U.S. patent application number 11/006931 was filed with the patent office on 2005-05-05 for procedure for the preparation of racemic derivatives of 1,5-diaryl-3-trifluoromethyl-delta2-pyrazolines.
This patent application is currently assigned to Laboratories Del Dr. Esteve, S.A.. Invention is credited to Alcon-Marrugat, Monserrat, Cuberes-Altisen, Maria Rosa, Frigola-Constansa, Jordi, Pericas-Brondo, Miguel Angel.
Application Number | 20050096474 11/006931 |
Document ID | / |
Family ID | 8498105 |
Filed Date | 2005-05-05 |
United States Patent
Application |
20050096474 |
Kind Code |
A1 |
Alcon-Marrugat, Monserrat ;
et al. |
May 5, 2005 |
Procedure for the preparation of racemic derivatives of
1,5-diaryl-3-trifluoromethyl-delta2-pyrazolines
Abstract
Procedure for preparation of compounds with the general formula
1, which include the racemic mixtures (.+-.)-1, and the
enantiomerically pure compounds (-)-1 and (+)-1, wherein R.sub.1
and R.sub.3, like or different, represent an atom of hydrogen,
chlorine, fluorine, a methyl, trifluoromethyl or methoxy group;
R.sub.2 represents an atom of hydrogen, chlorine, fluorine, a
methyl, trifluoromethyl, methoxy, trifluoromethoxy, methylsulphonyl
or aminosulphonyl group; R.sub.4 represents an atom of hydrogen,
chlorine, fluorine, a methyl, trifluoromethyl, methoxy,
trifluoromethoxy, methylsulphonyl or aminosulphonyl group, with the
condition that one of the substituents R.sub.2 or R.sub.4 is a
methylsulphonyl or aminosulphonyl group; which involves obtaining
the racemic mixture with the general formula (.+-.)-1 by reacting
an (E)-1,1,1-trifluoro-4-aryl-3-buten-2-one with a phenylhydrazine,
followed by a treatment with chlorosulphonic acid, or by reacting
with chlorosulphonic acid followed by a reaction with sodium
hydroxide and, finally, with thionyl chloride. The product obtained
by either of these methods is made to react with ammonium carbonate
or ammonia, or with sodium sulphite and methyl iodide or methyl
sulphate. In addition, to obtain the enantiomerically pure
compounds with the general formula 1 by resolving the racemic
mixture with the general formula (.+-.)-1, a reaction is effected
with optically active ephedrine, followed by formation of the
sodium salt of each enantiomer, reaction with thionyl chloride and
ammonium carbonate or ammonia, or instead with thionyl chloride
followed by sodium sulphite and methyl iodide or methyl sulphate to
thereby obtain separately the enantiomerically pure compounds with
the general formulae (-)-1 and (+)-1. 1
Inventors: |
Alcon-Marrugat, Monserrat;
(Barcelona, ES) ; Pericas-Brondo, Miguel Angel;
(Barcelona, ES) ; Cuberes-Altisen, Maria Rosa;
(Barcelona, ES) ; Frigola-Constansa, Jordi;
(Barcelona, ES) |
Correspondence
Address: |
OSTROLENK, FABER, GERB & SOFFEN, LLP
1180 Avenue of the Americas
New York
NY
10036-8403
US
|
Assignee: |
Laboratories Del Dr. Esteve,
S.A.
|
Family ID: |
8498105 |
Appl. No.: |
11/006931 |
Filed: |
December 8, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11006931 |
Dec 8, 2004 |
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10312194 |
Dec 17, 2002 |
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6846935 |
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10312194 |
Dec 17, 2002 |
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PCT/ES02/00274 |
Jun 6, 2002 |
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Current U.S.
Class: |
548/379.7 |
Current CPC
Class: |
C07D 231/06
20130101 |
Class at
Publication: |
548/379.7 |
International
Class: |
C07D 231/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 18, 2001 |
ES |
P 200101412 |
Claims
1-22. (canceled)
23. A method of preparing the racemic mixture of the compound with
formula (.+-.)-1, 20wherein each of R.sub.1 and R.sub.3 which may
be the same or different is selected from the group consisting of
hydrogen, chlorine, fluorine, methyl, trifluoromethyl and methoxy;
and each of R.sub.2 and R.sub.4 which may be the same or different
is selected from the group consisting of hydrogen, chlorine,
fluorine, methyl, trifluoromethyl, methoxy, trifluoromethoxy,
methylsulphonyl and aminosulphonyl; with the condition that one of
the substituents R.sub.2 or R.sub.4 is a methylsulphonyl or
aminosulphonyl group; said method comprising preparing the racemic
mixture with the general formula (.+-.)-1 by: (a) reacting an
(E)-1,1,1-trifluoro-4-aryl-3-buten-2-one (formula 2) with a
phenylhydrazine (formula 3), 00679974.1-8 21wherein each of R.sub.1
and R.sub.3, which may be the same or different is selected from
the group consisting of hydrogen, chlorine, fluorine, methyl,
trifluoromethyl and methoxy; and each of R.sub.2 and R.sub.4 which
may be the same or different is selected from the group consisting
of hydrogen, chlorine, fluorine, a methyl, trifluoromethyl, methoxy
and trifluoromethoxy group; with the condition that at least one of
the substituents R.sub.2 or R.sub.4 is a hydrogen; in order to
obtain a pyrazoline with the general formula (.+-.)-4, 22wherein
each of R.sub.1 and R.sub.3 which may be the same or different is
selected from the group consisting of hydrogen, chlorine, fluorine,
methyl, trifluoromethyl and methoxy; and each of R.sub.2 and
R.sub.4 which may be the same or different is selected from the
group consisting of hydrogen, chlorine, fluorine, methyl,
trifluoromethyl, methoxy and trifluoromethoxy; with the condition
