(19)
&
(11)
EP 1 991 534 B1
EUROPEAN PATENT SPECIFICATION
(12)
(45) Date of publication and mention
(51) Int Cl.:
C07D 265/30 (2006.01)
of the grant of the patent:
18.11.2009 Bulletin 2009/47
(86) International application number:
PCT/IT2007/000088
(21) Application number: 07713445.0
(87) International publication number:
(22) Date of filing: 12.02.2007
WO 2007/094022 (23.08.2007 Gazette 2007/34)
(54) PROCESS FOR THE PREPARATION OF 2-(4-HYDROXY-3-MORFOLYNIL)-2-CYCLOHEXENONE
VERFAHREN ZUR HERSTELLUNG VON 2-(4-HYDROXY-3-MORPHOLINYL)-2-CYCLOHEXENON
PROCÉDÉ POUR LA PRÉPARATION DE 2-(4-HYDROXY-3-MORPHOLINYL)-2-CYCLOHEXÉNONE
(84) Designated Contracting States:
(74) Representative: Cattaneo, Elisabetta et al
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR
HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI
SK TR
(30) Priority: 13.02.2006 IT MI20060258
(43) Date of publication of application:
Notarbartolo & Gervasi S.p.A.
Corso di Porta Vittoria, 9
20122 Milano (IT)
(56) References cited:
EP-A2- 0 314 147
WO-A-2004/111021
EP-A2- 1 518 536
DE-B- 1 004 191
19.11.2008 Bulletin 2008/47
(73) Proprietor: ABIOGEN PHARMA S.p.A.
56014 Ospedaletto (Pisa) (IT)
• JOHN S. BROWN: "Oxidation of reduced
nicotinamide nucleotides by diamide" BIOCHEM.
J., vol. 124, 1971, pages 665-667, XP002439691
(72) Inventor: NAPOLITANO, Elio
EP 1 991 534 B1
I-56100 Pisa (IT)
Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent
Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the
Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been
paid. (Art. 99(1) European Patent Convention).
Printed by Jouve, 75001 PARIS (FR)
1
EP 1 991 534 B1
Description
[0001] The present invention concerns a process for
the preparation of 2-(4-hydroxy-3-morpholynil)-2-cyclohexenone starting from N-hydroxymorpholine. The invention concerns also a new process for the preparation
of hydroxylamines, particularly N-hydroxymorpholine.
[0002] The compound 2-(4-hydroxy-3-morpholynil)-2cyclohexenone of Formula I
5
10
15
20
also known as BTG-1675A, is a substance which has
been recently described in the International application
n. PCT/GB2004/002324 (Publication n. WO2004/111021) as medicament for the treatment of depression
and anxiety, particularly for the treatment of anxiogenesis
caused by withdrawal from benzodiazepines, or caused
by abruptly ceasing the administration of substances
such as nicotine, alcohol and cocaine.
[0003] According to the International document, BTG1675A is obtained by a process which provides for the
reaction between a nitrone, i.e. a compound of Formula II
2
a) oxidising morpholine in order to produce the compound of Formula II, through a reaction of a catalysed
oxydation;
b) adding cyclohexenone; and
c) isolating and purifying BTG-1675A through distillation and chromatography.
[0005] As described in the example 1 of the cited international application, the step a) of reaction occurs at
a reaction temperature of 0°C for about an hour and half,
by using an excess of hydrogen peroxide as oxidant and
sodium tungstate as catalyst. In the same reaction vessel
cyclohexenone (of Formula III) of step b) is then added
and the cyclohexenone reacts with the nitrone of Formula
II, which is formed in situ after the step a), for further 48
hours in a temperature range from the room temperature
to 100°C. Subsequently the reaction mixture is heated
at a temperature of about 55 °C for two hours and then
at 65 °C for further 2 hours. As indicated in the document,
the formation of a intermediate of Formula IV (cycloaddition compound),
25
30
35
40
45
and cyclohexenone of Formula III
50
55
[0004] Specifically, in the International document,
BTG-1675A is obtained by a process which provides for
the following steps:
2
is obtained, from which the compound of the invention is
obtained in situ either by protonation or by basic catalysed reaction.
