U.S. patent application number 10/538342 was filed with the patent office on 2007-06-28 for method for producing 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-- 5-yl}methyl)-2-thiophenecarboxamide.
This patent application is currently assigned to Bayer Healthcare AG. Invention is credited to Christian R. Thomas.
Application Number | 20070149522 10/538342 |
Document ID | / |
Family ID | 32519617 |
Filed Date | 2007-06-28 |
United States Patent
Application |
20070149522 |
Kind Code |
A1 |
Thomas; Christian R. |
June 28, 2007 |
Method for producing
5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin--
5-yl}methyl)-2-thiophenecarboxamide
Abstract
The invention relates to a method for producing
5-chloro-N-({5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin--
5-yl}-methyl)-2-thiophene carboxamide starting from
5-chlorothiophene-2-carbonyl chloride,
(2S)-3-amino-propane-1,2-diol and
4-(4-aminophenyl)-3-morpholinone.
Inventors: |
Thomas; Christian R.;
(Wuppertal, DE) |
Correspondence
Address: |
JEFFREY M. GREENMAN
BAYER PHARMACEUTICALS CORPORATION
400 MORGAN LANE
WEST HAVEN
CT
06516
US
|
Assignee: |
Bayer Healthcare AG
Leverkusen
DE
D-51368
|
Family ID: |
32519617 |
Appl. No.: |
10/538342 |
Filed: |
December 24, 2003 |
PCT Filed: |
December 24, 2003 |
PCT NO: |
PCT/EP03/14871 |
371 Date: |
June 5, 2006 |
Current U.S.
Class: |
514/235.2 ;
544/137 |
Current CPC
Class: |
A61P 9/10 20180101; C07D
413/12 20130101; A61P 11/00 20180101; C07D 333/38 20130101; C07D
413/14 20130101; A61P 7/02 20180101; A61P 9/04 20180101 |
Class at
Publication: |
514/235.2 ;
544/137 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 413/14 20060101 C07D413/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 7, 2003 |
DE |
103 00 111.5 |
Claims
1. A process for preparing
5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin--
5-yl}methyl)-2-thiophenecarboxamide of the formula (I) ##STR11##
comprising preparing 5-chlorothiophene-2-carbonyl chloride (IV) in
a first step by chlorinating 5-chlorothiophene-2-carboxylic acid;
reacting said 5-chlorothiophene-2-carbonyl chloride (IV) in a
second step with (2S)-3-aminopropane-1,2-diol hydrochloride (VII)
to give
N--((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide
(VIII); converting said
N--((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII)
in a third step to
N--((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide
(IX); converting said
N--((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide
(IX) in a fourth step by reacting with
4-(4-aminophenyl)-3-morpholinone (III) to
N--{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorot-
hiophene-2-carboxamide (X); reacting said
N--{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorot-
hiophene-2-carboxamide (X) in a fifth step with phosgene or a
phosgene equivalent.
2. A process for preparing
N--((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide
(VIII), comprising reacting 5-chlorothiophene-2-carbonyl chloride
(IV) with (2S)-3-aminopropane-1,2-diol hydrochloride (VII).
3. A process for preparing
N--((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide
(IX), comprising reacting
N--((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII)
with hydrobromic acid in acetic acid.
4. A process for preparing
N--{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorot-
hiophene-2-carboxamide (X), comprising reacting
N--((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide
(IX) with 4-(4-aminophenyl)-3-morpholinone (III).
5. A process for preparing
5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin--
5-yl}methyl)-2-thiophenecarboxamide of the formula (I), comprising
reacting
N--{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}--
5-chlorothiophene-2-carboxamide (X) with phosgene or a phosgene
equivalent.
6. The process as claimed in claim 5, characterized in that the
phosgene equivalent is N,N-carbonyldiimidazole.
7. The process as claimed in claim 6, characterized in that from
1.1 to 1.3 equivalents of N,N-carbonyldiimidazole are used.
8. The process of claim 5, wherein the reaction takes place in a
solvent mixture of 1-methyl-2-pyrrolidone and toluene.
9. The process of claim 5, further comprising preparing said
N--{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorot-
hiophene-2-carboxamide (X) by reacting
N--((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide
(IX) with 4-(4-aminophenyl)-3-morpholinone (III).
10. The process of claim 9, further comprising preparing the
N--((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide
(IX) by reacting
N--((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII)
with hydrobromic acid in acetic acid.
