
3-(4-methyl-benzoyl)-2-bromo-propyl-dimethylamide
[0045] 18.6 g (84.8 mmol) of
3-(4-methyl-benzoyl)-propyl-dimethylamide are dissolved in 50 ml of
glacial acetic acid. A solution of 13.55 g (84.8 mmol) of bromine
and 45 ml of glacial acetic acid is added dropwise within 50
minutes at ambient temperature and the mixture is then stirred
overnight. The suspension formed is filtered and washed with 30 ml
of glacial acetic acid. The filter residue is added to 200 ml of
distilled water, triturated thoroughly and stirred for 1 hour. The
product is filtered again and washed with another 200 ml of water.
The crystals obtained (21.16 g) are dried for 6 hours in a vacuum
drying cupboard at 70.degree. C.
[0046] Yield 18.18 g of white crystals (71.9% of theory)
[0047] Melting point: 119-121.degree. C.
EXAMPLE 2
N,N-6-Trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide
[0048] 50 g (167.7 mmol) of
3-(4-methyl-benzoyl)-2-bromo-propyl-dimethylam- ide are placed in
500 ml of acetonitrile. A solution of 36.27 g (335.4 mmol) of
6-amino-3-picoline and 350 ml of acetonitrile is added dropwise at
60.degree. C. within 1.75 hours and once the solution has all been
added the mixture is stirred for another 4 hours. The resulting
solution is diluted with 1000 ml of dichloromethane and washed
three times with 2000 ml of distilled water. Then the organic phase
is extracted three times with 1000 ml of 2N hydrochloric acid. The
combined acid phases are adjusted to pH 8 with 20% sodium hydroxide
solution and, after being cooled, extracted three times with 1
litre of dichloromethane. These organic phases are combined, dried
with magnesium sulphate and concentrated by evaporation. The
crystals obtained are triturated with 500 ml of distilled water,
stirred overnight, filtered off, washed again with 50 ml of
distilled water and the residue is dried in a vacuum drying
cupboard for 5 hours at 60.degree. C.
[0049] Yield: 17.94 g of light-brown crystals (45.7% of
theoretical).
EXAMPLE 3
N,N-6-Trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide
[0050] 10.0 g (33.5 mmol) of
3-(4-methyl-benzoyl)-2-bromo-propyl-dimethyla- mide and 7.25 g
(67.0 mmol) of 6-amino-3-picoline are dissolved in 170 ml of
1,3-dimethyl-2-imidazolidinone and stirred for 3 hours at
60.degree. C. The reaction mixture is cooled and diluted with 100
ml of dichloromethane. It is then washed five times with 150 ml of
distilled water. The organic phase is washed twice with 150 ml of
2N hydrochloric acid. The combined acid phases are adjusted to pH 8
with 2N sodium hydroxide solution. The mixture is extracted twice
with 150 ml of dichloromethane, the organic phases are dried with
MgSO.sub.4 and concentrated by evaporation. The brown oil obtained
is mixed with 50 ml of n-heptane and stirred for 30 minutes. The
supernatant diluent is decanted off from the precipitated product
which is then washed twice with 10 ml of n-heptane. The residue is
evaporated down again, combined with 200 ml of distilled water and
stirred for 30 minutes. The product is filtered off, washed with 50
ml of distilled water and dried.
[0051] Yield: 2.38 g of beige crystals (23.1% of theoretical.)
[0052] Melting point: 194-195.degree. C.
EXAMPLE 4
N,N-6-Trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide
semitartrate
[0053] 17.94 g (94%) (54.9 mmol) of
N,N-6-trimethyl-2-(4-methylphenyl)imid-
azo[1,2-a]pyridine-3-acetamide are placed in 90 ml of methanol. A
solution of 4.13 g (27.5 mmol) of (2R, 3R)-(+)-tartaric acid and
125 ml of methanol are added, followed by 28 ml of
methyl-tert.-butyl-ether (MTBE) within 30 seconds. The mixture is
stirred for 15 h at ambient temperature. The light-brown suspension
formed is stirred for another 1 hour at 5.degree. C., filtered off,
the residue is washed with 50 ml of MTBE, and the crystals are
dried for 5 hours in a vacuum drying cupboard at 50.degree. C.
[0054] Yield: 18.3 g crystals (87.2% of theoretical.)
EXAMPLE 5
N,N-6-Trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide
[0055] 100 g (0.456 mol) of
3-(4-methyl-benzoyl)-propyl-dimethylamide are dissolved in 400 ml
of dichloromethane. 2 g (0.025 mol) of hydrogen bromide are piped
into the solution which is then refluxed. Then 86.1 g (0.539 mol)
of bromine is added dropwise within 45 minutes and the mixture is
stirred for 30 min. It is then cooled to ambient temperature and
washed with 600 ml of distilled water. The aqueous phase is
discarded. The organic phase is evaporated down to about 10% (v/v)
and then diluted with 300 ml of acetonitrile. This solution is
added dropwise within 45 min to a solution of 66.62 g (0.616 mol)
of 6-amino-3-picoline in 150 ml of acetonitrile at 70.degree. C.
and stirred for 1.5 h. Then 400 ml of toluene are added at
20-30.degree. C. and the mixture is then extracted with 500 ml of
2N hydrochloric acid. The toluene phase is discarded, the aqueous
phase is again combined with 400 ml of toluene and adjusted to pH 4
with 20% sodium hydroxide solution. The toluene phase is discarded,
the aqueous phase is combined with 400 ml of toluene and adjusted
to pH 8.5 with 20% sodium hydroxide solution. The toluene phase is
separated off and evaporated down to 10% (v/v). The residue is
combined with MTBE and stirred for 2 h at 5.degree. C. The crystals
obtained are suction filtered, washed with MTBE and dried.
[0056] Yield: 43 g of zolpidem (30.7%).
* * * * *