[0006] Although such a process is very simple in its
realization, it shows the drawback of producing only few
grams of BTG-1675A with a yield of only about 14%,
which makes it unsuitable for the application on industrial
scale. Furthermore, such a yield of 14% is obtained owing
to a complicated chromatographic purification process
which produces a considerable amount of waste products.
[0007] In order to increase the yield many attempts
were made by trying to make amendments of the reaction
condition or by applying recent methods of conversion
of morpholine to nitrone, i.e. the compound of Formula
II. All such attempts turned out to be vain, because from
the analysis of the reaction mixture an incomplete oxidation of morpholine, scarce conversion of the compound
of Formula IV, presence of high amount of N-hydroxymorpholine, spread decomposition of the reaction crude
material in the distillation were revealed, by obtaining
substantially scarce production of the compound of interest (Forcato, M.; Nugent, W. A.; Licini, G. Tetrahedron
3
EP 1 991 534 B1
Lett. 2003, 44, 49; Murray, R. W.; Iyanar, K. J. Org. Chem.
1996, 61, 8099; Goti, A.; Nannelli, L. Tetrahedron Lett.
1996, 37, 6025).
[0008] It is still felt the need of a process which allows
to obtain BTG-1675A in an amount of hundred grams
and which is therefore suitable to such a production on
industrial scale.
[0009] Therefore, an object of the present invention is
to obtain a high amount of BTG-1675A through a process
which is convenient for the production on industrial scale.
[0010] It is a further object of the invention to obtain
the compound BTG-1675A in high yield and purity so as
to be used as medicament.
[0011] Such objects have been achieved by a process
so as indicated in Claim 1. The process according to the
invention comprises the steps of:
5
10
15
i) reacting N-hydroxymorpholine of Formula V
20
25
with cyclohexenone of Formula III
30
35
in the presence of an oxidation agent thus obtaining
an isoxazolidine of Formula IV
40
45
50
and
ii) converting isoxazolidine of Formula IV into the
compound BTG-1675A.
[0012]
55
According to the invention, step i) occurs in the
3
4
presence of a wide variety of bland oxidation agents, preferably the metallic oxides such as mercury oxide, lead
dioxide, activated manganese dioxide and silver oxide.
[0013] In particular, mercury oxide allows an effective
oxidation of N-hydroxymorpholine according to the invention. However, its transformation during the oxidation
into metallic mercury is deemed slightly advantageous
on a wide scale process because of the high toxicity of
the metallic mercury. Activated manganese dioxide gives
less problems for its toxicity, but requires a difficult management of the manganese dioxides which are produced
by the reaction and whose elimination through the filtration from the apparatuses is hard.
[0014] In the attempt of searching alternative solutions, the inventors of the present invention have surprisingly found out that ester and amide derivatives of the
azodicarboxylic acid are optimal oxidation agents which
allow the oxidation of N-hydroxymorpholine in the presence of cyclohexenone reaching yields which are comparable to the ones obtainable by mercury oxide or activated manganese dioxide without having their drawbacks. Among the ester derivatives, diethylazodicarboxylate, diisopropylazodicarboxylate, diethylazodicarboxylate supported on a polymeric material, di-tert-buthylazodicarboxylate, dibenzylazodicarboxylate can be cited.
Among the amide derivatives of the azodicarboxylic acid,
azodicarboxamide, 1,1’-(azodicarbonyl)dipiperidine and
the cyclic derivative 1-phenyl-1,2,4-triazoline-2,5-dione
can be cited.
[0015] In still another aspect of the invention, the invention pertains the use of the ester and amide derivatives of the azodicarboxylic acid as oxidation agents . In
particular, ester and amide derivatives of azodicarboxylic
acid can be used for the oxidation of hydroxylamine. In
the present description the term "hydroxylamine" is intended as a secondary amine having alicyclic or cyclic
chain and which is N-hydroxy substituted. More preferably, such derivatives are used for the oxidation ofN-hydroxymorpholine according to claim 21.
[0016] Preferably, the oxidation agent of the process
according to the invention is azodicarboxamide. Such a
substance is known in industry as anti-foaming agent in
polymers and as additive in bread. The cost of azocarboxamide is low, particularly if compared to mercury oxide and activated manganese dioxide, which, besides
having a higher prize on the market, are generally used
in great excess. Advantageously, azodicarboxamide,
used in step i) of the process according to the invention,
turns into hydrazodicarboxamide which is a practically
insoluble solid in the reaction mixture and therefore can
be easily removed by filtration. More advantageously,
the so obtained hydrazodicarboxamide can be retransformed into azodicarboxamide, through an oxidation reaction with e.g. hydrogen peroxide or electrochemically.