11. The process of claim 10, further comprising preparing said
N--((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII)
by reacting 5-chlorothiophene-2-carbonyl chloride (IV) with
(2S)-3-aminopropane-1,2-diol hydrochloride (VII).
12.
N--{(R)-2-Hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chl-
orothiophene-2-carboxamide of the formula (X) ##STR12##
13.
N--((S)-3-Bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide of
the formula (IX) ##STR13##
14. The process of claim 3 or 10, wherein
N--((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII)
is reacted with hydrobromic acid in acetic acid in the presence of
acetic anhydride.
15.
N--{(R)-2-Hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chl-
orothiophene-2-carboxamide of the formula (X) ##STR14## produced in
accordance with the process of claim 4.
16. A composition consisting essentially of
N--{(R)-2-Hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorot-
hiophene-2-carboxamide of the formula (X) ##STR15##
Description
[0001] The present invention relates to a process for preparing
5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin--
5-yl}methyl)-2-thiophene-carboxamide starting from
5-chlorothiophene-2-carbonyl chloride, (2S)-3-aminopropane-1,2-diol
and 4-(4-aminophenyl)-3-morpholinone.
[0002] The compound
5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin--
5-yl}methyl)-2-thiophenecarboxamide is known from WO-A 01/47919 and
corresponds to the formula (I) ##STR1##
[0003] The compound of the formula (I) acts as an inhibitor of
clotting factor Xa and may be used as an agent for the prophylaxis
and/or treatment of thromboembolic disorders, especially myocardial
infarction, angina pectoris (including unstable angina),
reocclusions and restenoses after angioplasty or aortocoronary
bypass, stroke, transient ischemic attacks, peripheral arterial
occlusive diseases, pulmonary embolisms or deep venous
thromboses.
[0004] WO-A 01/47919 also describes a method for preparing the
compound of the formula (I) starting from
2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (II),
4-(4-aminophenyl)-3-morpholinone (III) and
5-chlorothiophene-2-carbonyl chloride (IV): ##STR2##
[0005] In this method, the epoxyphthalimide (II) is prepared by
reacting (2S)-1-chloropropane-2,3-diol (V) with potassium carbonate
via the stage of (S)-glycidol (VI) and subsequent Mitsunobu
reaction with phthalimide: ##STR3##
[0006] The process known from WO-A 01/47919 has various
disadvantages which have a particularly unfavorable effect when the
compound of the formula (I) is prepared on the industrial
scale:
[0007] For instance, the glycidol (VI), especially in relatively
large amounts, is polymerization-sensitive and thus not
storage-stable, additionally toxic and potentially carcinogenic.
The Mitsunobu reaction in the preparation of compound (II) is
technically costly and inconvenient, one reason being that
racemization occurs readily in relatively large batches. Another
reason is that the atom economy is extremely unsatisfactory, since
triphenylphosphine oxide and diisopropyl azodicarboxylate hydrazide
are generated in stoichiometric amounts as waste materials. In
addition, the nitrogen atom in the oxazolidinone ring of the target
molecule (I) is introduced in phthalimide-protected form. However,
the phthalic acid radical as a protecting group has to be removed
in the further course of the synthesis, which means an increase in
the number of stages and additional waste.
[0008] It is thus an object of the present invention to provide a
simplified process for preparing the compound of the formula (I) in
large amounts.
[0009] It has been found that, surprisingly, the compound of the
formula (I) can be prepared in improved yield in a shortened
reaction sequence using storage-stable and less toxic starting
materials, starting from 5-chlorothiophene-2-carbonyl chloride
(IV), (2S)-3-aminopropane-1,2-diol hydrochloride (VII) and
4-(4-aminophenyl)-3-morpholinone (III). In this reaction sequence,
the use of protecting groups is also avoided, which reduces the
number of stages and thus shortens the reaction time.
[0010] In the first step of the process according to the invention,
5-chlorothiophene-2-carbonyl chloride (IV) ##STR4## is prepared
from 5-chlorothiophene-2-carboxylic acid.
[0011] Compound (IV) may be prepared under the customary reaction
conditions for the preparation of carbonyl chlorides from the
corresponding carboxylic acids. Preference is given to the reaction
of 5-chlorothiophene-2-carboxylic acid with thionyl chloride as the
chlorinating reagent in toluene as the solvent.