that at least one of the substituents R.sub.2 or R.sub.4 is a
hydrogen; (b) reacting the compound of formula (.+-.)-4 with
chlorosulphonic acid to form a pyrazoline with the formula (i)-5,
23wherein each of R.sub.1 and R.sub.3 which may be the same or
different is selected from the group consisting of hydrogen,
chlorine, fluorine, methyl, trifluoromethyl and methoxy; and each
of R.sub.2 and R.sub.4 which may be the same or different is
selected from the group consisting of hydrogen, chlorine, fluorine,
methyl, trifluoromethyl, methoxy, trifluoromethoxy and sulphonyl
chloride, with the condition that one of the substituents R.sub.2
or R.sub.4 is a sulphonyl chloride group (SO.sub.2Cl); or
alternatively reacting the compound of formula (.+-.)-4 with
chlorosulphonic acid followed by reaction with sodium hydroxide to
form the pyrazoline with the formula (.+-.)-6, 24wherein each of
R.sub.1 and R.sub.3, which may be the same or different is selected
from the group consisting of hydrogen, chlorine, fluorine, methyl,
trifluoromethyl and methoxy group, and each of R.sub.2 and R.sub.4
which may be the same or different is selected from the group
consisting of hydrogen, chlorine, fluorine, methyl,
trifluoromethyl, methoxy, trifluoromethoxy and sodium sulphonate
group, with the condition that one of the substituents R.sub.2 or
R.sub.4 represents a sodium sulphonate group (SO.sub.3Na); (c)
reacting the pyrazoline of either the formula (.+-.)-5 or the
formula (.+-.)-6 with thionyl chloride to form the pyrazoline with
the formula (.+-.)-7, 25wherein each of R.sub.1 and R.sub.3, which
may be the same or different is selected from the group consisting
of hydrogen, chlorine, fluorine, a methyl, trifluoromethyl and
methoxy: and each of R.sub.2 and R.sub.4 which may be the same or
different is selected from the group consisting of hydrogen,
chlorine, fluorine, methyl, trifluoromethyl, methoxy,
trifluoromethoxy and sulphonyl chloride, with the condition that
one of the substituents R.sub.2 or R.sub.4 represents a sulphonyl
chloride group (SO.sub.2Cl); and (d) reacting the pyrazoline with
the formula (.+-.)-7 with one compound selected from the group
consisting of ammonium carbonate, ammonia, sodium sulphite combined
with methyl iodide and methyl sulphate resulting in the racemic
mixture of the compound with formula (.+-.)-1.
24. The method of claim 23, wherein the reaction of step (a) is
carried out in a medium selected from the group consisting of an
alcohol, an organic medium, an organic acid medium in the absence
of a solvent, an inorganic acid, and a basic medium at a
temperature ranging between ambient temperature and 150.degree. C.
for a time between 2 and 48 hours.
25. The method of claim 24, wherein said alcohol is ethanol or
isopropanol.
26. The method of claim 24, wherein said organic acid medium is
acetic acid or p-toluensulphonic acid.
27. The method of claim 24, wherein said inorganic acid is
hydrochloric acid.
28. The method of claim 24, wherein said organic medium is toluene
or chloroform.
29. The method of claim 24, wherein said basic medium comprises one
of the compounds selected from the group consisting of piperidine,
piperacine, sodium hydroxide, potassium hydroxide, sodium methoxide
and sodium ethoxide.
30. The method of claim 23, wherein the pyrazoline of formula
(.+-.)-6 is reacted in step (c) with thionyl chloride in a solvent
at temperatures between 40.degree. C. and the reflux temperature
for a time between 2 and 24 hours.
31. The method of claim 30, wherein the solvent of step (c) is
toluene.
32. The method of claim 23, wherein the reaction of step (d) is
carried out in a solvent at temperatures between 40.degree. C. and
the reflux temperature for a time between 1 and 12 hours.
33. The method of claim 32, wherein the solvent of step (d) is
selected from the group consisting of toluene, methanol and water.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a new, commercially useful
procedure for the preparation of compounds having the general
formula 1, which includes the racemic mixture (.+-.)--1, and the
enantiomerically pure compounds (-)-1 and (+)-1. 2
BACKGROUND OF THE INVENTION
[0002] Our patent WO 9962884 describes new derivatives of
A.sup.2-pyrazolines, also known as 4,5-dihydro-1H-pyrazoles, which
inhibit the enzyme cyclooxygenase-2, with application in human
and/or veterinary medicine as anti-inflammatories and in other
diseases in which cyclooxygenase-2 is involved, and which present a
low or zero gastric and renal toxicity, so that they are
anti-inflammatories with a greater safety profile. Certain racemic
mixtures (.+-.)-1, and the enantiomerically pure stereoisomers
(-)-1 and (+)-1 described in said patent are currently in a
clinical investigation stage. The aforementioned Patent describes
the preparation of (.+-.)-1 by reaction of
(E)-1,1,1-trifluoro-4-aryl-3-buten-2-one with
4-(aminosulphonyl)phenyl- hydrazine or
4-(methylsulphonyl)phenylhydrazine, or by reaction of
4-(aryl)phenylhydrazine with
(E)-1,1,1-trifluoro-4-(4-aminosulphonylpheny- l)-3-buten-2-one or
(E)-1,1,1-trifluoro-4-(4-methylsulphonylphenyl)-3-bute- n-2-one. It
also describes the production of (-)-1 and (+)-1 by resolution of
the racemic mixture (.+-.)-1 using high resolution liquid
chromatography with a CHIRALPAK AS column of de 10.mu. particle
size and dimensions 25.times.2 cm (Daicel), mobile phase 0.1% of
diethylamine in methanol and flow rate of 8 ml/min.
