U.S. patent application number 12/141596 was filed with the patent office on 2008-10-23 for process for making risperidone and intermediates therefor.
Invention is credited to Jiri Bartl, Pavel Slanina.
Application Number | 20080262227 12/141596 |
Document ID | / |
Family ID | 32313043 |
Filed Date | 2008-10-23 |
United States Patent
Application |
20080262227 |
Kind Code |
A1 |
Slanina; Pavel ; et
al. |
October 23, 2008 |
PROCESS FOR MAKING RISPERIDONE AND INTERMEDIATES THEREFOR
Abstract
The formation of risperidone is enhanced by the use of enriched
Z-isomer oxime intermediate(s) of formula (3) or (7). ##STR00001##
The oxime(s) can be isomerically enriched by a variety of
techniques including the use of the novel acetic acid salt thereof,
which affords, inter alia, resolution of the isomers and/or by heat
conversion.
Inventors: |
Slanina; Pavel; (Lelekovice,
CZ) ; Bartl; Jiri; (Strelice, CZ) |
Correspondence
Address: |
SYNTHON IP INC
7130 HERITAGE VILLAGE PLAZA, STE 202
GAINESVILLE
VA
20155
US
|
Family ID: |
32313043 |
Appl. No.: |
12/141596 |
Filed: |
June 18, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10705926 |
Nov 13, 2003 |
7405298 |
|
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12141596 |
|
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60425727 |
Nov 13, 2002 |
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Current U.S.
Class: |
544/282 |
Current CPC
Class: |
C07D 471/04 20130101;
C07D 211/58 20130101 |
Class at
Publication: |
544/282 |
International
Class: |
C07D 471/04 20060101
C07D471/04 |
Claims
1-15. (canceled)
16. A process, which comprises: providing an enriched Z-isomer
oxime of formula (3) or (7): ##STR00016## as an acetic acid salt
thereof, wherein said enriched Z-isomer oxime contains at least 80%
of said Z-isomer; and converting said enriched Z-isomer oxime into
risperidone.
17. The process according to claim 16, wherein said enriched
Z-isomer oxime contains at least 90% of said Z-isomer.
18. The process according to claim 17, wherein said enriched
Z-isomer oxime contains at least 98% of said Z-isomer.
19. The process according to claim 16, wherein said providing step
comprises preferentially precipitating said enriched Z-isomer oxime
as an acetic acid salt thereof from a solution containing said
oxime of formula (3) or (7) in Z- and E-isomer forms and isolating
said precipitated enriched Z-isomer oxime salt from said
solution.
20. The process according to claim 19, wherein said providing step
comprises forming said oxime of formula (3) or (7) as a mixture of
Z- and E-isomers in the presence of acetic acid and wherein said
preferential precipitation occurs substantially spontaneously upon
formation of said oxime isomers.
21. The process according to claim 16, wherein said providing step
comprises heating an oxime of formula (3) or (7) that contains an
E-isomer thereof in a solvent to convert a sufficient amount of
said E-isomer into Z-isomer to obtain said enriched Z-isomer
oxime.
22. The process according to claim 21, wherein said heating is
carried out in the presence of an acid catalyst.
23. The process according to claim 22, wherein said acid catalyst
is selected from the group consisting of acetic acid, ammonium
acetate, and piperidine acetate.
24. The process according to claim 23, which further comprises
cooling said enriched Z-isomer and precipitating said enriched
Z-isomer from said solvent as said enriched Z-isomer oxime
salt.
25-30. (canceled)
31. The process according to claim 16, wherein said enriched
Z-isomer is the Z-isomer of an oxime of formula (7).
32. The process according to claim 31, wherein said converting step
comprises cyclizing said oxime of formula (7) to form
risperidone.
33-39. (canceled)
40. The process according to claim 32, wherein said converting step
further comprises liberating the enriched Z-isomer oxime of formula
(7) from said enriched Z-isomer oxime salt prior to said
cyclizing.
41. The process according to claim 16, wherein said enriched
Z-isomer is the Z-isomer of the oxime of formula (3).
42. The process according to claim 41, wherein said converting step
comprises alkylating and cyclizing.
43. The process according to claim 42, wherein said converting step
further comprises liberating the enriched Z-isomer oxime of formula
(3) from said enriched Z-isomer oxime salt before said alkylating
and cyclizing steps.
44. The process according to claim 43, wherein said alkylating
comprises reacting said enriched Z-isomer oxime of formula (3) with
a compound of formula (5) ##STR00017## to form a compound of
formula (7) ##STR00018##
45. The process according to claim 44, wherein said cyclizing
comprises treating said compound of formula (7) with base to form
risperidone.
46. The process according to claim 43, wherein said cyclizing
comprises treating said enriched Z-isomer oxime of formula (3) with
base to form a compound of formula (4) ##STR00019##
47. The process according to claim 46, wherein said alkylating
comprises reacting said compound of formula (4) with a compound of
formula (5) ##STR00020## to form risperidone.
Description
[0001] This application is a Divisional of application Ser. No.
10/705,926 filed on Nov. 13, 2003, the entire contents being
incorporated herein by reference, which in turn claims the benefit
of priority under 35 U.S.C. .sctn. 119(e) from U.S. provisional
patent application Ser. No. 60/425,727, filed Nov. 13, 2002.
