U.S. patent application number 11/721697 was filed with the patent office on 2008-08-14 for process for preparing voriconazole.
Invention is credited to Surya Prabhakar Akundi, Vijayawardhan Chitta, Surya Narayana Devarakonda, Alekhya Donthula, Manoj Ramesh Kharkar, Venkateswarlu Muvva, Subba Reddy Peddireddy, Venkataraman Sundaram, Venkata Bhaskara Rao Uppala.
Application Number | 20080194820 11/721697 |
Document ID | / |
Family ID | 36588428 |
Filed Date | 2008-08-14 |
United States Patent
Application |
20080194820 |
Kind Code |
A1 |
Sundaram; Venkataraman ; et
al. |
August 14, 2008 |
Process For Preparing Voriconazole
Abstract
Voriconazole is prepared by a process comprising condensing
1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl)ethanone with
4-chloro-6-ethyl-5-fluoropyrimidine, in a ketone, ether, aliphatic
hydrocarbon, or aromatic hydrocarbon solvent, to give (2R,
3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1-(1H-
-1,2,4-triazole-1-yl)butan-2-ol.
Inventors: |
Sundaram; Venkataraman;
(Hyderabad, IN) ; Uppala; Venkata Bhaskara Rao;
(Hyderabad, IN) ; Akundi; Surya Prabhakar;
(Hyderabad, IN) ; Muvva; Venkateswarlu;
(Hyderabad, IN) ; Chitta; Vijayawardhan;
(Warangal, IN) ; Donthula; Alekhya; (Secunderabad,
IN) ; Kharkar; Manoj Ramesh; (Hyderabad, IN) ;
Devarakonda; Surya Narayana; (Hyderabad, IN) ;
Peddireddy; Subba Reddy; (Hyderabad, IN) |
Correspondence
Address: |
DR. REDDY'S LABORATORIES, INC.
200 SOMERSET CORPORATE BLVD, SEVENTH FLOOR,
BRIDGEWATER
NJ
08807-2862
US
|
Family ID: |
36588428 |
Appl. No.: |
11/721697 |
Filed: |
December 13, 2005 |
PCT Filed: |
December 13, 2005 |
PCT NO: |
PCT/US2005/044867 |
371 Date: |
June 14, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60635783 |
Dec 14, 2004 |
|
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|
60684667 |
May 26, 2005 |
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Current U.S.
Class: |
544/333 |
Current CPC
Class: |
C07D 403/02
20130101 |
Class at
Publication: |
544/333 |
International
Class: |
C07D 239/26 20060101
C07D239/26 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 13, 2005 |
IN |
427/CHE/2005 |
Jul 6, 2005 |
IN |
887/CHE/2005 |
Claims
1. A process for preparing voriconazole, comprising the step of
condensing 1(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl)
ethanone with 4-chloro-6-ethyl-5-fluoropyrimidine, in a ketone,
ether, aliphatic hydrocarbon, or aromatic hydrocarbon solvent, to
give
(2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1-
-(1H-1,2,4-triazole-1-yl)butan-2-ol.
2. The process of claim 1, wherein condensing is conducted in the
presence of an organolithium derivative.
3. The process of claim 1, wherein condensing is conducted in the
presence of a C.sub.1-C.sub.6 alkyl lithium compound.
4. The process of claim 1, wherein condensing is conducted in the
presence of a C.sub.1-C.sub.6 alkyl lithium compound, optionally
condensed with an amine having one or more C.sub.1-C.sub.6 alkyl
group substituents on a nitrogen atom.
5. The process of claim 1, wherein condensing is conducted in an
aliphatic hydrocarbon solvent.
6. A process for preparing voriconazole, comprising the steps of:
a) condensing 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl)
ethanone with 4-chloro-6-ethyl-5-fluoropyrimidine, in a ketone,
ether, aliphatic hydrocarbon, or aromatic hydrocarbon solvent, to
give
(2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1-
-(1H-1,2,4-triazole-1-yl)butan-2-ol; b) hydrogenating
(2R,3S/2S,3R)-3-(4-chloro-5-fluropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1--
(1H-1,2,4-triazole-1-yl)butan-2-ol to give
(2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2-
,4-triazol-1yl)butan-2-ol; c) resolving
(2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoro
pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1yl)butan-2-ol to afford a
diastereomeric salt of
(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-tri-
azol-1yl)butan-2-ol; and d) converting a diastereomeric salt to
voriconazole.
7. The process of claim 6, wherein condensing is conducted in the
presence of an organolithium derivative.
8. The process of claim 6, wherein condensing is conducted in the
presence of a C.sub.1-C.sub.6 alkyl lithium compound.
9. The process of claim 6, wherein condensing is conducted in an
aliphatic hydrocarbon solvent.
10. The process of claim 6, wherein resolving comprises reacting
(2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoro
pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1yl)butan-2-ol with a chirally
active acid to form a diastereomeric salt.
11. The process of claim 6, wherein a product from the condensing
is not subjected to a chromatographic separation, prior to step
b).
12. Voriconazole prepared by the process of claim 6, having a
purity at least about 95 area-percent, by high performance liquid
chromatography.
13. Voriconazole prepared by the process of claim 6, having a
purity at least about 99 area-percent, by high performance liquid
chromatography.
14. Voriconazole prepared by the process of claim 6, having a
purity at least about 99.5 area-percent, by high performance liquid
chromatography.
15. The voriconazole of claim 12, containing less than about 0.15
area-percent, by high performance liquid chromatography, of each of
the impurities: 2,4-difluro-1H-1-yl-1,2,4-triazolacetophenone;
6-ethyl-5-fluoropyrimidine; 4-chloro-6-ethyl-5-fluropyrimidine;
6-[(1-(5-fluoropyrimidinyl)-6-ethyl]-4-chloro-5-fluoropyrimidine;
(2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)--
1-(1H-1,2,4-triazol-1-yl)-butan-2-ol;
(2R,3R/2S,3S)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)--
1-(1H-1,2,4-triazol-1-yl)-butan-2-ol;
(2R,3R/2S,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2-
,4-triazol-1-yl)-butan-2-ol; and
(2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-tri-
azol-1-yl)-butan-2-ol.
16. The voriconazole of claim 12, containing the residual solvents:
acetone less than about 5000 ppm; isopropyl alcohol less than about
5000 ppm; and being substantially free from hexane, heptane, and
tetrahydrofuran.