Therefore the process according to the invention, when
the oxidation agent is azodicarboxamide, can provide a
step of recycling the oxidation agent by means of transformation of hydrazodicarboxamide into azodicarboxa-
5
EP 1 991 534 B1
mide.
[0017] The reaction between N-hydroxymorpholine
and cyclohexenone in the presence of the oxidation
agent of step i) occurs preferably in less than one hour
and at a temperature from 40 to 100 °C, still more preferably at about 70°C. The reaction of step i), apart from
the oxidation agent, allows yields of the product of Formula IV higher than at least 50% and when the oxidation
agent is selected from the group consisting of mercury
oxide, activated manganese oxide and azodicarboxamide the yield will be preferably about 75%.
[0018] N-hydroxymorpholine is a known compound
which is accessible through different routes (O’Neil, I.A.;
Cleator, E. T Tetrahedron Lett. 2001, 42, 8247; Rogers
M. A. T. J Chem. Soc. 1955, 769). It is surprisingly found
that it is possible to obtain N-hydroxymorpholine by a
synthetic route which is alternative to the known ones,
thus obtaining it with yield and purity levels suitable to
the aim according to the process and in a more convenient way. In another aspect therefore the invention concerns a process to obtain hydroxylamines, which comprises the step of reacting a secondary amine with an
oxidation agent in excess, in the presence of catalytic
amount of a ketone which is particularly electrophilic. The
term "particularly electrophilic ketone" is intended as a
ketonic organic compound capable to accept electrons
such as e.g. trihydrate hexafluoro acetone, ninidrine;
preferably it is trihydrate hexafluoro acetone. Preferably
according to the invention such a process allows to obtain
N-hydroxymorpholine. The product N-hydroxymorpholine is so obtained by starting from morpholine, with yield
of 95% and purity of 85%.
[0019] Advantageously, N-hydroxymorpholine can be
further purified by precipitating the salt which it forms with
p-toluenesulfonic acid. N-hydroxymorpholine is so obtained by decomposition with sodium carbonate in acetone. The yield according to this process is of about 60%
with respect to the initial morpholine.
[0020] In order to obtain N-hydroxymorpholine according to claim 16 the oxidation agent is preferably hydrogen
peroxide or hydrogen peroxide-urea complex. Still more
preferably such an oxidation agent is hydrogen peroxide
in excess.
[0021] Preferably the oxidation reaction of morpholine
to N-hydroxymorpholine occurs at a temperature from 20
to 80 °C, still more preferably at about 50 °C.
[0022] N-hydroxymorpholine obtained according to
the invention, either raw or purified, is preferably used
as a starting reagent to obtain BTG-1675A according to
the invention. According to such a process by means of
the reaction with cyclohexenone in the presence of oxidation agent, N-hydroxymorpholine turns into isoxazolidine of Formula IV, which is converted into BTG-1675A
in the subsequent step ii). Such a conversion reaction is
advantageously promoted either thermally or by basic
catalysis.
[0023] In case of basic catalysis, when a bland basic
catalyst is used, e.g. triethylamine in methanol or stoichi-
5
10
15
20
25
30
6
ometric amount of NaOH in methanol, BTG-1675A is
slowly formed thus producing a mixture in equilibrium in
which the compound of Formula IV and BTG-1675A are
in a ratio of 2:3. Advantageously the use of an excess of
sodium metoxide in order to shift the equilibrium to BTG1675A can be used.
[0024] In the present invention from the reaction promoted by the basic catalysis, preferably through triethylamine in-hot methanol, advantageously BTG-1675A can
be obtained as a pure compound with yield of 45%
through trituration in an aromatic hydrocarbon, wherein
isoxazolidine of Formula IV is considerably more soluble.
From the evaporation of mother waters of the trituration,
pure BTG-1675A can advantageously be obtained. In
such a way, according to the present invention, by taking
into account the recovery material which has not been
converted, it is hence possible to obtain a transformation
of isoxazolidine into BTG-1675A with yield of about 90%.
Preferably the aromatic hydrocarbon for the trituration is
toluene or benzene, still more preferably toluene.