BACKGROUND OF THE INVENTION
[0002] Risperidone, or
3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-te-
trahydro-2-methyl-4-H-pyrido[1,2-a]-pyrimidin-4-one, is a serotonin
antagonist approved for the treatment of psychotic disorders such
as schizophrenia. Its structure is shown in formula (1).
##STR00002##
The compound and its pharmaceutical activity are identified in U.S.
Pat. No. 4,804,663.
[0003] Various methods for making risperidone are known. Typically
the synthesis includes forming the benzisoxazole ring moiety by
cyclizing an oxime intermediate. For example, U.S. Pat. No.
4,804,663, which corresponds to EP 196132, discloses oximating a
4-(2,4-difluorobenzoyl)piperidine hydrochloride (2)
##STR00003##
by treating with hydroxylamine to yield a corresponding oxime
(3).
##STR00004##
The oxime is cyclized by a base in water to yield
6-fluoro-3-(4-piperidinyl)-1,2-benzizoxazole, compound (4) in
approximately 62% yield.
##STR00005##
The benzisoxazole compound (4) is N-alkylated with the
3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2a]pyrimidin-4--
one hydrochloride, compound (5)
##STR00006##
in the presence of sodium carbonate and potassium iodide in
dimethylformamide, to yield risperidone base in a relatively low
yield (46%). This last step was reportedly improved in WO 02/14286
and in WO 02/12200 by replacing the dimethylformamide with
acetonitrile, isopropanol, methyl ethylketone or iso-butanol as the
solvent.
[0004] An alternative oxime route is described in ES 2050069
wherein the starting piperidine compound (2) is first N-alkylated
with the pyridopyrimidinone compound (5), under essentially the
same alkylation conditions as above, to yield (63%) of a
dihydrochloride of an alkylated ketone compound (6).
##STR00007##
The ketone (6) is oximated by hydroxylamine hydrochloride to yield
(76%) of an alkylated oxime (7).
##STR00008##
The oxime (7) is then cyclized in the presence of a base in 80-85%
yield to the desired risperidone base.
[0005] In addition to these prior art procedures, another
oxime-based synthesis route has been proposed for compounds
analogous to risperidone in EP 368 888 and in EP 453042. While not
applied to risperidone, the general scheme suggests forming an
oxime analogous to the compound of (7) by first converting a ketone
(2) to the oxime (3). This oxime is then alkylated, prior to
cyclization, by the corresponding pyridopyrimidine compound to
yield an alkylated oxime analogous to compound (7). As in ES
2050069, the last step is to cyclize the oxime to form the
benzisoxazole ring.
[0006] The use of a different oxime compound in forming risperidone
is suggested in Spanish Patent No. 2,074,966. In this patent a
pyran-containing oxime of the formula
##STR00009##
is formed. After cyclization to form the isoxazole ring, the pyran
ring is opened and ultimately reacted with an
amino-pyridopyrimidinone compound to form risperidone. The patent
also discloses the isolation of the "syn" isomer of the oxime
molecule, using chromatographic methods, from the crude mixture
having a "syn/anti" ratio of 3:1.
[0007] It would be desirable to provide another useful method and
reagents for making risperidone, especially a method and reagents
that can provide for improved results.
SUMMARY OF THE INVENTION
[0008] The present invention relates to a process for making
risperidone and certain intermediates useful therein. In
particular, one aspect of the present invention relates to an
acetic acid salt compound of formula (3) or (7):
##STR00010##
Preferably, the acetic acid salt is in solid form and is at least
90% isomerically pure Z-isomer of formula (3) or (7).
[0009] Another aspect of the present invention relates to a
process, which comprises reacting acetic acid with a compound of
formula (3) or (7) to form the acetic acid salt thereof.
Preferably, the acetic acid salt is isolated in solid form and
contains more of a Z-isomer than an E-isomer.
[0010] A further aspect of the invention relates to an enriched
Z-isomer oxime of formula (3) or (7) or a salt thereof, wherein the
amount of Z-isomer is at least 80%, preferably at least 90%, and
more preferably at least 95% based on the total amount of the
oxime.
[0011] A still further aspect of the invention relates to a
process, which comprises providing an enriched Z-isomer of a
compound of formula (3) or (7) or salt thereof, wherein said oxime
contains 80% of said Z-isomer; and converting said Z-isomer into
risperidone. In one embodiment the enriched Z-isomer oxime can be
provided by preferentially precipitating the Z-isomer as an acetic
acid salt from a solution containing the oxime in Z- and E-isomer
forms and isolating the precipitated Z-isomer oxime. Alternatively,
the enriched Z-isomer oxime can be provided by heating an oxime of
formula (3) or (7), which contains the E-isomer, in a solvent, to
convert sufficient E-isomer into Z-isomer. Preferably, the
conversion is performed in the presence of an acid or a salt of an
acid.
[0012] Accordingly, another aspect of the invention relates to a
method which comprises reacting in a solvent and in the presence of
acetic acid, a compound of formula (2),
##STR00011##
with a hydroxylamine to form Z- and E-oxime isomers of formula (3)
wherein substantially upon formation said Z-isomer precipitates as
an acetic acid salt thereof.