17. Form A of voriconazole, having an X-ray powder diffraction
pattern, using copper K .alpha. radiation, substantially according
to FIG. 1.
18. The Form A of voriconazole of claim 17, having an X-ray powder
diffraction pattern, using copper K .alpha. radiation, comprising
peaks at about 6.9, 9.2, 10.7, 12.7, 13.7, 13.9, 14.4, 14.8, 15.3,
19.8, 20.8, and 27.0, .+-.0.2 degrees two theta.
19. The Form A of voriconazole of claim 17, prepared by a process
comprising: dissolving voriconazole in a solvent comprising water
at reflux temperatures; and cooling to obtain separation of solid
voriconazole.
20. The form A of voriconazole of claim 19, wherein a solvent
comprises water and an organic solvent.
21. Amorphous voriconazole.
22. The amorphous voriconazole of claim 21, prepared by a process
comprising: providing a solution of voriconazole and a carrier in
an organic solvent; and removing solvent to obtain a solid residue
comprising amorphous voriconazole.
23. The amorphous voriconazole of claim 21, wherein a carrier
comprises a polymer of N-vinylpyrrolidone.
24. A process for preparing crystalline Form B of voriconazole,
comprising: adding water to a solution of voriconazole in a solvent
at an elevated temperature; and cooling to obtain separation of
solid voriconazole.
25. The process of claim 24, wherein a solvent is a ketone.
Description
[0001] The present invention relates to processes for the
preparation of voriconazole and its polymorphs. More specifically,
the invention provides a process for the preparation of pure
voriconazole, substantially free from impurities. The invention
also relates to crystalline forms A and B of voriconazole as well
as its amorphous form. The invention further relates to processes
for the preparation of the different forms of voriconazole.
Voriconazole has the chemical name
(2R,3S)-2-(2,4-diflurophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-tria-
zol-1-yl)-butan-2-ol and is represented by the structural Formula
I.
##STR00001##
[0002] Voriconazole is used for the treatment of invasive
aspergilli; treatment of fluconazole-resistant, severe, invasive
candida infections (including C. krusei); treatment of severe
fungal infections with scedosporium spp. and Fusarium spp. Its
commercially available embodiment is sold as VFEND.TM. in the form
of an injectable formulation (200 mg per vial), solid oral
formulations as 50 mg and 200 mg tablets and an oral suspension
containing 200 mg of voriconazole/5 ml.
[0003] U.S. Pat. Nos. 5,278,175 and 5,567,817 disclose
voriconazole, its pharmaceutically acceptable salts, pharmaceutical
compositions comprising voriconazole and their use in the treatment
of fungal infections. They also disclose a process for the
preparation of voriconazole, which can be depicted by Scheme 1.
##STR00002##
[0004] In brief, the process includes the reaction of
1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl)ethanone of
Formula II with 4-chloro-6-ethyl-5-fluoropyrimidine of Formula III,
in the presence of lithium diisopropylamide and in a
tetrahydrofuran medium, to yield
3-(4-chloro-5-fluropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-tri-
azole-1yl) butan-2-ol as a residue. Column chromatography of the
residue on silica using 3:2 ethyl acetate/diethyl ether as the
eluant, first gave, after combination and evaporation of
appropriate fractions and trituration with diethyl ether, a 2R,3S
and 2S,3R enantiomeric pair of
3-(4-chloro-5-fluropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1-(1H-1,2,4-tria-
zole-1-yl) butan-2-ol of Formula IV, with a 12% yield. This, on
hydrogenation with a 10% Pd/C catalyst in ethanol, in the presence
of sodium acetate, followed by flash chromatographic separation
yields (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoro
pyrimidin-4-yl)-1-(1H-1,2,4- triazol-1 yl) butan-2-ol of Formula V.
The compound of Formula V on resolution with R-(-)-10-camphor
sulfonic acid in methanol gives a corresponding
camphorsulfonate.0.5 methanol, which on hydrolysis with aqueous
sodium bicarbonate solution gives voriconazole of Formula I.
[0005] The aforementioned process involves the chromatographic
separation of a 2R,3S and 2S,3R enantiomeric pair from the residue
containing four possible enantiomers of the intermediate compound
of Formula IV, leading to poor yields. The process also uses
palladium on charcoal as a catalyst in the reaction for preparation
of Formula V and involves chromatographic purification, resulting
in a process that is expensive and difficult to operate on an
industrial scale.
[0006] U.S. Pat. No. 6,586,594 discloses a process for the
preparation of voriconazole, which comprises condensing
1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone of formula
II with 6-(1-bromoethyl)-2,4-dichloro-5-fluoropyrimidine in the
presence of zinc powder, lead powder, and iodine in tetrahydrofuran
to give the compound of Formula IV. This compound on reduction
using a 10% Pd/C (palladium on carbon) catalyst followed by
resolution with R-(-)-camphor-10-sulphonic acid resulted in the
formation of voriconazole, which was isolated in isopropanol. The
product recovered from this process appears to correspond with the
crystalline form of voricanazole identified below as "Form B."
[0007] This process also involves the use of toxic and/or expensive
reagents such as zinc, lead, iodine, and Pd/C resulting in a
process that is expensive and difficult to operate on an industrial
scale.
[0008] There is always a need for newer routes of synthesis of
commercially important pharmaceutically active compounds,
especially routes that are commercially feasible, using reactants
and conditions that are non-toxic, cost effective, and
environmentally friendly.
[0009] Regulatory authorities internationally desire to have all
possible polymorphic forms of a new drug substance identified prior
to approval of a product containing the drug. However, as is well
known in the art, the existence of polymorphic forms of any given
compound cannot be predicted, and there is no standard procedure
for proceeding to make a previously unknown polymorphic form. Even
after a polymorph has been identified, there is no possibility of
predicting whether any additional forms will ever be discovered.
This situation has been the subject of recent articles, including
A. Goho, "Tricky Business," Science News, Vol. 166, No. 8, pages
122-123 (August 2004). So also, it is impossible to predict whether
it would be possible to obtain an amorphous or other form of a new
drug substance and what would be its stability. There is thus also
a need to prepare and identify different crystalline and amorphous
forms of such compounds.
[0010] Consequently, it would be a significant contribution to the
art to provide newer and improved processes for the synthesis of a
commercially important compound such as voriconazole, its different
polymorphic forms and its amorphous form, pharmaceutical
formulations containing these forms, and methods of use
therefor.