[0025] The conversion of isoxazolidine of Formula IV
into the compound BTG-1675A and the subsequent trituration in an aromatic hydrocarbon are, in the process
according to the invention, advantageous and useful solutions to obtain BTG-1675A on an industrial scale.
[0026] Examples of preparation of N-hydroxymorpholine and BTG-1675A, which are given for exemplificative
and non-limitative purposes, now follow.
Example 1
Preparation of N-hydroxymorpholine
35
40
45
50
55
4
[0027] To a solution containing morpholine (174 mL,
2 mol) and hexafluoroacetone trihydrate (3 mL, 21 mmol)
in acetone (350 mL), kept under mechanical stirring in a
three necked round bottom flask (surmounted by a reflux
condenser), H2O2 (200 mL of a solution 30%, 3,6 mol)
was added dropwise. The addition was followed by a
progressive increasing of temperature and, after the addition of about 50 mL, the solution started to vigorously
reflux; the addition was adjusted so as to keep a constant
reflux. When the addition was over, the solution was left
to stir for one hour and then evaporated under reduced
pressure by a rotavapor, while the temperature of the
bath was kept at 50 °C. The reddish yellow residue of
the evaporation was suspended in ethylacetate (500 mL)
and the mixture saturated with sodium chloride; the organic phase of the solution (the upper layer) was then
separated and the aqueous phase extracted twice with
ethyldiacetate (250 mL). The collected organic extracts
were dried on anhydrous sodium carbonate (20 g) and
evaporated at reduced pressure by rotavapor, while the
temperature of the bath was kept to 50 °C. Raw N-hydroxymorpholine was then obtained (190 g, 92%, yield
85% purity, the remaining being mainly constituted by
unreacted morpholine). Raw N-hydroxymorpholine was
then used for the preparation of BTG-1675A.
7
EP 1 991 534 B1
A sample (1 g, 10 mmol) of the raw obtained N-hydroxymorpholine was purified through the following method:
[0028] The sample was dissolved in acetone (10 mL);
in the solution so obtained and heated, p-toluenesulphonic acid was dissolved (1,9 g, 10 mmol); from the
mixture brought to 4 °C, p-toluenesulfonate of N-hydroxymorpholine (1,9 g, 65%) was separated as a white crystalline solid: m.p. 152-154 °C. 1H-NMR (DMDO-d6) 2.27
(3H, s), 1.54 (2H, m) 3.54-3.69 (4H, m), 3.97 (2H,m),
7.14 (2H, d, J=8 Hz), 7.51 (2H, d, J=8 Hz), 13C-NMR
(CDCl3): 20.9, 55.5, 62.6, 125.6, 128.5, 138.6, 144.6.
The salt so obtained was added to a suspension of anhydrous sodium carbonate (1 g, 10 mmol) in acetone (20
mL) and the mixture was magnetically stirred for 12
hours; the solid was then removed by filtration and from
the evaporation of the filtrate, purified N-hydroxymorpholine (0,65 g, 100%) was obtained as colourless oil. 1HNMR (CDCl3) 2.54 (2H, t, J=11 Hz), 3.04 (2H, d, J=11
Hz) 3.49, (2H, t, J=11 Hz), 3.80 (2H, d, J=11 Hz), 7.9
(1H, bs). 13C-NMR(CDCl3): 58.9, 66.6.
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Example 2
Preparation of 2-(4-hydroxy-3-morpholinyl)-2-cyclohexenone (BTG-1675A)
25
Step i) Reaction of N-hydroxymorpholine with cyclohexenone and production of isoxazolidine of Formula IV
30
[0029] A mixture containing raw N-hydroxymorpholine
obtained by Example 1 (190 g), 2-cyclohexenone (120
mL, 1,25 mol) and azodicarboxamide (235 g, 2 mol) in
ethylacetate (500 mL), which was kept under mechanical
stirring in a round bottom flask surmounted by a reflux
condenser, was cautiously heated until the reaction became exothermic, thus allowing the mixture to spontaneously reflux; at the end of the spontaneous heating,
the mixture was heated to reflux for 4 hours. In this time,
the bright yellow solid of azodicarboxamide turned into
a whitish solid. The still warm content of the round bottom
flask was then transferred in a glass column provided
with a porous septum and the solution was filtered by
applying pressure; the solid in the column was washed
with hot ethylacetate (400 mL). The collected filtrates
were evaporated under reduced pressure to give a semisolid residue to which methanol was added (200 mL);
the mixture was firstly heated in order to triturate the semisolid mass and solubilize the oily fraction, then let it to
cool at -20 °C; isoxazolidine of Formula IV (130 g, 54%
with respect to cyclohexenone) was collected as colourless crystalline solid; m.p. 101-102 °C. 13C-NMR (CDCl3)
17.8, 28.1, 39.2, 50.4, 53.2, 64.6, 65.6, 66.1, 76.0, 210.9.