[0012] In the second step of the process according to the
invention, 5-chlorothiophene-2-carbonyl chloride (IV) is reacted
with (2S)-3-aminopropane-1,2-diol hydrochloride (VII) ##STR5## to
give N--((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide
(VIII) ##STR6##
[0013] The reaction (IV)+(VII).fwdarw.(VIII) may be effected under
the reaction conditions customary for the formation of amide bonds
from the appropriate carbonyl chlorides and amines. Preference is
given to a biphasic system composed of aqueous sodium
hydrogencarbonate solution and 2-methyltetrahydrofuran as the
organic solvent. (2S)-3-Aminopropane-1,2-diol is used in the form
of the free base or in the form of the acid addition salt.
Preference is given to the hydrochloride (VII) which crystallizes
better than the free base and can therefore be handled readily. To
increase the reaction yield, optionally either an excess of amine
is used or an auxiliary base is added. The addition of from 1 to 3,
preferably 2, equivalents of an auxiliary base such as sodium
hydrogencarbonate is preferred. The reaction is effected generally
within a temperature range of from 0.degree. C. to 40.degree. C.,
preferably of from 5.degree. C. to 30.degree. C.
[0014] In the third step of the process according to the invention,
N--((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII)
is converted to
N--((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide
(IX) ##STR7##
[0015] The reaction (VIII).fwdarw.(IX) is carried out with from 1
to 5, preferably from 3 to 5, in particular 4, equivalents of a
solution of hydrobromic acid in acetic acid, optionally in the
presence of acetic anhydride. The reaction temperature is between
20.degree. C. and 80.degree. C., preferably between 60 and
65.degree. C. The amount of methanol added may be varied over a
wide range; preference is given to using from 40 to 80 mol, in
particular from 50 to 60 mol, of methanol per mole of (VIII). For
the workup, the solvents are distilled off, preferably under
reduced pressure. The remaining distillation residue is optionally
also neutralized before the filtration of the product.
[0016] In the fourth step of the process according to the
invention,
N--((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide
(IX) is reacted with 4-(4-aminophenyl)-3-morpholinone (III)
##STR8## to give
N--{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorot-
hiophene-2-carboxamide (X) ##STR9##
[0017] The solvent for the reaction (IX)+(III).fwdarw.(X) may be
varied widely; preference is given to toluene. The reaction
temperature is between 80.degree. C. and 200.degree. C.; preference
is given to a range between 90.degree. C. and 110.degree. C. The
reaction is effected optionally in the presence of an auxiliary
base, for example triethylamine, diisopropylethylamine or
collidine; preference is given to using collidine. The
stoichiometry of the reaction and the reaction time are variable
over a wide range; preference is given to a ratio of compound (IX)
to compound (III) to collidine of 1.2 to 1.0 to 1.0 and a reaction
time of from 4 to 8 hours, especially of from 5 to 6 hours.
[0018] In the fifth step of the process according to the invention,
N--{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorot-
hiophene-2-carboxamide (X) is reacted with phosgene or a phosgene
equivalent to give
5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin--
5-yl}methyl)-2-thiophene-carboxamide (I).
[0019] In the reaction (X).fwdarw.(I), one or more equivalents of
phosgene or phosgene equivalents are used in the presence of inert
solvents or solvent mixtures. Phosgene equivalents are, for
example, phosgene replacements such as di- or triphosgene, or
carbon monoxide equivalents, for example N,N-carbonylbisimidazole.
Preference is given to using from 1 to 2 equivalents, in particular
from 1.1 to 1.3 equivalents, of N,N-carbonylbisimidazole in a
solvent mixture of 1-methyl-2-pyrrolidone and toluene. For
purification of the product, a clarifying filtration and/or a
recrystallization optionally follows. The reaction is effected
generally within a temperature range of from 20.degree. C. to
150.degree. C., preferably of from 30.degree. C. to 110.degree. C.,
in particular of from 75.degree. C. to 85.degree. C.
[0020] The individual stages of the process according to the
invention may be carried out at standard, elevated or at reduced
pressure (for example of from 0.5 to 5 bar). In general, standard
pressure is used.
[0021] The following scheme summarizes the synthesis: ##STR10##
[0022] The invention is illustrated in detail below by a preferred
working example, to which it is not, however, restricted. Unless
stated otherwise, all quantitative data relates to percentages by
weight.