[0013] Finally, the invention relates to a process, which comprises
preferentially precipitating an acetic acid salt of a Z-isomer of
formula (3) or (7) from a solution containing a mixture of Z- and
E-isomers thereof.
DETAILED DESCRIPTION
[0014] It has been discovered that although oximes (3) and (7) are
formed as a mixture of Z and E geometric isomers in the prior
synthetic schemes, essentially only the Z-isomer cyclizes to a
benzisoxazole ring in risperidone synthesis. Thus, the method of
producing risperidone can be enhanced by providing an enriched Z
isomer oxime. Further, this surprisingly led to the discovery that
the Z and E isomer oxime can be readily separated from one another
when converted into an acetic acid salt form. Accordingly, an
acetic acid salt is a convenient way to provide an enriched isomer
oxime. Based on these and further discoveries the present invention
has been made.
[0015] Accordingly, the present invention relates to a process of
making risperidone using enriched oxime isomers. The process
includes providing an enriched Z-isomer oxime of a compound of
formula (3) or (7) or a salt thereof and converting it into
risperidone. An "enriched Z-isomer oxime" means that the oxime
contains at least 80% of the Z-isomer form of the oxime compound.
The Z- and E-isomer oximes can generally be represented as follows
with reference to formula (3):
##STR00012##
In the Z-isomer, the terminal hydroxyl group is near to the
fluorine atom on the phenyl ring (a "syn" position) while the
E-isomer is the opposite; i.e., the hydroxyl group is away from the
fluorine atom (an "anti" position). The proof of the configuration
may be made, e.g. by NMR. Typically, the enriched Z-isomer oxime
contains at least 90%, more preferably at least 95% of the Z-isomer
and in some embodiments at least 97%, at least 98% or even at least
99% Z-isomer. Because of the discovery that the E-isomer oxime is
not merely slower reacting than the Z-isomer oxime but rather is
essentially unreactive, the less the amount of the E-isomer oxime
content, the more advantageous and productive the synthetic pathway
is made.
[0016] The enriched Z-isomer oxime can be provided by any suitable
technique. That is any technique or method, alone or in
combination, that results in an enriched Z-isomer oxime of formula
(3) or (7) including the salts thereof, is intended to satisfy the
term "providing." Conveniently, an acetic acid salt can be used to
provide an enriched Z-isomer oxime. For example, preferentially
precipitating an acetic acid salt of the Z-isomer oxime of formula
(3) or (7) from a solution containing a mixture of the Z- and
E-isomer oximes is one useful technique. The precipitation is
"preferential" in that the precipitate, generally crystalline
material, contains a higher Z:E ratio than the solution. Thus, the
precipitation favors or prefers forming the Z-isomer oxime over the
E-isomer oxime. The precipitation can be essentially spontaneous
upon formation of the acetic acid salt of the oxime or it can be
induced using generally known methods and techniques including,
among others, lowering the temperature of the solution, reducing
the amount of solvent in the solution, adding a contrasolvent,
adding a seeding crystal, or a combination of two or more of these
techniques. It is also contemplated that during or after an initial
(spontaneous) precipitation, one or more inducement techniques may
be applied to enhance the yield. The preferential precipitation can
be repeated one or more times as needed by dissolving the
precipitate into the same or different solvents to form a new
solution and performing another preferential precipitation, until
the desired enrichment in Z-isomer oxime is obtained.
[0017] Preferably the solution is based on a polar solvent.
Generally, the solubility of the acetic acid salt of the E-isomer
oxime (3) or (7) is much higher than that of the Z-isomer in water,
lower alcohols, and combinations thereof. The lower alcohols have 1
to 6 carbon atoms and preferably are ethanol or n-butanol, although
methanol, isopropanol, and n-propanol can also be used. While the
solution is based on such solvents, others may also be present in
minor amounts. Alternatively, these solvents can be added as
contrasolvents in major or minor amounts to induce preferential
precipitation.
[0018] The acetic acid salts of the oximes of formulae (3) and (7)
form a preferred aspect of the present invention. Any salt that
results from the acid addition reaction of acetic acid with an
oxime of formula (3) or (7) is included within the meaning of an
acetic acid salt. The form of the salt is not limited and
specifically includes solid state forms such as crystalline forms
and liquid or dissolved/dissociated forms. Further, the ratio of
acetic acid cation to oxime while normally 1:1 is not limited
thereto and includes 2:1 and 1:2 ratios for example. The
crystalline forms include any polymorphic forms as well as solvates
including hydrates and alcoholates. The ratio of Z:E isomer ranges
from 0:1 to 1:0. Preferably the acetic acid salt of an oxime of
formula (3) or (7) contains more Z-isomer oxime than E-isomer
oxime, more preferably the salt is at least 80% isomerically pure
Z-isomer (i.e. enriched Z-isomer), still more preferably at least
90% isomerically pure Z-isomer, etc., as described above for the
preferred enriched Z-isomer content.
[0019] The acetic acid salt of the oxime of formula (3) or (7) can
be formed by contacting an acetic acid with the oxime, usually in a
suitable reaction medium, typically a solvent, so as to allow a
salt forming reaction to occur. The acetic acid salt can be
isolated in solid form if desired. Preferably the reaction occurs
in water or a lower alcohol solvent and Z-isomer oxime salt
preferentially precipitate as described above. Accordingly, the
mother liquor is obtained enriched by the undesired E-isomer oxime.