SUMMARY OF THE INVENTION
[0011] The present invention relates to processes for the
preparation of voriconazole and its polymorphs. The invention also
relates to novel crystalline form A of voriconazole, as well as to
its amorphous form.
[0012] In one aspect, the invention provides a process for
preparing voriconazole, comprising condensing
1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl) ethanone with
4-chloro-6-ethyl-5-fluoropyrimidine, in a ketone, ether, aliphatic
hydrocarbon, or aromatic hydrocarbon solvent, to give
(2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1-
-(1H-1,2,4-triazole-1-yl)butan-2-ol.
[0013] An aspect of the present invention relates to a process for
the preparation of voriconazole of Formula I comprising the steps
of:
[0014] a) condensing
1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl) ethanone with
4-chloro-6-ethyl-5-fluoropyrimidine to give
(2R,3S/2S,3R)-3-(4-chloro-5-fluropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1--
(1H-1,2,4-triazole-1-yl)butan-2-ol;
[0015] b) hydrogenating
(2R,3S/2S,3R)-3-(4-chloro-5-fluropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1--
(1H-1,2,4-triazole-1-yl)butan-2-ol to give
(2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoro
pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1 yl)butan-2-ol;
[0016] c) resolving
(2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoro
pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1yl) butan-2-ol to afford a
diastereomeric salt; and
[0017] d) converting the diastereomeric salt to voriocnazole.
[0018] In another aspect, the present invention provides
substantially pure voriconazole free from impurities and a process
for preparation thereof.
[0019] According to this embodiment of the invention, voriconazole
containing low concentrations of any one or more of the following
impurities as determined by HPLC, is provided:
[0020] a) 2,4-difluro-1H-1-yl-1,2,4-triazole acetophenone;
[0021] b) 6-ethyl -5- fluoro pyrimidine;
[0022] c) 4-chloro-6-ethyl-5-fluro pyrimidine;
[0023] d) 6-[(1-(5-fluoro pyrimidinyl)-6-ethyl]-4-chloro-5-fluoro
pyrimidine
[0024] e) (2R,3S/2S,3R)-3-(4-chloro-5-
fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-
an-2-ol;
[0025] f) (2R,3R/2S,3S)-3-(4-chloro-5-
fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)but-
an-2-ol;
[0026] g) (2R, 3R/2S,
3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1(1H-1,2,4-triazol--
1-yl)butan-2-ol; and
[0027] h)
(2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1(1H-1-
,2,4-triazol-1-yl)butan-2-ol.
[0028] In yet another aspect, the present invention provides
crystalline Form A of voriconazole.
[0029] In a further aspect, the present invention provides
processes for the preparation of crystalline Form A and Form B of
voriconazole.
[0030] In a still further aspect, the present invention provides
amorphous voriconazole either alone or in combination with a
pharmaceutically acceptable carrier and a process for the
preparation thereof.
[0031] In another aspect the present invention provides a
pharmaceutical composition containing one or more of crystalline
form A, crystalline form B and amorphous voriconazole, and
processes for the preparation thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 is an X-ray powder diffraction ("XRPD") pattern for
crystalline Form A of voriconazole as prepared in Example 5.
[0033] FIG. 2 is a differential scanning calorimetry curve for
crystalline Form A of voriconazole as prepared in Example 5.
[0034] FIG. 3 is an infrared absorption spectrum of crystalline
Form A of voriconazole as prepared in Example 5.
[0035] FIG. 4 is an X-ray powder diffraction pattern for the
crystalline Form B of voriconazole as prepared in Example 7.
[0036] FIG. 5 is a differential scanning calorimetry curve for
crystalline Form B of voriconazole as prepared in Example 7.
[0037] FIG. 6 is an infrared absorption spectrum of crystalline
Form B of voriconazole as prepared in Example 7.
[0038] FIG. 7 is an X-ray powder diffraction pattern for the
amorphous voriconazole as prepared in Example 10.
DETAILED DESCRIPTION
[0039] The X-ray diffraction information presented herein is
obtained using copper K.alpha. radiation (1.541 .ANG. wavelength).
The XRPD patterns show intensity on the vertical axis and the
2.theta. angle, in degrees, on the horizontal axis.
[0040] This invention, in certain aspects, relates to processes for
making voriconazole and its different polymorphic forms, including
its amorphous form.
[0041] In one aspect, the invention provides a process for the
preparation of voriconazole of Formula I comprising the steps
of:
[0042] a) condensation of the compound
1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl) ethanone of
Formula II
##STR00003##
with the compound 4-chloro-6-ethyl-5-fluoropyrimidine of Formula
III
##STR00004##
in the presence of an organolithium derivative in a suitable inert
solvent medium to give the compound
(2R,3S/2S,3R)-3-(4-chloro-5-fluropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1--
(1H-1,2,4-triazole-1-yl)butan-2-ol of Formula IV;
##STR00005##
[0043] b) hydrogenation of the compound of Formula IV in the
presence of a noble metal catalyst in a suitable solvent medium to
give the racemic compound
(2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoro
pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1yl)-butan-2-ol of Formula
V;
##STR00006##
[0044] c) resolution of the racemic compound of Formula V, with
R-(-)-10-camphor sulfonic acid in a suitable solvent, to afford the
diasteriomeric salt
(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-tri-
azol-1yl)butan-2-ol R-(-)-10-camphor sulphonate of Formula VI;
and
##STR00007##
[0045] d) conversion of the compound of Formula VI to voriconazole
by hydrolysis with a suitable base in a suitable solvent.
[0046] Step a) involves the condensation of
1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl) ethanone of
Formula II with the compound 4-chloro-6-ethyl-5-fluoropyrimidine of
Formula III in the presence of an organolithium derivative in a
suitable inert solvent medium to give the compound
(2R,3S/2S,3R)-3-(4-chloro-5-fluropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1--
(1H-1,2,4-triazole-1-yl)-butan-2-ol of Formula IV.
[0047] Suitable inert solvents include but are not limited to any
solvent or mixture of solvents in which the required components are
soluble, such as for example: ethers such as diethyl ether,
dimethyl ether, diisopropyl ether, methyl tertiary-butyl ether,
tetrahydrofuran, 1,4-dioxane and the like; aliphatic hydrocarbons
such as C.sub.1-C.sub.10 straight chain or branched hydrocarbons,
and the like; and aromatic hydrocarbons such as toluene, xylene and
the like.