[0003] In addition, the methods for resolution of racemic mixtures
described in the literature are numerous and have been widely used
[a) for a monograph of the properties of racemates and their
resolutions see Jacques, Collet, Wilen "Enantiomers Racemates and
Resolutions", Wiley: New York, 1981; for reviews see: b) Wilen,
Top. Stereochem., 1971, 6, 107; c) Boyle, Q. Rev. Chem. Soc., 1971,
25; d) Buss, Vermeulen, Ind. Eng. Chem., 1968, 60, 12]. However,
there are few examples in the scientific literature regarding
resolution of .DELTA..sup.2-pyrazolines [Toda, J. Chem. Soc., Chem.
Commun., 1995, 1453]. This paper describes the resolution of a
.DELTA..sup.2-pyrazoline by formation of an inclusion complex. A
prior paper [Mukai, Can. J. Chem., 1979, 57, 360-366] develops the
resolution of an optically active assembly of
A.sup.2-pyrazolines-sod- ium benzenosulphate from the corresponding
racemics, using as resolution agents cinconidine,
(-)-.alpha.-methylbenzylamine and brucine, depending on the
substrate. This method has the disadvantage of using successive
recrystallisations in both the process of formation of sodium
sulphonate (between 3 and 7 recrystallisations), and in the process
of formation and separation of the mixture of diastereoisomeric
salts (between 4 and 7 recrystallisations), which results in a
considerable reduction of the yield.
[0004] We have now found a strategy for preparing compounds with
the general formula 1 which consists of using derivatives of
benzaldehyde much cheaper than 4-(aminosulphonyl)benzaldehyde or
4-(methylsulphonyl)benzaldehyde for obtaining
(E)-1,1,1-trifluoro-4-aryl-- 3-buten-2-one, and derivatives of
phenylhydrazine much cheaper than 4-(aminosulphonyl)phenylhydrazine
or 4-(methylsulphonyl)phenylhydrazine. The enone and hydrazine are
used to obtain the ring of .DELTA..sup.2-pyrazoline, which process
when sequentially combined with a sulphonation and an optical
resolution process to obtain the enantiomerically pure compounds of
the racemic sulphonic acid using an optically active base, or a
mixture of bases in which at least one is optically active, leads
to the formation of diastereoisomeric salts. The process continues
with the separation of these salts, transformation into the sodium
salt, formation of the acid chloride and obtaining the
enantiomerically pure sulphonamide or sulphone 1.
DETAILED DESCRIPTION OF THE INVENTION
[0005] The object of the present invention consists of providing a
commercially useful procedure for preparing compounds with the
general formula 1, which includes the racemic mixture (.+-.)-1 and
the enantiomerically pure compounds (-)-1 and (+)-1, where
[0006] R.sub.1 and R.sub.3, identical or different, represent an
atom of hydrogen, chlorine, fluorine, a methyl, trifluoromethyl or
methoxy group,
[0007] R.sub.2 represents an atom of hydrogen, chlorine, fluorine,
a methyl, trifluoromethyl, methoxy, trifluoromethoxy,
methylsulphonyl or aminosulphonyl group,
[0008] R.sub.4 represents an atom of hydrogen, chlorine, fluorine,
a methyl, trifluoromethyl, methoxy, trifluoromethoxy,
methylsulphonyl or aminosulphonyl group,
[0009] With the condition that one of the substituents R.sub.2 or
R.sub.4 is a methylsulphonyl or aminosulphonyl group.
[0010] The present invention discloses a method for obtaining the
racemic mixture (.+-.)-1 that is less expensive than the one
described previously in patent WO 9962884 as it uses
phenylhydrazine instead of 4-(aminosulphonyl)phenylhydrazine or
4-(methylsulphonyl)phenylhydrazine, or benzaldehyde instead of
4-(aminosulphonyl)benzaldehyde or 4-(methylsulphonyl)benzaldehyde
to obtain the ring of .DELTA..sup.2-pyrazoline, represented in the
scheme 1 as the compound (.+-.)-2. By means of sulphonation the
acid chloride is obtained, which is made to react with ammonia or
ammonium carbonate to obtain the sulphonamide (R.sub.2 or
R.sub.4.dbd.SO.sub.2NH.sub.2), or with sodium sulphite and the
sodium sulphinate obtained with methyl sulphate or methyl iodide to
obtain the methylsulphone (R.sub.2 or
R.sub.4.dbd.SO.sub.3CH.sub.3), (.+-.)-1. It is also possible to
isolate the corresponding sodium salt: by sulphonation and
treatment with sodium hydroxide the salt (.+-.)-3 is obtained,
which is reacted with thionyl chloride and the acid chloride
obtained is reacted with ammonia or ammonium carbonate to obtain
the sulphonamide (R.sub.2 or R.sub.4.dbd.SO.sub.2NH.sub.2), or
instead with sodium sulphite and the sodium sulphinate obtained
with methyl sulphate or methyl iodide to obtain the methylsulphone
(R.sub.2 or R.sub.4.dbd.SO.sub.2CH.sub.3), (.+-.)-1.