In an advantageous way, even such "waste" may be reprocessed,
particularly by isomerization into the Z-isomer, as explained more
fully hereinafter.
[0020] In another embodiment, the acetic acid salt is formed in
conjunction with the formation or synthesis of the oxime of formula
(3) or (7). In this embodiment, the formation of the oxime, such as
by one of the prior known techniques, is modified so as to include
the presence of acetic acid. For example, reacting a ketone of
formula (2)
##STR00013##
with hydroxylamine in a solvent, preferably n-butanol, in the
presence of acetic acid, preferably at least about 1 molar
equivalent, can allow for preferential precipitation, and
preferably substantially spontaneous preferential precipitation of
the formed Z-isomer oxime of formula (3), while the E-isomer
remains in the solution. In this way, the synthesis of the oxime of
formula (3) can provide an enriched Z-isomer oxime. Similarly, the
formation of the oxime of formula (7) can be carried out in the
presence of acetic acid to directly produce the acetic acid salt,
optionally with preferential precipitation, especially
substantially spontaneous preferential precipitation.
[0021] The acetate salt of enriched Z-isomer oxime of formula (3)
or (7) can be used in further synthesis in the salt form. However,
preferably, the oxime is liberated therefrom as a free base, by
treatment of the above acetate salt with a suitable base in a
suitable solvent. An example of a suitable base is sodium
hydroxide, and an example of a suitable solvent is water.
Preferably, the liberated Z-isomer oxime base is isolated in solid
state such as by filtration or centrifugation.
[0022] An enriched Z-isomer oxime of formula (3) or (7) can also be
obtained by conversion of the E-isomer oxime into the Z-isomer
form. Specifically, by heating the E-isomer, typically a mixture of
the Z- and E-isomers, in a solvent, the E-isomer is converted into
the Z-isomer. More specifically, the undesired E-isomer of the
oxime of formula (3) may be isomerised to the Z-isomer by heating
it in an inert solvent, such as, n-butanol, at a sufficient
temperature, preferably, higher than 80.degree. C. Furthermore, the
heating process may be carried out faster in the presence of an
acid catalyst. The acid catalyst may be an acid or an ammonium or
amine salt of an acid. The suitable acid catalysts include acetic
acid, ammonium acetate, and piperidine acetate. The acid catalyst
is preferably present in a molar excess to the oxime, typically at
least 2-10:1. For example, when heating essentially pure E-isomer
of the oxime of formula (3) with 5 equivalents of acetic acid or
ammonium acetate in n-butanol at 110.degree. C., approximately 90%
converts into the desired Z-isomer in about 6 hours time. Although
both the oximes of formulae (3) and (7) may be used to convert the
E-isomer into Z-isomer, the conversion can occur faster with the
oxime of formula (3). For example, heating essentially pure
E-isomer of the oxime of formula (7) in n-butanol with 5
equivalents of acetic acid at 100.degree. C., a 70% conversion is
obtained after 12 hours. Thus, it is preferred to convert the
E-isomer into the Z-isomer by heating the oxime of formula (3).
[0023] Generally, after cooling the reaction mixture, the produced
enriched Z-isomer oxime can be isolated by conventional methods.
Preferably, the Z-isomer is converted to an acetic acid salt and
preferentially precipitated from the solution and isolated by
filtration or centrifugation. When acetic acid is used as an acid
catalyst for the conversion, spontaneous crystallization as an
acetate salt can occur and/or be induced upon cooling, etc.
[0024] In addition, the enriched Z-isomer oxime of formula (3) or
(7) can be provided by a combination of preferential precipitation
of the acetic acid salt thereof and conversion. For example, the
reaction mixture obtained after separation of the Z-isomer oxime
acetate (a mother liquor) and which contains the undesired E-isomer
oxime acetate can be heated to effect conversion. In particular,
such mother liquor can be concentrated or evaporated, mixed with an
inert solvent of desirably high boiling point, typically at least
100.degree. C., for instance with n-butanol, and isomerised by
heating, e.g. for 2-8 hours, preferably for about 6 hours. After
cooling the reaction mixture, the produced (Z)-oxime can be
separated by conventional methods, but preferably it spontaneously
crystallizes from n-butanol as an acetate salt. For example, the
process of making the oxime (3) may be further improved in that the
ketone (2) reacts with hydroxylamine in n-butanol under presence of
acetic acid, and the reaction mixture is subsequently heated at
enhanced temperature to increase the content of the (Z)-oxime by
isomerization. The produced (Z)-oxime (3) precipitates from the
reaction mixture as the acetate salt.
[0025] In summary, essentially all the oxime (3), whenever produced
by an oximation reaction, may be obtained as a substantially pure
Z-isomer, if using the above procedures according to the invention.
Additionally, the enriched Z-isomer oxime of formula (7) can be
obtained not only by preferential precipitation of an acetate salt
and/or by conversion/isomerization, but it can also be provided
synthetically by using an enriched Z-isomer oxime of formula (3) as
the starting material. Suitable reaction conditions for converting
the oxime of formula (3) into the oxime of formula (7) are
described in the above-mentioned prior art.