[0048] Suitable organolithium compounds include C.sub.1-C.sub.6
alkyl lithium compounds, optionally condensed with amines having
one or more C.sub.1-C.sub.6 alkyl group substituents on a nitrogen
atom.
[0049] After completion of the condensation, the reaction mass can
be quenched by adding a suitable acid such as acetic acid and then
diluting with water. After removal of the solid that is produced,
such as by filtration, the organic layer of the filtrate can be
separated and cooled to form the solid product
(2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)--
1-(1H-1,2,4-triazole-1-yl)-butan-2-ol of Formula IV. No
chromatographic separation is needed to recover this product,
before it is subjected to further processing.
[0050] Suitable temperatures for solid product formation can range
from about -40 to 40.degree. C., or about -20 to -0.degree. C., or
about -10 to 31 15.degree. C.
[0051] If desired, the solid product can be dried using any
technique, such as for example fluid bed drying (FBD), aerial
drying, oven drying or other techniques known in the art. The
drying can be conducted at temperatures of about 50-100.degree. C.
or about 30-40.degree. C., with or without application of vacuum.
It is also contemplated that the drying can be carried out under
inert atmosphere conditions, if desired.
[0052] Step b) involves hydrogenation of
(2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)--
1-(1H-1,2,4-triazole-1-yl)-butan-2-ol of Formula IV in the presence
of a noble metal catalyst in a suitable solvent medium, to afford
the compound
(2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2-
,4-triazol-1yl)-butan-2-ol of Formula V.
[0053] Examples of the noble metal catalyst that can be used in
this process include without limitation Raney nickel, platinum,
iridium, ruthenium, and the like.
[0054] The suitable solvent medium includes but is not limited to
alcohol solvents such as C.sub.1-10 straight chain or branched
alcohols, or their mixtures.
[0055] The temperatures for conducting the reaction can range from
about 20-80.degree. C., or about 30-50.degree. C., or about
40-45.degree. C., under hydrogen pressures ranging from about 2-10
kg/cm.sup.2, or about 4-6 kg/cm.sup.2.
[0056] Step c) involves resolution of racemic compound
(2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2-
,4-triazol-1yl)-butan-2-ol of Formula V, with a suitable reagent in
a suitable solvent to form the diastereomeric salt
(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-tri-
azol-1 yl)-butan-2-ol-R-(-)-10-camphor sulphonate of Formula
VI.
[0057] Suitable reagents that can be used in the resolution
reaction of step c) include any chirally active acid which will
form salts and separate the isomers. Examples include
R-(-)-10-camphor sulfonic acid, L-(-)-mandelic acid, and
L-(-)-tartaric acid, and the like.
[0058] The solvents useful in this step of the process include
solvents such as, for example: ketones such as acetone, ethyl
methyl ketone and the like; alcohols such as methanol, ethanol, and
isopropanol and like; or their mixtures.
[0059] In one embodiment a mixture of a ketone solvent and an
alcohol solvent may be used, such as for example acetone and
methanol.
[0060] Step d) involves conversion of
(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro
pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1yl)-butan-2-ol-R-(-)-10-camphor
sulphonate of Formula VI to voriconazole by the hydrolysis of the
compound of Formula VI in a mixture of solvents, such as water and
dichloromethane, and in the presence of a base such as aqueous
sodium bicarbonate. The layers obtained are separated, the aqueous
layer is extracted with a solvent such as dichloromethane, and the
combined organic layer is washed with water. The solvent is removed
by distillation under vacuum at temperatures below about 70.degree.
C. The obtained crude voriconazole is crystallized form isopropyl
alcohol to get pure voriconazole.
[0061] In another aspect, the present invention provides
substantially pure voriconazole and a process for preparation
thereof. Voriconazole prepared according to this embodiment has a
low level of impurities, as determined by high performance liquid
chromatography ("HPLC"). For example, it contains less than about
0.15 area-%, or about 0.05 area-%, of each of the following
impurities:
[0062] a) 2,4-difluro-1H-1-yl-1,2,4-triazolacetophenone;
[0063] b) 6-ethyl-5-fluoropyrimidine;
[0064] c) 4-chloro-6-ethyl-5-fluropyrimidine;
[0065] d)
6-[(1-(5-fluoropyrimidinyl)-6-ethyl]-4-chloro-5-fluoropyrimidine-
;
[0066] e) (2R,3S/2S,3R)-3-(4-chloro-5-
fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-bu-
tan-2-ol;
[0067] f)
(2R,3R/2S,3S)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluor-
ophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol;
[0068] g)
(2R,3R/2S,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)--
1-(1H-1,2,4-triazol-1-yl)-butan-2-ol; and
[0069] h)
(2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H--
1,2,4-triazol-1-yl)-butan-2-ol.
[0070] In general, the voriconazole product purity, as determined
by HPLC, will not be less than about 95 area-%, or about 99 area-%,
or about 99.5 area-%.
[0071] Voriconazole prepared in this process contains residual
solvents at concentrations equal to or less than the requirement of
ICH guidelines. For example voriconazole prepared according to this
process contains the residual solvent acetone at less than about
5000 ppm, or less than about 1000 ppm, or less than about 500 ppm;
residual isopropyl alcohol at less than about 5000 ppm, or less
than about 1000 ppm, or less than about 500 ppm; and the
voriconazole is substantially free from contamination with hexane
(LOD: 15 ppm, LOQ: 55 ppm), heptane (LOD: 10 ppm, LOQ: 35 ppm),
tetrahydrofuran (LOD: 26 ppm, LOQ: 85 ppm), and methanol (LOD: 30
ppm, LOQ: 100 ppm). The term "LOD" is the approximate limit of
detection of an impurity by gas chromatography ("GC") analysis, and
the term "LOQ" is the lowest concentration that can be quantified
using GC. "Substantially free" means that the concentration of an
impurity is less than about twice the LOQ value.
[0072] Voriconaozle prepared according to this embodiment has a
mean particle size less than about 200 .mu.m, or less than about
100 .mu.m, or less than about 80 .mu.m. This means that about 50
volume percent of the particles have sizes less than, or equal to,
the specified size, such as is measured using a laser light
scattering instrument.
[0073] In yet another aspect, the present invention provides
crystalline Form A and Form B of voriconazole and processes for
their preparation.