[0011] It also provides an industrial application method for
obtaining the enantiomerically pure stereoisomers (+)-1 and
(-)-1.0. One pair of enantiomers can be resolved by various
methods, with conversion to diastereoisomeric salts and their
separation by fractioned crystallisation being the most commonly
used. Once the diastereoiseomeric salts have been obtained and
separated the enantiomers (acids or bases) can be easily liberated,
and the chiral acid or base recovered, so that this simple and
inexpensive method has been widely used for industrial
applications. If the racemic compound contains an amine group in
its structure it is possible to form diastereoisomeric salts with
an optically active acid, and it the racemic compound contains an
acid group it is possible to form diastereoisomeric salts with an
optically active base. Since the compound 1 lacks any acid or basic
groups strong enough to form diastereoisomeric salts the present
invention develops a procedure which is described schematically
below (Schematic 1) for obtaining the racemic mixture (.+-.)-1 and
the enantiomerically pure compounds (-)-1 and (+)-1. 34
[0012] The procedure developed in the present invention is
described schematically below for two specific examples: firstly
(Schematic 2) for obtaining the enantiomerically pure compound
(-)-8. Schematic 2 5
[0013] The compound (-)-8 is synthesised, in accordance with the
present invention, by the method described below with the schematic
indicating certain preferred conditions. The third stage involves
the resolution of the racemic mixture (.+-.)-6 into its two
enantiomers, using as a resolution agent (+)-ephedrine. Ephedrine
is an excellent resolving agent, as both enantiomers can be used in
the resolution, they are available in a high enantiomeric
concentration, are commercially available and are easily
recoverable and crystallisable. The compound (+)-8 is prepared by
the same synthesis path as in the previous case, changing only the
ephedrine enantiomer in the resolution process (step 3). Synthesis
of the racemic compound (.+-.)-8 is performed in the same manner,
skipping the steps related to resolution, that is, directly by
reaction of the acid chloride with ammonium or ammonium
carbonate.
[0014] The first stage consists of preparing the pyrazoline
(.+-.)-5 from
(E)-1,1,1-trifluoro-4-(2,4-difluorophenyl)-3-buten-2-one and
phenylhydrazine, in a suitable solvent, for example in alcohols
such as methanol, ethanol or isopropanol, or in the absence of a
solvent. The reaction takes place in an acid medium, which can be
organic such as acetic acid or p-toluensulphonic acid, or inorganic
such as hydrochloric acid, or a mixture of both, or instead in an
alkali medium such as in piperidine, piperazine, sodium hydroxide,
potassium hydroxide, sodium methoxide or sodium ethoxide, or a
mixture thereof. The same acid or alkali medium can also act as a
solvent. The most suitable temperatures range from ambient
temperature to 150.degree. C., and reaction times lie between 2 and
48 hours. Purification of pyrazoline (.+-.)-5 is carried out by
crystallisation.
[0015] In the second step a sulphonation is performed on the
pyrazoline (.+-.)-5 with chlorosulphonic acid without a solvent or
using a chlorinated solvent such as dichloromethane at temperatures
ranging between 0.degree. C. and the boiling temperature of the
solvent, providing the corresponding sulphonic acid after an
aqueous treatment. Addition of sodium hydroxide precipitates the
sodium sulphonate (.+-.)-6.
[0016] In the third step the racemic mixture (.+-.)-6 is resolved
into its two enantiomers by forming a mixture of two
diastereoisomeric salts and the subsequent separation of one of
these by precipitation in the same reaction medium. The procedure
object of the present invention does not suffer from the
aforementioned drawbacks in resolution of a similar product as
performed by Mukai et al. [Can. J. Chem. 1979 57, 360-366], and
separation of the twos diastereoisomeric salts is performed in the
same reaction medium during the process of forming the mixture of
diastereoisomeric salts, that is, a single crystallisation is
required. The resolution agent employed is (+)-ephedrine, which by
reaction of the racemic mixture (.+-.)-6 with (+)-ephedrine
chlorhydrate in a chlorinated solvent such as chloroform and at
temperatures oscillating ranging from ambient temperature and the
reflux temperature provides the mixture of diastereoisomeric salts,
and in the cooling process only the enantiomer (-)-7 precipitates
in the form of a salt of (+)-ephedrine, with an enantiomeric excess
above 98%. It is possible to obtain from the filtration liquids the
diatereoisomeric salt of (+)-7 and (+)-ephedrine, by evaporation of
the solvent and subsequent recrystallisation in an alcohol, such as
isopropyl alcohol, or mixtures of an alcohol and water. In
addition, by the same process of step 3 of the schematic but using
(-)-ephedrine chlorhydrate, the diastereoisomeric salt formed by
(+)-7 and (-)-ephedrine is obtained by precipitation and from the
filtration liquids can be obtained the diatereoisomeric salt of
(-)-7 and (-)-ephedrine, by evaporation of the solvent and
subsequent recrystallisation in an alcohol, such as isopropyl
alcohol, or mixtures of an alcohol and water.
[0017] In the fourth stage shown in the reaction scheme the sodium
sulphonate (-)-6 is released in enantiomerically pure form by basic
hydrolysis of the salt (-)-7.(+)-ephedrine, with aqueous sodium
hydroxide and using and alcohol such as isopropanol as solvent.