Synthesis of
5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin--
5-yl}methyl)-2-thiophenecarboxamide (I)
1st Step
5-Chlorothiophene-2-carbonyl chloride (IV)
[0023] 53.6 g of 5-chlorothiophene-2-carboxylic acid (commercially
available) are suspended in 344 g of toluene and heated to
80.degree. C. At this temperature, 47.2 g of thionyl chloride are
added dropwise over a period of 20 minutes, then the mixture is
stirred at from 75 to 80.degree. C. for 30 minutes and then at
reflux temperature for two hours until completion of gas evolution.
After cooling, the reaction mixture is concentrated to a volume of
approx. 200 ml at from 30 to 35.degree. C. and a pressure of from
40 to 48 mbar. The thus obtained solution of the acid chloride in
toluene is reacted directly in the next stage.
2nd Step
N--((S)-2,3-Dihydroxypropyl)-5-chlorothiophene-2-carboxamide
(VIII)
[0024] 461 g of sodium hydrogencarbonate and 350 g of
(2S)-3-aminopropane-1,2-diol hydrochloride (VII) (commercially
available) are initially charged at from 13 to 15.degree. C. in 2.1
l of water and admixed with 950 ml of 2-methyltetrahydrofuran.
535.3 g of 5-chlorothiophene-2-carbonyl chloride (approx. 93%) in
180 ml of toluene are added dropwise to this mixture with cooling
at from 15 to 18.degree. C. over a period of two hours. For workup,
the phases are separated and the organic phase is admixed in
several steps with a total of 1.5 l of toluene. The precipitated
product is filtered off with suction, washed with ethyl acetate and
dried.
[0025] Yield: 593.8 g; corresponds to 91.8% of theory.
[0026] Melting point: 114 to 114.5.degree. C.
3rd Step
N--((S)-3-Bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide
(IX)
[0027] 301.7 ml of a 33% solution of hydrobromic acid in acetic
acid are added to a suspension of 100 g of
N--((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII)
in 250 ml of glacial acetic acid at from 21 to 26.degree. C. over a
period of 30 minutes. Subsequently, 40 ml of acetic anhydride are
added and the reaction mixture is stirred at from 60 to 65.degree.
C. for three hours. At 20 to 25.degree. C., 960 ml of methanol are
then added over a period of 30 minutes. The reaction mixture is
stirred under reflux for 2.5 hours and then overnight at from 20 to
25.degree. C. For workup, the solvents are distilled off under
reduced pressure at approx. 95 mbar. The remaining suspension is
admixed with 50 ml of 1-butanol and 350 ml of water. The
precipitated product is filtered off with suction, washed with
water and dried.
[0028] Yield: 89.8 g; corresponds to 70.9% of theory.
[0029] Melting point: 120.degree. C.
4th Step
N--{(R)-2-Hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chloro-t-
hiophene-2-carboxamide (X)
[0030] 55 g of
N--((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide
(IX) and 29.4 g of 4-(4-aminophenyl)-3-morpholinone (III) (a
preparation method is described, for example, in WO-A 01/47919 on
pages 55 to 57) are suspended at from 20 to 25.degree. C. in 500 ml
of toluene and admixed with 18.5 g of collidine and 10 ml of
ethanol. The reaction mixture is heated to from 103 to 105.degree.
C. for 6 hours and then admixed while hot with 50 ml of 1-butanol.
After cooling to 30.degree. C., the precipitated reaction product
is filtered off with suction, washed with toluene and water and
dried.
[0031] Yield: 42.0 g; corresponds to 61.8% of theory.
[0032] Melting point: 198.5.degree. C.
5th Step
5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-
-yl}methyl)-2-thiophenecarboxamide (I)
[0033] 25 g of
N--{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorot-
hiophene-2-carboxamide (X) are suspended at from 20 to 25.degree.
C. in 250 ml of toluene and admixed with 37.5 ml of
1-methyl-2-pyrrolidone and 11.9 g of N,N-carbonyldiimidazole. The
reaction mixture is heated to from 80 to 83.degree. C. for 20
minutes and subsequently heated to 115.degree. C. for one hour.
After cooling to 20.degree. C., the precipitated reaction product
is filtered off with suction, washed twice with 25 ml each time of
water and dried at 60.degree. C. under reduced pressure.
[0034] Yield: 23.7 g; corresponds to 91.5% of theory.
[0035] Melting point: 230.degree. C.
* * * * *