[0074] An embodiment of a process for preparing crystalline Form A
of voriconazole comprises:
[0075] a) suspending voriconazole in a suitable solvent;
[0076] b) heating the reaction mass to reflux to obtain a clear
solution;
[0077] c) cooling the reaction mass to 90-95.degree. C. to allow
separation of the voriconazole; and
[0078] d) separating and washing the solid voriconazole at
90-95.degree. C. with water and then drying by conventional methods
to afford crystalline Form A of voriconazole.
[0079] The suitable solvent that can be used in step a) includes
any solvent or mixture of solvents, in which the required
components are soluble. Examples include: alcohols such as
C.sub.1-C.sub.10 straight chain or branched alcohols; nitrites such
as acetonitrile, propionitrile and the like; ketones such as
acetone, methyl ethyl ketene and the like; polar aprotic solvents
such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and
the like; water; and mixtures thereof.
[0080] The separation of solid of step d) can be carried out by
using conventional techniques, such as centrifugation, gravity
filtration, or vacuum filtration or other techniques known in the
art for the separation of solids.
[0081] The drying operation of step d) is carried out by using any
technique, such as for example fluid bed drying (FBD), air drying,
oven drying or other techniques known in the art. The drying can be
conducted at temperatures of about 20-100.degree. C. or about
60-70.degree. C. with or without application of vacuum. It is also
conceived that the drying could be carried out under inert
atmosphere conditions.
[0082] The crystalline Form A of voriconazole is characterized by
its XRPD pattern substantially in accordance with that shown in
FIG. 1. The crystalline Form A of voriconazole is also
characterized by its XRPD pattern, wherein the most characteristic
peaks are located at about 6.9, 9.2, 10.7, 12.7, 13.7, 13.9, 14.4,
14.84, 15.3, 19.8, 20.8, and 27.0, .+-.0.2 degrees two theta.
[0083] The crystalline Form A of voriconazole is also characterized
by a differential scanning calorimetric pattern substantially in
accordance with that depicted in FIG. 2. The crystalline Form A of
voriconazole is also characterized by a differential scanning
calorimetry curve having endotherms at about 90.4.degree. C. and
118.5.degree. C.
[0084] The crystalline Form A of voriconazole is also characterized
by an infrared absorption spectrum substantially in accordance with
that shown in FIG. 3.
[0085] According to another aspect, an embodiment of a process for
the preparation of crystalline Form B of voriconazole is provided
which comprises:
[0086] a) providing a solution of voriconazole in a suitable
solvent(s);
[0087] b) precipitating the solid by adding water at reflux
temperature;
[0088] c) cooling the solution;
[0089] d) isolation of the precipitated solid; and
[0090] e) drying the solid compound of step (d) to get Form B of
voriconazole
[0091] The step of providing a solution of voriconazole may include
dissolving any form of voriconazole in a suitable organic solvent
or obtaining an existing solution from a previous processing
step.
[0092] A suitable solvent that can be used in step a) includes any
solvent or mixture of solvents. Examples include ketones such as
acetone, methyl ethyl ketone, methyl isobutyl ketone and the
like.
[0093] The dissolution temperature may range from about 0 to
100.degree. C. or about 20 to 50.degree. C. or about 25 to
30.degree. C. or at the reflux temperature of the solvent used. Any
temperature can be chosen as long as a clear solution of
voriconazole in the solvent(s) is formed and the stability of the
voriconazole is not compromised.
[0094] The reaction mass of step b) can be cooled to a temperature
that may range from about 0 to 50.degree. C. or about 25 to
30.degree. C.
[0095] The isolation of solid of step d) can be carried out by
using conventional techniques, such as centrifugation, gravity
filtration, or vacuum filtration or other techniques known in the
art for the separation of solids.
[0096] The drying operation of step e) is carried out by using any
technique, such as for example fluid bed drying (FBD), aerial
drying, oven drying or other techniques known in the art. The
drying can be conducted at temperatures of about 20-100.degree. C.
or about 60-70.degree. C. with or without application of vacuum. It
is also conceived that the drying could be carried out under inert
conditions.
[0097] An embodiment of an alternative process for the preparation
of crystalline Form B of voriconazole comprises:
[0098] a) providing a solution of voriconazole in a suitable
solvent;
[0099] b) cooling the solution for solid separation.
[0100] c) isolation of the solid; and
[0101] d) optionally, drying the solid to get Form B of
voriconazole
[0102] The step of providing a solution of voriconazole may include
dissolving any form of voriconazole in a suitable organic solvent
or obtaining an existing solution from a previous processing step,
such as the final step in a voriconazole synthesis.
[0103] A suitable solvent that can be used in step a) includes any
solvent or mixture of solvents, in which voriconazole is soluble.
Examples include: chlorohydrocarbons such as dichloromethane,
ethylene dichloride, chloroform and the like; nitriles such as
acetonitrile, propionitrile and the like; alcohols such as
methanol, ethanol, isopropanol and the like; ketones such as
acetone methyl ethyl ketone, methyl isobutyl ketone and the like;
ethers such as tetrahydrofuran, 1,4-dioxane and the like; or
mixtures thereof.
[0104] The dissolution temperature may range from about 0 to
100.degree. C., or about 20 to 50.degree. C., or about 25 to
30.degree. C., or at the reflux temperature of the solvent used.
Any temperature can be chosen as long as it results in a clear
solution of voriconazole in the solvent or mixture of solvents and
the stability of the voriconazole is not compromised.
[0105] The solution of step a) can be cooled to a temperature that
may range from about 20 to 50.degree. C., or about 25 to 30.degree.
C., or at a temperature where the voriconazole is precipitated.
[0106] The isolation and drying operations can be carried out as
described above for the previous process for preparing Form B.
[0107] The crystalline Form B of voriconazole is characterized by
its XRPD pattern substantially in accordance with that shown in
FIG. 4. The crystalline form B of voriconazole is also
characterized by its XRPD pattern, wherein the most characteristic
peaks are located at about 6.9, 12.6, 13.8, 14.8, 15.9, 16.5, 17.4,
19.8, 21.2, 22.5, 23.3, 26.1, and 27.8.+-.0.2 degrees two
theta.
[0108] The crystalline Form B of voriconazole is also characterized
by its differential scanning calorimetry curve substantially in
accordance with that shown in FIG. 5. The crystalline Form B of
voriconazole is also characterized by a differential scanning
calorimetry curve having an endotherm at about 130.9.degree. C.