From the filtration liquids it is simple to recover the ephedrine
by eliminating the solvent and acidifying the residue dissolved in
ethanol with ethanolic hydrochloric acid. The enantiomer (+)-6 is
obtained in the same manners from the salt (+)-7.(+)-ephedrine or
(+)-7.(-)-ephedrine. 6
[0018] The fifth and last step shown in the schematic involves
preparation of the stereoisomer (-)-8 with an enantiomeric excess
above 98% by reaction of the optically active sodium sulphonate
(-)-6 with thionyl chloride in the absence of a solvent or in a
suitable solvent such as toluene, at temperatures between ambient
temperature and the reflux temperature, and subsequent formation of
the sulphonamide adding ammonia or ammonium carbonate to the
reaction medium. In the same manner the enantiomer (+)-8 can be
obtained from (+)-6. Eliminating the steps related to resolution it
is possible to obtain the racemic compound (.+-.)-8.
[0019] Scheme 3 shows another specific example for obtaining the
compounds object of the invention: preparation of (-)-13. 78
[0020] The compound (-)-13 is synthesised, according to the present
invention, by the method described below, with preferred conditions
indicated in the schematic. The third stage involves the resolution
of the racemic mixture (.+-.)-11 into its two enantiomers, by
formation of a mixture of diastereoisomeric salts, using as a
resolving agent (+)-ephedrine to obtain the enantiomer (-)-13. The
compound (+)-13 is prepared by the same synthesis path of the
previous case, changing only the enantiomer of ephedrine in the
resolution process (step 3). Synthesis of the racemic compound
(.+-.)-13 is effected in the same way, skipping the formation
process for the ephedrine salt and its subsequent hydrolysis.
[0021] The first step consists of preparation of pyrazoline
(.+-.)-10 from (E)-1,1,1-trifluoro-5-phenyl-3-buten-2-one and
2,4-difluorophenylhydrazin- e chlorhydrate in a suitable solvent,
such as alcohols as ethanol, or in the absence of a solvent. The
reaction takes place in an acid medium, such as with acetic acid or
p-toluensulphonic acid. The most suitable temperatures lie between
ambient temperature and 110.degree. C., and reaction times are
between 2 and 24 hours. Purification of the pyrazoline (.+-.)-10 is
performed by crystallisation.
[0022] In the second step a sulphonation is performed of the
pyrazoline (.+-.)-10 with chlorosulphonic acid without a solvent or
with a chlorinated solvent such as dichloromethane, at temperatures
between 0.degree. C. and the boiling point of the solvent,
obtaining the corresponding sulphonic acid after an aqueous
treatment. Addition of sodium hydroxide precipitates the sodium
sulphonate (.+-.)-11.
[0023] In the third step the racemic mixture (.+-.)-11 is resolved
into its two enantiomers by forming a mixture of two
diastereoisomeric salts and a subsequent separation of one by
precipitation in the same reaction medium, with a single
crystallisation being required. The mixture of diastereoisomeric
salts is prepared by reacting the racemic mixture (.+-.)-11 with
(+)-ephedrine chlorohydrate in a suitable solvent such as toluene,
at temperatures between ambient temperature and the reflux
temperature. In the cooling process only the enantiomer (-)-12
precipitates in the form of a salt of (+)-ephedrine, with an
enantiomeric excess of 84%. From the filtration liquids can be
obtained the diastereoisomeric salt of (+)-12 and (+)-ephedrine. In
addition, by means of the same process of step 3 of the schematic
but using (-)-ephedrine chlorhydrate is obtained by precipitation
the diastereoisomeric salt formed by (+)-12 and (-)-ephedrine and
from the filtration liquids is obtained the diastereoisomeric salt
of (-)-12 and (-)-ephedrine.
[0024] In the fourth step shown in the reaction schematic the
sodium sulphonate (-)-11 is obtained enantiomerically pure by a
basic hydrolysis of the salt (-)-12.(+)-ephedrine with aqueous
sodium hydroxide using water as a solvent. From the filtration
liquids it is simple to recover the ephedrine, as described above,
by acidifying the residue dissolved in ethanol with ethanolic
hydrochloric acid. Preparation of the enantiomer (+)-11 is effected
in the same manner from the salt (+)-12.(+)-ephedrine or
(+)-12.(-)-ephedrine. 9
[0025] In the fifth and last step shown the stereoisomer (-)-13 is
prepared by reacting the optically active sodium sulphonate (-)-11
with thionyl chloride in the absence of a solvent or in a suitable
solvent such as toluene, at temperatures between ambient
temperature and the reflux temperature, with subsequent formation
of the sodium sulphinate by reaction of the acid chloride with
sodium sulphite in a basic aqueous medium, and finally by reaction
of the sodium sulphinate obtained with methyl iodide or methyl
sulphate in an alcoholic or aqueous medium. In the same manner the
enantiomer (+)-13 is obtained from (+)-11. Eliminating the steps
related to the resolution the racemic compound (.+-.)-13 is
obtained.
[0026] The resolution process object of the present invention can
be used or racemic mixtures (those in which the two enantiomers are
present in the ratio 1:1) or for non racemic mixtures in which one
of the enantiomers is predominant, obtained by any physical or
chemical method.
[0027] Below is shown by way of example the process for preparation
of some of the compounds to which the present invention relates.
These examples are shown for purposes of illustration only and
should not be considered to limit the scope of the invention in any
way.