Step ii) Conversion of isoxazolidine of Formula IV into
the compound BTG-1675A
[0030]
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8
IV obtained as above in step i) (500 g, 2,5 mol), triethylamine (100 mL) and methanol (1 L) was heated to reflux
for 24 hours and thus evaporated under reduced pressure. The residue was suspended in toluene (1,3 L) and
a portion of solvent was evaporated under reduced pressure in a rotavapor (bath temperature: 70°C) until the
distillate was clear; the volume of the mixture was brought
to about 800 mL, by adding toluene and the mixture was
cooled in a bath of water and ice. The precipitate was
collected by filtration under vacuum and washed once
with cold toluene to give a mixture of isoxazolidine of
Formula IV and BTG-1675A as a colourless crystalline
mass (490g, 98%). The mass was suspended in toluene
(1 L) preheated at 70 °C and the mixture was kept under
vigorous stirring while it was left to re-equilibrate with the
room temperature; the solid, collected by filtration under
vacuum, was subjected still twice to the above described
cycle of trituration in hot toluene followed by cooling and
filtering; thus pure BTG-1675A (230 g, 46%, 90% based
on the amount of collected mixture of isoxazolidine and
BTG-1675A; purity higher than 98%) was obtained as a
crystalline solid of ice-white colour; m.p. 127-128 °C. 1HNMR (CDCl3) 1.96 (2H, m), 2.41 (4H, m), 2.83 (1H, dt, J
= 3.5 and 11.5 Hz), 3.06 (1H, t, J = 11.5 Hz), 3.20 (1H,
d, J = 11 Hz), 3.54-3.90 (4H, m), 5.45 (1H, bs), 7.12 (1H,
t, 4.3 Hz). 13C-NMR (CDCl3): 23.2, 26.5, 38.9, 58.9, 64.5,
67.2, 71.9, 136.2, 148.8, 199.1. The collected filtrates
coming from triturations were evaporated to give a residue from which a mixing consisting of isoxazolidine and
BTG-1675A in the ratio of 5:1 (245 g, 49%) was obtained
by trituration in cold ethylether.
[0031] As the above example shows, the process according to the invention allows to obtain 2-(4-hydroxy-3morpholinyl)-2-cyclohexenone in an amount of hundreds
of grams and with high yields, which makes the process
according to the invention suitable for producing BTG1675A on an industrial scale.
[0032] Furthermore BTG-1675A obtained by the process according to the invention can be advantageously
purified and used as a medicament.
[0033] The invention was described with reference to
two examples of preparation, but modifications, such as
the use of a different oxidation agent, can be provided
without going beyond the scope of protection of the appended claims.
Claims
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A mixture consisting of isoxazolidine of Formula
5
1.
A process for the preparation of 2-(4-hydroxy-3-morpholinyl)-2-cyclohexenone of Formula I
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EP 1 991 534 B1
10
ylic acid.
3.
The process according to claim 2 wherein the oxidation agent is selected from the group consisting
of mercury oxide, lead dioxide, activated manganese
dioxide, silver oxide, diethylazodicarboxylate, diisopropylazodicarboxylate and azodicarboxamide.
4.
The process according to claim 3 wherein the oxidation agent is mercury oxide or activated manganese dioxide.
5.
The process according to claim 3 wherein the oxidation agent is azodicarboxamide.
6.
The process according to claim 5 further comprising
a step of recycling of the oxidation agent azodicarboxamide through separation of the reaction product
hydrazodicarboxamide obtained by step i) and its
conversion into azodicarboxamide.
7.
The process according to any one of claims from 1
to 6, wherein the step i) occurs in less than one hour
and at a temperature from 40 to 100°C, preferably
at about 70°C.
8.