[0109] The crystalline Form B of voriconazole is also characterized
by an infrared absorption spectrum substantially in accordance with
that shown in FIG. 6.
[0110] Any form of voriconazole may be used for the preparation of
the solutions resulting in the formation of either Form A or B
according to the processes of the invention.
[0111] In a still further aspect, the present invention provides an
amorphous voriconazole in combination with a pharmaceutically
acceptable carrier, and a process for its preparation.
[0112] An embodiment of a process for preparing an amorphous
voriconazole composition comprises:
[0113] a) providing a solution of voriconazole and a
pharmaceutically acceptable carrier in an organic solvent;
[0114] b) removing the solvent to obtain a solid residue which is
comprises an amorphous form of voriconazole.
[0115] The step of providing a solution of voriconazole and a
pharmaceutically acceptable carrier may include dissolving any form
of voriconazole and a pharmaceutically acceptable carrier in a
suitable organic solvent, or obtaining an existing solution of
voriconazole from a previous processing step, such as a final step
in a voriconazole synthesis, and dissolving a pharmaceutically
acceptable carrier in that solution or adding a solution of a
pharmaceutically acceptable carrier in a suitable organic solvent
to an existing solution of voriconazole.
[0116] The organic solvents that can be used to prepare an
amorphous voricanazole composition will be chosen based on the
technique used for removal of solvent, the solubility and stability
of the voriconazole and the carrier in the solvent and other
factors known to a person skilled in the art. The same solvent may
be used for the dissolution of the voriconazole and the
pharmaceutical carrier or different solvents may be used for the
two components and then the solutions mixed together to form a
clear homogeneous solution. Examples include: halogenated
hydrocarbons such as dichloromethane, ethylene dichloride,
chloroform and the like; ketones such as acetone, methyl ethyl
ketone, methyl isobutyl ketone and the like; nitriles such as
acetonitrile, propionitrile and the like; ethers such as diethyl
ether, diisopropyl ether, methyl tertiary butyl ether and the like;
esters such as ethyl acetate, propyl acetate and the like; alcohols
such as methanol, ethanol, propanol and the like, hydrocarbons such
as C.sub.1-C.sub.6 straight chain, branched, or cyclic hydrocarbons
and the like; or mixtures thereof.
[0117] The pharmaceutical carriers that can be used for preparing
amorphous voriconazole compositions include, but are not limited
to: hydrophilic carriers like polymers of N-vinylpyrrolidone
commonly known as polyvinylpyrolidine ("PVP" or "povidone"); gums;
cellulose derivatives; cyclodextrins; gelatins; hypromellose
phthalate; sugars; polyhydric alcohols; polyethylene glycols;
polyethylene oxides; polyoxyethylene derivatives; polyvinyl
alcohol; propylene glycol derivatives; and the like.
[0118] Pyrrolidones that are useful in the practice of this
invention are homopolymers or copolymers of N-vinylpyrrolidone.
Such polymers are known to form complexes with a variety of
compounds. The water-soluble forms of N-vinylpyrrolidone are
available in a variety of viscosity and molecular weight grades and
may be chosen from but are not limited to PVP K-12, PVP K-15, PVP
K-17, PVP K-25, PVP K-30, PVP K-120, and the like. A
water-insoluble N-vinylpyrrolidone can be a cross-linked PVP such
as, for example, crospovidone. Any of these PVPs may be chosen, or
their mixtures, or their mixtures with any of the other carriers
mentioned above.
[0119] Any pharmaceutical carrier is acceptable as long as it
allows the preparation of the amorphous voriconazole as described
herein, is compatible with the voriconazole and is acceptable for
human use. The choice of such a carrier is within the scope of
understanding of a person skilled in the art and is not limited by
the list of polymers and excipients provided above.
[0120] The dissolution temperatures may range from about 0 to
125.degree. C., or about 20 to 50.degree. C., or about
25-30.degree. C., or at the reflux temperature of the solvent used.
Any temperature can be chosen as long as the stability of the
voriconazole and the pharmaceutically acceptable carrier is not
compromised.
[0121] The ratio of the pharmaceutically acceptable carrier to the
voriconazole can include any proportions as long as the required
amorphous voriconazole is obtained.
The solvent can be removed from the solution using distillation
under vacuum, or spray drying, or agitated thin film drying. The
solvent can also be removed from the solution using other
techniques known in art, including, for example, distillation,
evaporation, oven drying, tray drying, rotational drying (such as
using the Buchi Rotavapor), freeze-drying, fluidized bed drying,
flash drying, spin flash drying, and the like.
[0122] The process may include optionally further drying of the
product obtained from the solution by known drying methods, as will
be apparent to the skilled artisan.
[0123] The amorphous form of voriconazole of the present invention
is characterized by a diffuse halo in its XRPD pattern, which is
substantially as shown in FIG. 8.
[0124] In yet another aspect, the present invention provides
pharmaceutical compositions containing the substantially pure
voriconazole either as one or more of crystalline form A, form B or
amorphous voriconazole either alone or in amorphous combination
with pharmaceutically acceptable excipients and processes for the
preparation thereof.
[0125] The substantially pure voriconazole obtained according to
the processes of the invention or any of the polymorphic forms of
this voriconazole are all useful in the preparation of
pharmaceutical compositions for the treatment of a variety of
disease conditions. Such conditions include for example without
limitation, invasive aspergilli; treatment of
fluconazole-resistant, severe, invasive candida infections
(including C. krusei); and treatment of severe fungal infections
involving scedosporium spp. and Fusarium spp. Other medical
conditions where voriconazole could be utilized for treatment or
prophylaxis are completely within the scope of the invention.
[0126] Such pharmaceutical compositions can include without
limitation, solid oral formulations such as tablets, capsules,
powders, granules, and the like, suspensions, injectable
compositions, and other forms of drug delivery where voriconazole
would find use. Suitable excipients required for the processing of
the voriconazole and converting it into the final composition are
within the scope of understanding of a person skilled in the art of
preparing pharmaceutical compositions for drug delivery.
[0127] The dose administration of the compositions prepared from
the voriconazole forms of the invention will be determined by the
medical practitioner.
[0128] Certain aspects and embodiments of the processes and forms
described herein are further described in the following examples.
These examples are provided solely for the purpose of illustrating
particular aspects and embodiments of the invention, and therefore
should not be construed as limiting the scope of the invention.