EXAMPLE 1
Preparation of
(-)-4-[5-(2,4-difluorophenyl)-4,5-dihydro-3-(trifluoromethy-
l)-1H-pyrazol-1-il]-benzenosulphonamide, (-)-8
Preparation of
(.+-.)-1-phenyl-5-(2,4-difluorophenyl)-4,5-dihydro-3-triflu-
oromethyl-1H-pyrazol, (.+-.)-5
[0028] 10
[0029] In a 50 mL beaker are introduced
(E)-1,1-trifluoro-4-(2,4-difluorop- henyl)-3-buten-2-one (2.66 g,
11.2 mmol), monohydrated p-toluensulphonic acid (2.1 g, 11.2 mmol)
and phenylhydrazine chlorhydrate (1.33 g, 12.3 mmol) and heated to
110.degree. C. A small amount of ethyl alcohol can be used to
facilitate the initial mixture. After approximately 2 h (control by
CCF) the mixture is allowed to cool and it is diluted with ethyl
acetate. It is then washed with a saturated solution of
NaHCO.sub.3, dried with MgSO4, filtered and the solvent evaporated
at low pressure. The crude thus obtained (3.9 g) is recrystallised
with methanol (2 mL) to precipitate 3.67 g (65%) of the pyrazoline
(.+-.)-5: pf=83-84.degree. C.; IR (KBr) .mu. max (cm.sup.-1) 1600,
1505, 1326; .sup.1H-RMN (CDCl.sub.3) 8 (ppm): 7.28-6.72 (m, 8H),
5.64 (dd, J=13 Hz, J=7.5 Hz, 1H), 3.8-3.6 (m, 1H), 2.94 (dd, J=17.2
Hz, J=7 Hz, 1H).
Preparation of
(.+-.)-4-[5-(2,4-difluorophenyl)-4,5-dihydro-3-(trifluorome-
thyl)-1H-pyrazol-1-il]-sodium benzenosulphonate, (.+-.)-6
[0030] 11
[0031] In a 100 mL beaker the pyrazoline (.+-.)-5 (4.0 g, 12.27
mmol) is dissolved in dichloromethane (12 mL). The mixture is
cooled at 0.degree. C. and added on it drop by drop is
chlorosulphonic acid (0.82 mL, 12.27 mmol). The stirring and
temperature are maintained for 20 minutes, after which time the
reaction mixture is slowly added on water (20 mL) at 4.degree. C.,
stirring the assembly for 14 h at ambient temperature. The two
phases are separated and the aqueous phase is washed with
dichloromethane (5 mL). The aqueous phase is concentrated to two
thirds of the initial volume and to this is added, under stirring,
an aqueous solution of sodium hydroxide 1M (12.27 mL, 12.27 mmol).
This precipitates a white solid which corresponds to sodium
sulphonate (.+-.)-6, which is filtered, washed with more water and
dried (3.93 g, 75% yield): pf=292-295.degree. C.; IR (KBr) .mu. max
(cm.sup.-1) 3430, 1600, 1570, 1425; .sup.1H-RMN
(CDCl.sub.3/CD.sub.3OD: 10/1) .delta. (ppm): 7.6 (d, J=8.8 Hz, 2H),
7.1-6.7 (m, 3H), 6.9 (d, J=8.8 Hz, 2H), 5.69 (dd, J=12.6 Hz, J=6.3
Hz, 1H).
Preparation of
(-)-4-[5-(2,4-difluorophenyl)-4,5-dihydro-3-(trifluoromethy-
l)-1H-pyrazol-1-il]-benzenesulphonate de (+)-ephedrine,
(-)-7.(+)-ephedrine.
[0032] 12
[0033] In a 2 L beaker are introduced sodium sulphonate (.+-.)-6
(3.95 g, 9.23 mmol), (+)-ephedrine chlorhydrate (1.86 g, 9.23 mmol)
and chloroform (79 mL). The mixture is shaken and heated to reflux
for 10 minutes. It is allowed to cool slowly to ambient
temperature, precipitating a solid (2.49 g) mixture of the salt
(-)-7.(+)-ephedrine (enantiomeric excess above 98%) and sodium
chloride formed in the process. This sample is used directly in the
following reaction. If the sample is dissolved with a small amount
of AcOEt, Washed with water, dried with MgSO.sub.4 and the solvent
is evaporated a pure fraction is obtained of the salt
(-)-7.(+)-ephedrine: [.alpha.r].sub.20.sup.D=-94.6 (c=2, MeOH); IR
(KBr) .mu. max (cm.sup.-1): 3410, 3040, 2860, 2780, 1595, 1570,
1500, 1420; .sup.1H-RMN (CDCl.sub.3/CD.sub.3OD: 10/1) .delta.
(ppm): 7.7 (d, J=9 Hz, 2H), 7.4-7.2 (m, 5H), 7.1-6.7 (m, 3H), 6.95
(d, J=9 Hz, 2H), 5.65 (dd, J=12.5 Hz, J=6.5 Hz, 1H), 5.3 (d, J=2.2
Hz, 1H), 3.9-3.6 (m, 1H), 3.4-3.1 (m, 1H), 3.0 (dd, J=18.4 Hz,
J=5.8 Hz, 1H), 2.76 (s, 3H), 1.9 (wide band, 1H), 1.0 (d, J=6 Hz,
3H).
Preparation of
(-)-4-[5-(2,4-difluorophenyl)-4,5-dihydro-3-(trifluoromethy-
l)-1H-pyrazol-1-il]-sodium benzenesulphonate, (-)-6
[0034] 13
[0035] In a 50 mL beaker are introduced isopropyl alcohol (50 mL)
and a mixture of the salt (-)-7.(+)-ephedrine (enantiomeric excess
above 98%) and sodium chloride (2.49 g). The suspension obtained is
shaken and sodium hydroxide 10M (0.4 mL) is added on it. The
solution is heated to reflux and 10 minutes later it is allowed to
cool slowly to ambient temperature. A precipitate is obtained which
once filtered, washed with isopropyl alcohol and dried corresponds
to a mixture of sodium sulphonate (-)-6 and sodium chloride (1.86
g), which is directly used in the preparation of (-)-8. In order to
determine the optical rotation of the compound (-)-6 it is possible
to purify part of the sample by washing with water:
[.alpha.].sub.20.sup.D=-170.1 (c=1, MeOH).