The process according to any one of previous claims
from 1 to 7, wherein the yield of isoxazolidine of Formula IV is higher than at least 50%.
9.
The process according to any one of claims 1, 4, 5
and 8 wherein the yield of isoxazolidine is about 75%.
5
10
comprising the steps of:
i) reacting N-hydroxymorpholine of Formula V
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20
25
with cyclohexenone of Formula II
30
35
in the presence of an oxidation agent thus obtaining an isoxazolidine of Formula IV
40
45
10. The process according to any one of claims from 1
to 9, wherein the conversion of step ii) is carried out
thermally or by basic catalysis.
11. The process according to claim 10, wherein the conversion is carried out by basic catalysis by means of
a basic catalyst selected from triethylamine in methanol and NaOH in methanol:
12. The process according to claim 10 or 11 wherein
2-(4-hydroxy-3-morpholinyl)-2-cyclohexenone
is
obtained pure by trituration in an aromatic hydrocarbon.
13. The process according to claim 12, wherein the aromatic hydrocarbon is toluene or benzene.
50
14. The process according to claim 13 wherein the aromatic hydrocarbon is toluene.
and
ii) converting isoxazolidine of Formula IV into
2-(4-hydroxy-3-morpholinyl)-2-cyclohexenone.
55
2.
The process according to claim 1 wherein the oxidation agent is selected from the group consisting
of metal oxides, esters and amides of azodicarbox-
15. The process according to claim 14 wherein 2-(4-hydroxy-3-morpholinyl)-2-cyclohexenone is obtained
with yield of about 45%.
16. The process according to any one of claims 1 to 15,
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EP 1 991 534 B1
wherein N-hydroxymorpholine of step i) is N-hydroxymorpholine obtained by the process comprising the
step of reacting morpholine with an oxidation agent
in excess, in the presence of catalytic amounts of a
particularly electrophilic ketone.
12
5
17. The process according to claim 16, wherein the oxidation agent is hydrogen peroxide in excess or a
hydrogen peroxide-urea complex.
10
18. The process according to claim 17 wherein the oxidation agent is hydrogen peroxide in excess.
19. The process according to any one of claims 16 to
18, wherein the particularly electrophilic ketone is
trihydrate hexafluoro-acetone or ninidrine.
20. The process according to claim 19, wherein the particularly electrophilic ketone is hexafluoro-acetone
trihydrate.
15
mit Cyclohexenon gemäß der Formel II
20
21. Use of ester or amide derivative of azodicarboxylic
acid for oxidizing N-hydroxymorpholine.
22. Use of claim 21, wherein the amide derivative of
azodicarboxylic acid is azodicarboxamide.
25
Patentansprüche
30
1.
Verfahren zur Herstellung von 2-(4-Hydroxy-3-morpholinyl)-2-cyclohexenon gemäß der Formel I
in der Gegenwart eines Oxidationsmittels, um
so ein Isoxazolidin gemäß der Formel IV zu erhalten
35
40
45
umfassend die Schritte:
i) Reagieren von N-Hydroxymorpholin gemäß
der Formel V
50
und
ii) Umsetzen des Isoxazolidins gemäß der Formel IV zu 2-(4-Hydroxy-3-morpholinyl)-2-cyclohexenon.
55
2.
7
Verfahren nach Anspruch 1, wobei das Oxidations-
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EP 1 991 534 B1
mittel aus der Gruppe ausgewählt wird, welche aus
Metalloxiden, Estern und Amiden von Azodicarbonsäure besteht.
3.
Verfahren nach Anspruch 2, wobei das Oxidationsmittel aus der Gruppe ausgewählt wird, welche aus
Quecksilberoxid, Bleidioxid, aktiviertem Mangandioxid, Silberoxid, Diethylazodicarboxylat, Diisopropylazodicarboxylat und Azodicarboxamid besteht.
4.
Verfahren nach Anspruch 3, wobei das Oxidationsmittel Quecksilberoxid oder aktiviertes Mangandioxid ist.
3-morpholinyl)-2-cyclohexenon mit einer Ausbeute
von ungefähr 45 % erhalten wird.
5
10
5.
6.
7.
Verfahren nach Anspruch 3, wobei das Oxidationsmittel Azodicarboxamid ist.