EXAMPLE 1
Preparation of
(2R,3S/2S,3R)-3-(4-Chloro-5-Fluropyrimidin-6-yl)-2-(2,4-Diflurophenyl)-1--
(1H-1,2,4-Triazole-1-yl)Butan-2-ol (Formula IV)
[0129] 1258 g of diisopropylamine was charged into a reactor
containing a mixture of n-heptane (15 L) and tetrahydrofuran (2 L),
under a nitrogen atmosphere and cooled to about -18 to -23.degree.
C. 27.9 g of n-butyl lithium (1.6 molar solution in hexanes) was
added dropwise, while maintaining the temperature at -18 to
-23.degree. C. The reaction mixture was stirred for about 2 hours
at the same temperature and then cooled to about -65 to -70.degree.
C. 7.5 kg of 4-chloro-6-ethyl-5-fluoropyrimidine was added at about
-69 to -73.degree. C. over about 15 minutes. 20.8 kg of
2,4-difluoro-1H-1-yl-1,2,4-triazolacetophenone was dissolved in 60
L of tetrahydrofuran in another vessel at about 50-55.degree. C.
and filtered through paper to remove extraneous particulate matter.
This filtered solution was added slowly to the reaction mass at -68
to -74.degree. C. over a period of about 2 hours and maintained at
-68 to -74.degree. C. for about 3 hours. 7.5 L of acetic acid was
added slowly to the reaction mass at -57 to -69.degree. C. after
confirming the reaction completion by thin layer chromatography. 75
L of water was added at below -10.degree. C. and then the
temperature was raised to about 10-15.degree. C. The suspension was
filtered through cloth at 10-15.degree. C. and washed with 7.5 L of
n-heptane. The organic layer was separated from the resultant
filtrate and washed with a total of 240 L water in four portions.
The organic layer was gradually cooled to about -10 to -15.degree.
C., and stirred for about 90 minutes. The separated solid was
filtered and washed with 7.5 L of n-heptane. Obtained solid was
dried at 35-40.degree. C. under vacuum (about 600 mm Hg) for about
6 hours to yield 4.6 kg of the title compound as a crystalline
solid. (Yield: 26.3%)
EXAMPLE 2
Preparation of (2R, 3S/2S, 3R)-2-(2,4-Difluorophenyl)-3-(5-Fluoro
Pyrimidin-4-yl)-1-(1H-1,2,4-Triazol-1yl) Butan-2-ol (Formula V)
[0130] 4.3 kg of
(2R,3S/2S,3R)-3-(4-chloro-5-fluropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1--
(1H-1,2,4-triazole-1-yl)butan-2-ol was charged into a stainless
steel autoclave reactor containing 26 L of methanol. 1100 g of
sodium acetate and 860 g of Raney nickel were charged and a 3
kg/cm.sup.2 hydrogen pressure was applied. The reaction mass was
heated to about 54-56.degree. C., and maintained for about 5 hours
at 4-5 kg/cm.sup.2 hydrogen pressure. Reaction completion was
confirmed by thin layer chromatography and the mixture was cooled
to 25-35.degree. C. The catalyst was recovered by vacuum filtration
and washed with 9 L of methanol. The filtrate was charged into the
reactor and solvent was removed by distillation under reduced
pressure of about 650 mm Hg at below 45.degree. C. until a thick
compound separated. Cooled the reaction mass to about 33.degree. C.
and 19.5 L of water was added. Reaction suspension was stirred for
10 minutes and then gradually cooled to about 5-10.degree. C. and
stirred for about 2 hours. The separated solid was filtered and was
washed with chilled water (4 L). Obtained solid was dried at
55-60.degree. C. for about 6 hours to yield 2.6 kg of the title
compound in the form of a crystalline solid. (Yield: 66.4%)
EXAMPLE 3
Preparation of (2R,3S)-2-(2,4-Difluorophenyl)-3-(5-Fluoro
Pyrimidin-4-yl)-1-(1H-1,2,4-Triazol-1yl)Butan-2-ol-R-(-)-10-Camphor
Sulphonate Salt (Formula VI)
[0131] 2.5 kg of
(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-tri-
azol-1yl)butan-2-ol was charged into a reactor containing 25 L of
acetone. 1.65 kg of R-(-)-10-camphor sulphonic acid was added and
heated to about 50.degree. C. 12.5 L of methanol was added to the
reaction mass to make a clear solution. It was then heated to
reflux and maintained for 20 minutes. The reaction mass was then
cooled to about 30.degree. C. and maintained for about 1 hour. The
separated solid was centrifuged and washed with 2.5 L of chilled
acetone. The obtained solid was dried at about 55-60.degree. C.
under a vacuum of about 650 mm Hg for about 8 hours to yield 1.35
kg of the title compound as a crystalline solid. (Yield: 65.0%)
EXAMPLE 4
Preparation of (2R,3S)-2-(2,4-Difluorophenyl)-3-(5-Fluoro
Pyrimidin-4-Yl)-1-(1H-1,2,4-Triazol-1Yl) BUTAN-2-Ol
(Voriconazole)
[0132] 4.9 kg of (2R,
3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-
-1yl)butan-2-ol-R-(-)-10-camphor sulfonate salt was charged into a
reactor containing 10 L of water and 25 ml of dichloromethane.
Reaction mass pH was adjusted to about 10 with 20% sodium carbonate
solution (10 L) at room temperature. Stirred the reaction mass for
20 minutes. The aqueous layer was separated and extracted with
dichloromethane (5 L). Combined organic layer was washed with water
2.5 L each of in two portions. 0.25 kg of activated charcoal was
added to the organic layer and stirred for 5 minutes. Filtered the
carbon through a candle filter and washed with 2.5 L of
dichloromethane. The solvent was distilled completely in an
agitated thin film dryer ("ATFD") under vacuum of about 600 mm Hg
at below 40.degree. C. The solid material thus obtained from the
ATFD was charged into a reactor containing 17.5 L of isopropyl
alcohol. Reaction mass was heated to 59.5.degree. C. and maintained
for 15 minutes to form a clear solution. The solution was cooled to
about 5.degree. C. and stirred for 1 hour and 15 minutes at
2-5.degree. C. The separated solid was centrifuged and washed with
2.5 L of chilled isopropyl alcohol. Obtained solid was dried at
about 57-60.degree. C. for about 7 hours and 20 minutes to yield
2.28 kg of the title compound as a crystalline solid. (Yield: 76%,
Purity: 99.96% by HPLC, crystalline Form B).