Preparation of
(-)-4-[5-(2,4-difluorophenyl)-4,5-dihydro-3-(trifluoromethy-
l)-1H-pyrazol-1-il]-benzenosulphonamide, (-)-8
[0036] 14
[0037] In a 1 L beaker is introduced a sample (72 g) mixture of
sodium sulphonate (-)-6 (48.3 g, 112.8 mmol) and NaCl (23.7 g) on
toluene (250 mL). The suspension is heated to 60.degree. C.,
thionyl chloride is added (18 mL, 247.5 mmol), it is heated to
reflux and left at this temperature for 2 hours at least. After the
acid chloride formation reaction has finished the excess thionyl
chloride is eliminated by its azeotropic distillation with toluene
(190 mL; 76.degree. C. at 60 mmHg). More toluene is added (190 mL)
and it is again distilled in the same conditions.
[0038] For preparation of the sulphonamide the previous sample is
diluted with toluene (190 mL), the mixture is cooled to 70.degree.
C., solid ammonium carbonate is added (22.6 g, 235 mmol), it is
heated to 90.degree. C. and shaken at this temperature for 2 h.
When the reaction has finished (if necessary more ammonium
carbonate is provided) water is added (300 mL) and it is maintained
for 30 minutes at 90.degree. C. the mixture is cooled to ambient
temperature and an aqueous solution of 17.5% HCl is added until
obtaining a pH of 6-7 and it is kept stirred for another 10
minutes. The precipitated solid is filtered, washed with toluene
and dried to provide the sulphonamide (-)-8 (38.4 g, 84% yield).
The product can be recrystallised with a mixture of isopropyl
alcohol and water (60:40), giving an ee above 99%:
pf=173-174.degree. C.; [.alpha.].sub.20.sup.D=-192.8 (c=1, MeOH);
IR (KBr) .mu. max (cm.sup.-1): 3310, 3230, 1600, 1500, 1430;
.sup.1H-RMN (CDCl.sub.3) .delta. (ppm): 7.76 (d, J=9 Hz, 2H), 7.04
(d, J=9 Hz, 2H), 7.1-6.75 (m, 3H), 5.71 (dd, J=12.4 Hz, J=6.2 Hz,
1H), 4.74 (s, 2H), 3.9-3.7 (m, 1H), 3.03 (dd, J=19.8 Hz, J=6.2 Hz,
1H).
EXAMPLE 2
Preparation of
(-)-1-(2,4-difluorophenyl)-4,5-dihydro-5-(4-methylsulphonyl-
phenyl)-3-(trifluoromethyl)-1H-pyrazol, (-)-13
Preparation of
(.+-.)-1-(2,4-difluorophenyl)-4,5-dihydro-5-phenyl-3-(trifl-
uoromethyl)-1H-pyrazol, (.+-.)-10
[0039] 15
[0040] In a 50 mL beaker are introduced
(E)-1,1,1-trifluoro-5-phenyl-3-but- en-2-one (3.04 g, 15.2 mmol),
monohydrated p-toluensulphonic acid (2.9 g, 15.2 mmol) and
2,4-difluorophenylhydrazine chlorhydrate (3.01 g, 16.7 mmol) and
heated to 110.degree. C. A small amount of ethyl alcohol can be
used to facilitate the initial mixture. After approximately 2 hour
(controlled by CCF) the mixture is allowed to cool and it is
diluted with ethyl acetate. It is washed with a saturated solution
of NaHCO.sub.3, dried with MgSO4, filtered and the solvent is
evaporated at low pressure. The crude thus obtained is
recrystallised with isopropyl alcohol (1 g/1 mL) precipitating 3.95
g (80%) of pyrazoline (.+-.)-10: pf=52-54.degree. C.; IR (KBr) .mu.
max (cm.sup.-1) 1598, 1511, 1414, 1324; .sup.1H-RMN (CDCl.sub.3)
.delta. (ppm): 7.4-6.6 (m, 8H), 5.7-5.4 (m, 1H), 3.8-3.5 (m, 1H),
3.3-3.0 (m, 1H).
Preparation of
(.+-.).sub.4-[1-(2,4-difluorophenyl)-4,5-dihydro-3-(trifluo-
romethyl)-1H-pyrazol-5-il]-sodium benzenesulphonate, (.+-.)-11
[0041] 16
[0042] In a 100 mL beaker are dissolved pyrazoline (.+-.)-10 (3.0
g, 9.2 mmol) in dichloromethane (1.5 mL). The mixture is cooled to
0.degree. C. and onto it is added, drop by drop, chlorosulphonic
acid (6.1 mL, 92 mmol). Coolant is coupled to it and the
temperature is increased to 50.degree. C. The shaking and
temperature are maintained during 5 hours (controlled by CCF), the
mixture is allowed to cool and diluted with dichloromethane (90
mL), at which time the reaction is slowly added on water (90 mL) at
4.degree. C. the two phases are separated and two extractions are
performed of the aqueous phase with dichloromethane (25 mL). The
organic phase is dried with MgSO.sub.4, filtered and the solvent
evaporated at low pressure. The crude thus obtained (3.6 g) is
introduced in a 25 mL beaker coupled to a coolant and on it is
added water (13.4 mL). The suspension is heated to 70.degree. C.