Verfahren nach Anspruch 5, welches des Weiteren
den Schritt des Recyclens des Oxidationsmittels
Azodicarboxamid durch Abtrennen des Reaktionsproduktes Hydrazodicarboxamid, welches in dem
Schritt i) erhalten wird, und dessen Umsetzung zu
Azodicarboxamid umfasst.
16. Verfahren nach einem der Ansprüche 1 bis 15, wobei
das N-Hydroxymorpholin des Schritts i) N-Hydroxymorpholin ist, welches durch ein Verfaharen erhalten
worden ist, welches den Schritt des Reagierens von
Morpholin mit einem Oxidationsmittel in Überschuss
in der Gegenwart von katalytischen Mengen eines
besonderen elektrophilen Ketons umfasst.
17. Verfahren nach Anspruch 16, wobei das Oxidationsmittel Wasserstoffperoxid in Überschuss oder ein
Wasserstoffperoxid-Harnstoff-Komplex ist.
15
18. Verfahren nach Anspruch 17, wobei das Oxidationsmittel Wasserstoffperoxid in Überschuss ist.
20
19. Verfahren nach einem der Ansprüche 16 bis 18, wobei das besondere elektrophile Keton Hexafluoraceton-Trihydrat oder Ninhydrin ist.
20. Verfahren nach Anspruch 19, wobei das besondere
elektrophile Keton Hexafluoraceton-Trihydrat ist.
Verfahren nach einem der Ansprüche 1 bis 6, bei
dem der Schritt i) in weniger als einer Stunde und
bei einer Temperatur von 40 bis 100°C, vorzugsweise bei ungefähr 70°C, durchgeführt wird.
25
8.
Verfahren nach einem der vorherigen Ansprüche 1
bis 7, wobei die Ausbeutung von Isoxazolidin gemäß
der Formel IV höher als wenigstens 50 % ist.
30
9.
Verfahren nach einem der Ansprüche 1, 4, 5 und 8,
wobei die Ausbeute von Isoxazolidin ungefähr 75 %
beträgt.
21. Verwendung eines Esters oder eines Amidderivats
von Azodicarbonsäure zum Oxidieren von N-Hydroxymorpholin.
22. Verwendung nach Anspruch 21, wobei das Amidderivat von Azodicarbonsäure Azodicarboxamid ist.
Revendications
35
1.
10. Verfahren nach einem der Ansprüche 1 bis 9, wobei
die Umsetzung gemäß dem Schritt ii) thermisch oder
durch basische Katalyse durchgeführt wird.
40
11. Verfahren nach Anspruch 10, wobei die Umsetzung
durch Basenkatalyse mittels eines Basenkatalysators, welcher aus Triethylamin in Methanol und NaOH in Methanol ausgewählt wird, durchgeführt wird.
45
12. Verfahren nach Anspruch 10 oder 11, wobei reines
2-(4-Hydroxy-3-morpholinyl)-2-cyclohexenon durch
Triturierung in einem aromatischen Kohlenwasserstoff erhalten wird.
50
Procédé pour la préparation de 2-(4-hydroxy-3-morpholinyl)-2-cyclohexénone de formule I
comportant les étapes consistant à :
i) faire réagir de la N-hydroxymorpholine de formule V
13. Verfahren nach Anspruch 12, wobei der aromatische
Kohlenwasserstoff Toluol oder Benzol ist.
14. Verfahren nach Anspruch 13, wobei der aromatische
Kohlenwasserstoff Toluol ist.
14
55
15. Verfahren nach Anspruch 14, wobei 2-(4-Hydroxy-
8
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EP 1 991 534 B1
16
outre une étape de recyclage de l’agent d’oxydation
azodicarboxamide par séparation du produit de
réaction hydrazodicarboxamide obtenu par l’étape
i) et sa conversion en azodicarboxamide.
5
7.
Procédé selon l’une quelconque des revendications
1 à 6, dans lequel l’étape i) a lieu en moins d’une
heure et à une température de 40 à 100 C, de préférence à environ 70°C.
8.
Procédé selon l’une quelconque des revendications
1 à 7 précédentes, dans lequel le rendement en
isoxazolidine de formule IV est supérieur à au moins
50 %.
9.
Procédé selon l’une quelconque des revendications
1, 4, 5 et 8, dans lequel le rendement en isoxazolidine
est d’environ 75 %.