[0026] Having provided an enriched Z-isomer oxime of formula (3) or
(7) or salt thereof, the oxime is converted to risperidone, with or
without isolation of the enriched Z-isomer oxime and if in a salt
form, with or without converting to the oxime free base form.
"Converting" to risperidone means any one or more reaction steps
that result in the transformation of the oxime of formula (3) or
(7) into risperidone or a salt thereof. The "converting" process
can include cyclization and/or alkylation of the enriched Z-isomer
oxime to form the end product of risperidone. In this context,
cyclization refers to the ring forming reaction wherein the oxime
moiety together with other atoms is converted into a benzisoxazole
moiety and alkylation refers to alkylating the ring nitrogen of the
piperidinyl moiety. However, any process may be used to convert the
enriched Z-isomer oxime to form the end product risperidone. The
following chart illustrates several convenient pathways for making
risperidone.
##STR00014##
Conveniently, the enriched Z-isomer oxime of formula (3) may be
converted to risperidone by a process that comprises cyclizing and
alkylating. For example, first converting the enriched Z-isomer
oxime to the benzisoxazole compound (4) by a cyclization reaction
using a base, followed by alkylation of compound (4) with the
chloroethyl compound (5) to form risperidone.
##STR00015##
[0027] Additionally, the enriched Z-isomer oxime can be converted
to risperidone by the Z-isomer oxime first alkylating with the
chloroethyl compound (5) to yield an alkylated oxime (7). The
alkylated oxime (7) is then cyclized to risperidone under treatment
with a base. Accordingly, the oxime (3) is alkylated with the
chloroethyl compound (5) in acetonitrile under presence of a
suitable base, preferably potassium carbonate. The alkylation of
the oxime (3) with compound (5) proceeds readily by heating under
reflux for several hours, preferably between 3-5 hours. Upon
dilution with water, or any dilutent, and optional adjustment of
pH, the alkylated oxime (7) precipitates from the reaction mixture
at room temperature. It may be isolated and dried by conventional
techniques. The relative content of the Z-isomer in the produced
oxime (7) (Z/E isomer ratio) after alkylation with (5) is
approximately the same as in the starting oxime (3). Thus no
racemization occurs during the alkylation reaction with the
chloroethyl compound (5) under conventional conditions. As no
racemization proceeds, the alkylation may provide the Z-isomer of
the oxime (7) substantially free from the E-isomer, if starting
from the accordingly pure Z-isomer of the oxime (3). For instance,
the obtained alkylated oxime (7) is enriched preferably by more
than 95% of the desired (Z) isomer.
[0028] The enriched Z-isomer oxime of formula (7) can be converted
to risperidone by cyclization. For example, conversion may occur by
a process of a cyclization under presence of a base, with the
specific feature that the yield of the obtained risperidone is
higher and the content of the contaminating side products,
particularly the uncyclized E-oxime (7), is lower. Suitable solvent
for cyclization can be water, lower alcohol, such as methanol,
ethanol or isopropanol, suitable base is an alkali metal hydroxide,
such as, sodium hydroxide.
[0029] The above techniques for converting the enriched Z-isomer
oxime into risperidone are not exhaustive; other techniques can
also be used. Further, all of the above reagents and reaction
partners are readily available and/or can be made from known or
commercially available starting materials using known methods and
techniques.
[0030] The risperidone is preferentially isolated from the reaction
mixture as a free base, which is a solid, and the crude product may
be optionally further purified, e.g. by a recrystallization from a
suitable solvent. Examples of such solvents are given, e.g., in WO
02/14286.
[0031] The publicly available, under FOIA, Summary Basis of
Approval of US New Drug Application 20-272, incorporated herein by
reference, teaches that risperidone base may be isolated in two
polymorphic modifications, one of them being thermodynamically
stable. Such modification (Form A) exhibits a melting point of
about 169-173.degree. C. and was obtained by crystallization from
ethanol. Also the crystalline structure of risperidone base was
determined by single crystal X-ray diffraction by Peeters et al in
Acta Cryst. (1993), C49, 1698-1700. From these data, X-ray powder
diffraction pattern (XRPD) may be simulated. The risperidone
product obtained by crystallization from ethanol (the Form A) has
crystalline structure corresponding to that shown in the cited
article. In the present invention, the same solid state product
(form A) and having the same properties may also be obtained by
crystallization from most ordinary solvents, such as an
alcohol/water mixture or isopropanol.
[0032] In a preferred mode of crystallization, a water/alcohol
solvent mixture is used. More preferably, the crude risperidone
base is dissolved in water by aid of an acid, e.g. acetic acid,
alcohol is added and the acid is neutralized by a base, e.g. sodium
hydroxide. This technique allows the use of higher concentrations
of risperidone and lower, even ambient, crystallization
temperatures, thus improving economy of the process and purity of
the product. The produced risperidone is typically a white or
off-white crystalline product. Its purity, as determined by HPLC,
is typically higher than 99% and it contains less than 1% of
related impurities, particularly is essentially free (less than
0.2%, and preferably below limits of detection) from 9-hydroxy
risperidone. Dried risperidone product is also essentially free
from bound water or other solvents. Typically, it contains less
than 5%, preferably less than 1% of water or a solvent,
particularly alcohol. For pharmaceutical applications, a product
with an average particle size of less than 100 microns is
preferred.