and slowly added onto it, stirring, is an aqueous solution of
sodium hydroxide 10M (1.7 mL, 17.04 mmol). The mixture is heated to
reflux and is kept at this temperature for 10 minutes. It is
allowed to cool slowly until reaching ambient temperature,
precipitating a white solid that corresponds to sodium sulphonate
(.+-.)-11, which is filtered, washed with more water and dried (3.0
g, 82% yield): pf=271-273.degree. C.; IR (KBr) .mu. max (cm.sup.-1)
3477, 1617, 1513, 1416; .sup.1H-RMN (CDCl.sub.3) 6 (ppm): 7.59 (d,
J=8.5 Hz, 2H), 7.3-7.0 (m, 3H), 6.95 (d, J=8.5 Hz, 2H), 5.4 (m,
1H), 3.5 (m, 1H), 2.9 (m, 1H).
Preparation of
(-)-4-[1-(2,4-difluorophenyl)-4,5-dihydro-3-(trifluoromethy-
l)-1H-pyrazol-5-yl]-benzenesulphonate of (+)-ephedrine, (-)-12
(+)-ephedrine
[0043] 17
[0044] In a 50 mL beaker are introduced sodium sulphonate (.+-.)-11
(2.45 g, 5.72 mmol), (+)-ephedrine chlorhydrate (1.15 g, 5.72 mmol)
and toluene (24.5 mL). The mixture is shaken and heated to reflux
for 10 minutes. It is allowed to cool slowly until reaching ambient
temperature, precipitating a solid which is filtered and washed
with more toluene. This provides 1.18 g, mixture of the salt
(-)-12.(+)-ephedrine (enantiomeric excess of 84%) and of the sodium
chloride formed in the process. This sample is directly used in the
following reaction; IR (KBr) .mu. max (cm.sup.-1) 3377, 3031, 1603,
1515, 1399; .sup.1H-RMN (CDCl.sub.3/CD.sub.3OD: 10/1) .delta.
(ppm): 7.76 (d, J=8 Hz, 2H), 7.4-7.2 (m, 6H), 7.19 (d, J=8 Hz, 2H),
6.75 (m, 2H), 5.6 (m, 1H), 5.35 (s, 1H), 3.65 (m, 1H), 3.3 (m, 1H),
3.15-3.0 (m, 1H), 2.76 (s, 3H), 2.65 (m, 2H), 1.07 (d, J=7 Hz,
3H).
Preparation of
(-)-4-[1-(2,4-difluorophenyl)-4,5-dihydro-3-(trifluoromethy-
l)-1H-pyrazol-5-il]-sodium benzenesulphonate, (-)-11
[0045] 18
[0046] In a 10 mL beaker are introduced water (2.8 mL) and the
mixture (1 g) of the salt (-)-7.(+)-ephedrine and sodium chloride
(28% of total weight). The suspension obtained is shaken and added
to it is sodium hydroxide 10M (0.3 mL). The solution is heated to
reflux and 10 minutes later allowed to cool slowly to ambient
temperature. A precipitate is obtained which once filtered, washed
with water and dried corresponds to sodium sulphonate (-)-11 (0.34
g), which is used directly in preparation of the compound (-)-13:
[.alpha.].sub.20.sup.D=-104.3 (c=1, MeOH).
Preparation of
(-)-1-(2,4-difluorophenyl)-4,5-dihydro-5-(4-methylsulphonyl-
phenyl)-3-(trifluoromethyl)-1H-pyrazol, (-)-13
[0047] 19
[0048] In a 10 mL beaker are dissolved the compound (-)-11 (230 mg,
0.54 mmol) in toluene (1.1 mL). The suspension is heated to
60.degree. C., thionyl chloride is added (88 .mu.L, 1.18 mmol), and
it is kept at said temperature for at least 2 hours. At the end of
the acid chloride formation reaction the excess thionyl chloride is
eliminated by azeotropic distillation with toluene (76.degree. C.
at 60 mmHg). More toluene (1 mL) is added and again distilled in
the same conditions. On the crude thus obtained are added water
(1.15 mL), NaHCO.sub.3 (95 mg, 1.13 mmol) and Na.sub.2SO.sub.3 (124
mg, 0.97 mmol), heating to 75.degree. C. It is kept at this
temperature for 2 hours and then allowed to cool to room
temperature. The solvent is evaporated at low pressure and on the
crude is added methyl alcohol (14 mL). After 1 hour at reflux it is
filtered hot and the solvent evaporated at reduced pressure. The
solid thus obtained (297 mg) is dissolved in methyl alcohol (2.8
mL) and onto this is added methyl iodide (44 .mu.L, 0.7 mmol). This
is heated to 55.degree. C. and kept at this temperature for 16
hours. The solvent is evaporated at low pressure, yielding 168 mg
(77%) of crude. The product can be recrystallised with a mixture of
toluene and cyclohexane: pf=86-90.degree.;
[.alpha.].sub.20.sup.D=-.sub.86, 1 (c=1, CH.sub.3OH); IR (KBr) .mu.
max (cm.sup.-1): 1598, 1513, 1416; .sup.1H-RMN (CDCl.sub.3) .delta.
(ppm): 7.87 (d, J=8.4 Hz, 2H), 7.5-7.2 (m, 3H), 6.9-6.6 (m, 2H),
5.7 (dd, J=6.5 Hz, J=2.6 Hz, 1H), 3.8-3.6 (m, 1H), 3.2-2.9 (m, 1H),
3.02 (s, 3H).
* * * * *