10
avec une cyclohexénone de Formule II
15
20
en présence d’un agent d’oxydation obtenant
ainsi une isoxazolidine de formule IV
25
et
ii) convertir l’isoxazolidine de formule IV en 2-(4hydroxy-3-morpholinyl)-2-cyclohexénone.
2.
3.
Procédé selon la revendication 1, dans lequel l’agent
d’oxydation est choisi parmi le groupe constitué
d’oxydes métalliques, d’esters et d’amides d’acide
azodicarboxylique.
Procédé selon la revendication 2, dans lequel l’agent
d’oxydation est choisi parmi le groupe constitué
d’oxyde de mercure, de dioxyde de plomb, de dioxyde de manganèse activé, d’oxyde d’argent, de diéthylazodicarboxylate, de diisopropylazodicarboxylate et d’azodicarboxamide.
12. Procédé selon la revendication 10 ou 11, dans lequel
la 2-(4-hydroxy-3-morpholinyl)-2-cyclohexénone
est obtenue pure par trituration dans un hydrocarbure aromatique.
35
13. Procédé selon la revendication 12, dans lequel l’hydrocarbure aromatique est le toluène ou le benzène.
14. Procédé selon la revendication 13, dans lequel l’hydrocarbure aromatique est le toluène.
40
15. Procédé selon la revendication 14, dans lequel la
2-(4-hydroxy-3-morpholinyl)-2-cyclohexénone est
obtenue avec un rendement d’environ 45 %.
45
Procédé selon la revendication 3, dans lequel l’agent
d’oxydation est l’oxyde de mercure ou le dioxyde de
manganèse activé.
5.
Procédé selon la revendication 3, dans lequel l’agent
d’oxydation est l’azodicarboxamide.
6.
Procédé selon la revendication 5, comportant en
11. Procédé selon la revendication 10, dans lequel la
conversion est exécutée par catalyse basique au
moyen d’un catalyseur basique choisi parmi la triéthylamine dans le méthanol et NaOH dans le méthanol.
30
50
4.
10. Procédé selon l’une quelconque des revendications
1 à 9, dans lequel la conversion de l’étape ii) est
exécutée thermiquement ou par catalyse basique.
55
16. Procédé selon l’une quelconque des revendications
1 à 15, dans lequel la N-hydroxymorpholine de l’étape i) est la N-hydroxymorpholine obtenue par le procédé comportant l’étape consistant à faire réagir de
la morpholine avec un agent d’oxydation en excès,
en présence de quantités catalytiques d’une cétone
particulièrement électrophile.
17. Procédé selon la revendication 16, dans lequel
l’agent d’oxydation est du peroxyde d’hydrogène en
excès ou un complexe peroxyde d’hydrogène-urée.
18. Procédé selon la revendication 17, dans lequel
l’agent d’oxydation est du peroxyde d’hydrogène en
9
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EP 1 991 534 B1
excès.
19. Procédé selon l’une quelconque des revendications
16 à 18, dans lequel la cétone particulièrement électrophile est l’hexafluoroacétone trihydraté ou la ninhydrine.
20. Procédé selon la revendication 19, dans lequel la
cétone particulièrement électrophile est l’hexafluoroacétone trihydraté.
5
10
21. Utilisation d’un dérivé ester ou amide d’acide azodicarboxylique pour oxyder la N-hydroxymorpholine.
22. Utilisation selon la revendication 21, dans laquelle
le dérivé amide d’acide azodicarboxylique est l’azodicarboxamide.
15
20
25
30
35
40
45
50
55
10
18
EP 1 991 534 B1
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European
patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be
excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description
•
GB 2004002324 W [0002]
•
WO 2004111021 A [0002]
•
Goti, A. ; Nannelli, L. Tetrahedron Lett., 1996, vol.
37, 6025 [0007]
O’Neil, I.A. ; Cleator, E. T. Tetrahedron Lett., 2001,
vol. 42, 8247 [0018]
Rogers M. A. T. J Chem. Soc., 1955, 769 [0018]
Non-patent literature cited in the description
•
•
Forcato, M. ; Nugent, W. A. ; Licini, G. Tetrahedron
Lett., 2003, vol. 44, 49 [0007]
Murray, R. W. ; Iyanar, K. J. Org. Chem., 1996, vol.
61, 8099 [0007]
•
•
11