[0033] The invention is further illustrated by the following
non-limiting examples:
EXAMPLES
Example 1
Preparation of Z- and E-Isomers of the Oxime (3)
Step 1
[0034] 19.9 g of hydroxylamine hydrochloride is suspended in 200 ml
of ethanol and 38.2 g of 50% water solution of sodium hydroxide is
added. The suspension is stirred for 10 min. 50 g of
4-(2,4-difluorobenzoyl)piperidine hydrochloride is added and the
suspension stirred for the next 10 min. Then the crystals are
filtered off and washed with 2.times.25 ml of ethanol. 25 g of
ammonium acetate is added to the filtrate and the reaction mixture
agitated at 60.degree. C. for 10 hrs. The reaction mixture is
acidified with 6.5 ml of acetic acid and cooled to -15.degree. C.
for 4 hours. A white solid is filtered off and washed at
-15.degree. C. with 2.times.25 ml of ethanol. The product is
air-dried. Yield: 43.42 g (75.7% of theoretical yield) of Z-isomer
oxime (3) acetate.
Step 2
[0035] The solvent is evaporated from the mother liquor of the Step
1 at 70.degree. C. and the oily residue diluted with 100 ml of
water and acidified with 10 ml of acetic acid. The solution is
extracted with 3.times.50 ml of ethyl acetate, the ethyl acetate
extracts are extracted with 50 ml of water. 100 ml of ethyl acetate
is added to the water solution and the emulsion alkalinized to
pH=11 with 50% NaOH. The water layer is extracted with next
3.times.50 ml of ethyl acetate. Collected ethyl acetate solutions
are extracted with 50 ml of water. The solvent is evaporated at
70.degree. C. The crude product is dissolved in 410 ml of ethyl
acetate at 77.degree. C. A clear solution is slowly cooled and a
suspension obtained. The crystallization was finished by standing
in a refrigerator at -15.degree. C. for 14 hours. The crystals are
filtered off and washed with 2.times.20 ml of ethyl acetate. The
crystals are air-dried. Yield: 13.15 g (28.5% of theoretical yield)
of E-isomer oxime (3).
Step 3
[0036] 43.42 g of risperidone oxime Z-isomer acetate from Step (1)
is suspended in 170 ml of water and the suspension alkalized with
50% NaOH to pH=10 and stirred for 1 hour at room temperature. The
white solid is filtered off and washed with 3.times.100 ml of
water. The product is air-dried. Yield: 27.79 g (60.5% of
theoretical yield) of Z-isomer oxime (3).
Example 2
Z-Isomer of the Oxime Compound (3)
Step 1--Acetate Salt of the Z-Isomer of the Oxime (3)
[0037] 15.93 g of hydroxylamine hydrochloride is suspended in 125
ml of ethanol and 33.62 g of 50% water solution of sodium hydroxide
is added dropwise at 20-30.degree. C. After 15 minutes of stirring,
32.8 ml of acetic acid and 50 g of
4-(2,4-difluorobenzoyl)piperidine hydrochloride is added. The
suspension is then heated for 7 hours at 78-80.degree. C. (reflux).
The solid is then filtered off after 1 hour of agitating at
20.degree. C. and is then washed with 2.times.30 ml of ethanol.
Yield: Wet product containing 63.43 g of dry substance comprising
Z-oxime (3) acetate. Purity (HPLC): 98.3%.
Step 2--Isomerization of the (E)-Oxime(3) Acetate to the (Z)-Oxime
(3) Acetate
[0038] The filtrate from the step (1) is evaporated to approx. 35
ml at reduced pressure and 15 ml of n-butylalcohol is added. The
suspension is heated for 6.5 hours at 110.degree. C. The reaction
mixture was cooled to 20.degree. C. and agitated for 1 hour. White
solid is filtered off and washed with 10 ml of ethanol. Yield: Wet
product-containing 17.3 g of Z-oxime (3) acetate. Purity (HPLC):
97.0%
Step 3--Recovery of the Z-oxime (3) from the Z-oxime(3) acetate
[0039] Both parts of wet Z-oxime(3) acetate from step 1 and step 2
are suspended in 230 ml of water at 60.degree. C. and the
suspension is alkalinized with 68 ml of 10% NaOH to pH=10. The
suspension is agitated for 30 minutes at 60.degree. C. and 60
minutes at 20.degree. C. The solid is filtered off and washed with
2.times.10 ml of water. The crystals are dried. Yield: 44.5 g
(96.9%) of Z-oxime (3) base. Purity (HPLC): 98.6%
Example 3
Preparation of Z-Isomer of the Oxime (7)
[0040] 1.11 g of potassium iodide, 51.2 ml of acetonitrile, 8.76 g
of
3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2a]pyrimidin-4--
one hydrochloride, 4.6 g of potassium carbonate and 8.0 g of