EXAMPLE 5
Preparation of Voriconazole Crystalline Form A
[0133] 5 g of voriconazole and 15 ml of water were charged into a
round bottom flask and heated to reflux to get a clear solution.
Reaction mass was cooled to 90-95.degree. C. for compound
separation and was filtered at 90-95.degree. C. The obtained solid
was dried at 60-70.degree. C. to afford 4.1 g of the title
compound.
EXAMPLE 6
Preparation of Voriconazole Crystalline Form B
[0134]
(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1(1H-1,2,-
4-triazol-1-yl)-butan-2-ol-R(-)-10-camphor sulphonate (4 g), water
(11 ml) and dichloromethane (19 ml) were charged into a round
bottom flask. Reaction mass pH was adjusted to 11-12 with 10%
sodium hydroxide solution (4 ml). The organic layer was separated
from the aqueous layer and the aqueous layer was extracted with
dichloromethane (4 ml). Combined organic layers were washed with
water (3.times.11 ml). Solvent from the organic layer was removed
completely under reduced pressure at below 45.degree. C. Acetone
(12 ml) was added to the residue and was stirred for about 15
minutes at 25-35.degree. C. Solvent was removed completely under
reduced pressure at below 45.degree. C. to form a residue. Acetone
(20 ml) was added to the residue and the mixture was heated to
reflux. Water (80 ml) was slowly added into the mixture at reflux
for the precipitation of the compound. The mixture was cooled to
40.degree. C. and was maintained at 40.degree. C. for about 30
minutes. The separated solid was collected by filtration and was
washed with water (4 ml). The obtained solid was dried at about
60.degree. C. for about 3 hours to afford 1.3 g of the title
compound.
EXAMPLE 7
Alternate Preparation of Voriconazole Crystalline Form B
[0135] A mixture of polymorphs of
(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1(1H-1,2,4-tria-
zol-1-yl)butan-2-ol (voriconazole) (20 g) and acetone (80 ml) were
charged into a round bottom flask and was heated to reflux. Water
(240 ml) was added to the mixture at reflux. The mixture was cooled
to 40.degree. C. and was maintained for about 60 minutes at
40.degree. C. The separated solid was filtered and was washed with
water (20 ml) and was dried at about 60.degree. C. to afford 11.6 g
of the title compound.
EXAMPLE 8
Alternate Preparation of Voriconazole Crystalline Form B
[0136] 5 g of voriconazole and methanol (20 ml) were charged into a
round bottom flask and stirred for 10 minutes. The mixture was then
cooled to about 0.degree. C. and was maintained at 0.degree. C. for
about 30 minutes. The separated solid was filtered and was washed
with chilled methanol (5 ml). The obtained solid was dried at about
60.degree. C. to afford 1.4 g of the title compound.
EXAMPLE 9
Alternate Preparation of Voriconazole Crystalline Form B
[0137] 5 g of voriconazole and acetonitrile (5 ml) were charged
into a round bottom flask and heated to reflux to get a clear
solution. The solution was cooled to 25-35.degree. C. and was
maintained for about 30 minutes. The separated solid was filtered
and washed with acetonitrile (5 ml). The obtained solid was dried
at about 52.degree. C. for about 6 hours to afford 1.0 g of the
title compound.
EXAMPLE 10
Preparation of Amorphous Voriconazole Composition
[0138] 2.5 g of voriconazole and povidone (PVP K-30, 2.5 g) were
suspended in methanol (20 ml) at 25-30.degree. C. and stirred for
about 15 minutes to obtain a clear solution. Distilled the solvent
to dryness in a Buchi Rotavapor at 50-55.degree. C. under a vacuum
of 500-600 mm Hg, followed by drying the solid obtained at
50-55.degree. C. under a vacuum of 700-750 mm Hg for about 60
minutes to afford 4.8 g of the desired amorphous voriconazole
composition.
EXAMPLE 11
Preparation of Amorphous Voriconazole Composition
[0139] Voriconazole (2.5 g) and povidone (PVP K-30, 2.5 g) were
suspended in dichloromethane (15 ml) at 25-30.degree. C. and
stirred for about 10 minutes to obtain a clear solution. Distilled
the solvent to dryness in a Buchi Rotavapor at 30-40.degree. C.
under a vacuum of 550-700 mm Hg for about 2 hours, to afford 5.0 g
of the desired amorphous voriconazole composition.
[0140] The amorphous voriconazole composition had the following
properties:
[0141] Bulk density: 0.46 g/ml (without tapping), 0.72 g/ml (after
tapping).
[0142] Hausner ratio: 1.56.
[0143] Carr Compressibility Index: 36.4%.
[0144] Angle of repose: 39.35 degrees.
[0145] Stability (under accelerated conditions: 75% relative
humidity and 40.degree. C.): converts to a crystalline form after 5
days, moisture uptake 11% by weight.
[0146] Solubility comparison at room temperature (values in
mg/l):
TABLE-US-00001 Crystalline Solvent Amorphous Form B Methanol 167
125 Acetone 250 250 Water 0 0
EXAMPLE 12
Preparation of Amorphous Voriconazole Composition by Spray
Drying
[0147] Voriconazole (5.0 g) and povidone (PVP K-30, 5.0 g) were
suspended in methanol (40 ml) at 25-30.degree. C. and stirred for
10 minutes to obtain a clear solution. The solvent was removed
using a spray drier under the following set of conditions: feed
pump 10 rpm; aspirator 1000 rpm; inlet air temperature 80.degree.
C.; outlet air temperature, 38.degree. C.; N.sub.2 pressure, 2
kg/cm.sup.2; feed temperature, room temperature; to afford 4.5 g of
the desired voriconazole amorphous composition.
EXAMPLE 13
Preparation of Amorphous Voriconazole Composition by Agitated Thin
Film Drying
[0148] Voriconazole (50 g) and povidone (PVP K-30, 50 g) were
suspended in methanol (400 ml) at 25-30.degree. C. and stirred for
about 15 minutes to obtain a clear solution. The solvent was
removed using an agitated thin film dryer at a feed rate of 10
L/hour, under a vacuum of 650-700 mm Hg, and a jacket temperature
of about 65.degree. C., to afford 88.0 g of the desired
voriconazole amorphous composition.
* * * * *