Z-oxime (3) base are mixed. The suspension is heated at reflux
(78.degree. C.) for 3.5 h. The reaction mixture is cooled to room
temperature and 104 ml of water is added. The pH of the suspension
is adjusted to 10 (50% KOH) and is agitated at room temperature for
4 hrs. The crystals are filtered off, washed with 30 ml of water
and dried. Yield: 13.42 g (93.6% of theoretical yield). Purity
(HPLC): 96.23%
Example 4
(Z)-Oxime (7) from (Z)-Oxime (3) Acetate
[0041] 22.9 g of the
3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2a]pyrimidin-4--
one hydrochloride, 26.1 g of Z-oxime (3) acetate and 4.6 g of
potassium iodide were suspended in 92 ml of ethanol and 20.5 g of
50% KOH was added. The suspension was stirred at 70.degree. C. for
11 hours. The reaction mixture (pH=9) was evaporated to dryness,
the residue was dissolved in 350 ml of water and was extracted with
3.times.350 ml of ethyl acetate. Collected organic layers were
extracted with 2.times.500 ml of 2% acetic acid and the organic
layer was extracted with 50 ml of water. The water extracts were
alkalized with 35 ml of 50% KOH to pH=10-10.5. The emulsion was
extracted with 2.times.400 ml of ethyl acetate and then with
2.times.200 ml of ethyl acetate. Ethyl acetate layers were
extracted with 100 ml of water and 50 ml of saturated brine. The
organic solution was evaporated at 70.degree. C. Yield: 26.0 g
(69.4% of theoretical yield) of crude oxime (7) base Z-isomer. The
residue was dissolved at 80.degree. C. in 250 ml of ethanol. The
solution was slowly cooled to 20.degree. C. and stirred for 1 hour;
then cooled to -15.degree. C. and let stand for 12 hours. The
crystals were filtered off and washed with 2.times.10 ml of
ethanol. Yield: 17.86 g (47.7% of theoretical yield) of
crystallized oxime (7) base Z-isomer (purity 97.6%).
Example 5
Preparation of the (E)-Oxime (7)
[0042] 13.0 g of 4-(2,4-difluorobenzoyl)piperidine hydrochloride,
14.83 g of E-oxime (3) acetate and 2.6 g of potassium iodide are
suspended in 52 ml of ethanol and 11.6 of 50% KOH is added. The
suspension is stirred at 60.degree. C. for 9 hours. The reaction
mixture (pH=9) was evaporated to dryness, the residue was dissolved
in 200 ml of water, pH was set up to 10-10.5 and the product was
extracted with 3.times.200 ml of chloroform. Collected organic
layers are extracted with 50 ml of water, 500 ml of 2% acetic acid
and then 2.times.250 ml of 2% acetic acid. The water extract is
alkalized with 50% NaOH to pH=10.5 and the solution extracted with
3.times.150 ml of chloroform. Chloroform solution is extracted with
2.times.50 ml of water. The solvent is evaporated at 60.degree. C.
Yield: 25.35 g of crude E-isomer oxime (7) base. The residue is
dissolved at 80.degree. C. in 122 ml of methanol. The solution is
slowly cooled to 20.degree. C. and stirred for 1 h. Then it is
cooled to -15.degree. C. and left standing for 12 hours. The
crystals are filtered off and washed with 2.times.10 ml of
methanol. Yield: 10.34 g (48.6% of theoretical yield) of
crystallized oxime (7) base E-isomer.
Example 6
Cyclization Experiments on the Oxime (7)
[0043] 0.2 g of essentially pure Z- or E-isomer of the oxime (7) is
attempted to be converted into risperidone by dissolving in 2 ml of
ethanol, adding 0.1 g of 50% aqueous KOH and heating the mixture
under stirring at 80.degree. C. Samples of the reaction mixture are
taken and analyzed by HPLC.
TABLE-US-00001 Results of HPLC (in area %): t = 0 t = 1 t = 3 t = 5
hrs a) E-oxime (7) 99.6 91.5 91.5 90.0 Risperidone: 0 3.7 4.0 4.2
b) Z-oxime(7) 97.6 0.7 0.6 0.5 Risperidone 0 97.8 96.7 95.5
Observations: Sub a): Adding another KOH and prolonged heating did
not lead to an increase of risperidone in the reaction mixture. Sub
b): One hour is sufficient to perform a conversion. Prolonged
heating leads to an increased amount of by-products.
Example 7
Cyclization Experiments on Oxime (3)
[0044] 0.2 g of essentially pure Z- or E-isomer of the oxime (3) is
attempted to convert into the benzisoxazole compound (4) by
dissolving in 2 ml of ethanol, adding 0.18 g of 50% aqueous KOH and
heating the mixture under stirring at 80.degree. C. Samples of the
reaction mixture were taken and analyzed by HPLC.
TABLE-US-00002 Results of HPLC (in area %): a) t = 0 t = 2 t = 4 t
= 6 hrs E-oxime (3) 99.3 88.4 88.5 89.2 Benzisoxazole (4): 0 7.1
7.1 7.4 b) t = 0 t = 1 t = 2 hrs Z-oxime(3) 97.7 1.0 1.0
Benzisoxazole (4): 0 96.9 96.5
Example 8
Risperidone from the Z-Oxime (7)
[0045] 85 ml of ethanol, 6.97 g of sodium hydroxide, 3.32 g of
borax and 50.0 g of the Z-oxime (7) are agitated for 30 min. at
70.degree. C. The reaction mixture is diluted with 200 ml of water
at 40.degree. C. and the suspension is agitated for 2 hours at room
temperature. The crystals are filtered off, washed with 25 ml of
water and dried. Yield: 45.26 g (94.9% of the theoretical yield) of
crude risperidone. Purity (HPLC): 97.2%
Example 9
Risperidone from Z-Oxime (7)
[0046] 1.7 ml of ethanol, 0.40 g of 50% solution of potassium
hydroxide, 0.07 g of borax and 1.00 g of oxime (7) Z-isomer base
are agitated at 40.degree. C. for 15 min. The temperature is
increased to 70.degree. C. and the suspension agitated for 15
minutes. The reaction mixture is diluted with 8.0 ml of water and
the suspension agitated for 1 hour at room temperature. The
crystals are filtered off, washed with 10 ml of water and dried.
Yield: 0.8 g (83.9% of theoretical yield) of risperidone.
Example 10
Crystallization of Risperidone from 2-Propanol/Water
[0047] 5.08 g of risperidone is dissolved at room temperature in
10.2 ml of water and 0.81 g of acetic acid. The solution is
filtered and diluted with 20.3 ml of water and 10.2 ml of
isopropanol. To the stirred solution is added dropwise a solution
of 1.52 g of 50% sodium hydroxide solution in 10.2 ml of water.
Upon completion, stirring was continued for 1 hour at 70.degree. C.
The crystals are filtered off and washed with 2.0 ml of water. The
product is dried in air. Yield: 4.73 g (93.11% of theory). DSC:
Form A.
Example 11
Crystallization of Risperidone from Ethanol/Water
[0048] 5.05 g of risperidone is dissolved at room temperature in
10.1 ml of water and 0.81 g of acetic acid. The solution is
filtered and diluted with 20.2 ml of water. The solution is poured
dropwise into a solution of 1.52 g of 50% sodium hydroxide solution
in 10.1 ml of water and 10.1 ml of ethanol. Upon completion,
stirring is continued for 1 hour at 25.degree. C. temperature. The
crystals are filtered off and washed with 2.0 ml of water. The
product is dried in air. Yield: 4.68 g (92.67% of theory). DSC:
Form A.
Example 12
Crystallization of Risperidone from N,N-dimethylformamide
[0049] 5.62 g of risperidone is dissolved at 78.degree. C. in 62.0
ml of N,N-dimethylformamide. The solution is cooled to 20.degree.
C. The mixture is stirred for 1 hour. The crystals are filtered off
and washed with 2.times.3 ml of 2-propanol. The product is dried.
Yield: 3.95 g (70.29% of theory). DSC: Form A.
Example 13
Crystallization of Risperidone from 2-propanol
[0050] 5.62 g of risperidone is dissolved at 78.degree. C. in 82.0
ml of 2-propanol. The solution is cooled to 20.degree. C. The
mixture is stirred for 1 hour. The crystals are filtered off and
washed with 2.times.3 ml of 2-propanol. The product is dried.
Yield: 4.60 g (81.85% of theory). DSC: Form A.
Example 14
Crystallization of Risperidone from Ethanol/Water
[0051] 5.00 g of crude risperidone is suspended in 10 ml of water
and 0.80 g of acetic acid is added. After dissolving, the solution
is filtered. The clear solution diluted with 30 ml of ethanol and
then alkalized dropwise during 20 minutes with a solution of 1.5 g
of 50% sodium hydroxide in 10 ml of water at 35-40.degree. C.
(pH=9.5-10). The suspension is agitated at 20.degree. C. for 1
hour. The product is filtered off and washed with 5 ml of distilled
water (neutral reaction). Yield: 3.91 g (78% of the theoretical
yield)
Example 15
Crystallization of Risperidone from Methanol/Water
[0052] 5.00 g of crude risperidone is suspended in 10 ml of water
and 0.80 g of acetic acid is added. After dissolving, the solution
is filtered. The clear solution is diluted with 30 ml of methanol.
The solution is alkalized dropwise during 20 minutes with a
solution of 1.5 g of 50% sodium hydroxide in 10 ml of water at
35-40.degree. C. (pH=9.5-10). The suspension is agitated at
22.degree. C. for 1 hour. The product is filtered off and was
washed with 5 ml of distilled water (neutral reaction). Yield: 4.61
g (92% of the theoretical yield).
Example 16
Crystallization of Risperidone from Ethanol
[0053] 5 g of risperidone is dissolved in 20 ml of ethanol at
reflux. The solution is cooled spontaneously to ambient temperature
and agitated for 1 hour. The crystals are filtered off and dried.
Yield: 4.58 g (91.6% of the theoretical yield). DSC: Form A.
Example 17
Crystallization of Risperidone from Methanol
[0054] 6 g of risperidone is dissolved in 21.8 ml of methanol at
reflux. The solution is cooled spontaneously to ambient temperature
and agitated for 1 hour. The crystals are filtered off and dried.
Yield: 4.77 g (80% of the theoretical yield). DSC: Form A. Each of
the patents, articles, and publications mentioned above is
incorporated herein by reference in its entirety. The invention
having been thus described, it will be obvious to the worker
skilled in the art that the same may be varied in many ways without
departing from the spirit of the invention and all such
modifications are included within the scope of the present
invention as set forth in the following claims.
* * * * *