U.S. patent application number 13/690736 was filed with the patent office on 2013-06-27 for 4-[17beta-methoxy-17alpha-methoxymethyl-3-oxoestra-4,9-dien-11-beta-yl]ben- zaldehyde (e)-oxime (asoprisnil).
This patent application is currently assigned to BAYER PHARMA AG. The applicant listed for this patent is Bayer Pharma AG. Invention is credited to Klaus BAHL, Ulf BOHLMANN, Robert EILERS, Bernd ERHART, Hagen GERECKE, Sabine GLIESING, Detlef GRAWE, Peter HOESEL, Jurgen JACKE, Uwe KNABE, Thomas MICHEL, Michael MOSEBACH, Uwe MUELLER, Michael SANDER, Ulf TILSTAM, David VOIGTLAENDER, Dieter WEHMEIER.
Application Number | 20130165421 13/690736 |
Document ID | / |
Family ID | 40382773 |
Filed Date | 2013-06-27 |
United States Patent
Application |
20130165421 |
Kind Code |
A1 |
GRAWE; Detlef ; et
al. |
June 27, 2013 |
4-[17BETA-METHOXY-17ALPHA-METHOXYMETHYL-3-OXOESTRA-4,9-DIEN-11-BETA-YL]BEN-
ZALDEHYDE (E)-OXIME (ASOPRISNIL)
Abstract
The present invention relates to a method for the reliable and
reproducible preparation of
4-[17.beta.-methoxy-17.alpha.-methoxymethyl-3-oxoestra-4,9-dien-11.beta.--
yl]benzaldehyde (E)-oxime (asoprisnil) on the pilot and
manufacturing scale. Asoprisnil, which is prepared by this method,
is distinguished by a very good physical stability and is therefore
particularly suitable for the manufacture of solid pharmaceutical
forms (tablets, coated tablets, etc.).
Inventors: |
GRAWE; Detlef;
(Kleinromstedt, DE) ; GLIESING; Sabine; (Jena,
DE) ; GERECKE; Hagen; (Jena, DE) ; HOESEL;
Peter; (Jena, DE) ; MUELLER; Uwe; (Jena,
DE) ; MICHEL; Thomas; (Leipzig, DE) ; EILERS;
Robert; (Jena, DE) ; KNABE; Uwe; (Trockenborn,
DE) ; ERHART; Bernd; (Kahla, DE) ; MOSEBACH;
Michael; (Berlin, DE) ; VOIGTLAENDER; David;
(Bad Vilbel, DE) ; TILSTAM; Ulf; (Belgium, DE)
; JACKE; Jurgen; (Unna, DE) ; BAHL; Klaus;
(Herne, DE) ; BOHLMANN; Ulf; (Koln, DE) ;
WEHMEIER; Dieter; (Bergkamen, DE) ; SANDER;
Michael; (Frechen (Koenigsdorf), DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bayer Pharma AG; |
Berlin |
|
DE |
|
|
Assignee: |
BAYER PHARMA AG
Berlin
DE
|
Family ID: |
40382773 |
Appl. No.: |
13/690736 |
Filed: |
November 30, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12987850 |
Jan 10, 2011 |
8324412 |
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13690736 |
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11785421 |
Apr 17, 2007 |
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12987850 |
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60792643 |
Apr 18, 2006 |
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Current U.S.
Class: |
514/179 ; 264/12;
427/180; 552/648 |
Current CPC
Class: |
A61P 43/00 20180101;
Y10T 428/2982 20150115; C07J 3/00 20130101 |
Class at
Publication: |
514/179 ;
552/648; 264/12; 427/180 |
International
Class: |
C07J 75/00 20060101
C07J075/00; C07J 41/00 20060101 C07J041/00 |
Claims
1. Amorphous, physically pure asoprisnil microparticles obtainable
by a method comprising reacting on the pilot or manufacturing scale
##STR00003## by a process comprising: a) synthesizing nordienedione
ketal from hydroxyestradienone either by oxidation of
17.beta.-hydroxyestra-4,9-dien-3-one (hydroxyestradienone) to
estra-4,9-diene-3,17-dione (nordienedione) and subsequent selective
ketalization to 3,3 dimethoxyestra-5(10),9(11)-diene-17-one
(nordienedione ketal) or ketalizing hydroxyestradienone to
17.beta.-hydroxy-3,3-dimethoxyestra-5(10),9(11)-diene (hydroxy
ketal) and subsequent oxidation subsequently oxidizing to
nordienedione ketal, b) synthesizing trimethoxydiene from
nordienedione ketal in three steps via the stages
3,3-dimethoxyestra-5 (10),9 (11)-diene-17.beta.-spiro-1',2'-oxirane
(nordienespirane) and 3,3-dimethoxy-17.alpha.-methoxymethylestra-5
(10),9 (11)-dien-17.beta.-ol (nordiene ether), not isolating
nordienespirane and nordiene ether, c) synthesizing
3,3,17.beta.-trimethoxy-11.beta.-[4-(dimethoxymethyl)phenyl]-17.alpha.-me-
thoxymethylestr-9-en-5.alpha.-ol (dimethoxy acetal) from
trimethoxydiene via
17.alpha.-(methoxymethyl)-3,3,17.beta.-trimethoxy-5.alpha.,10.alpha.--
epoxyestr-9(11)-ene (enepoxide) in a Cu(I)-catalyzed Grignard
reaction with bromobenzaldehyde dimethyl acetal, d) synthesizing
the dienone aldehyde by reaction with acids, e) synthesizing
asoprisnil from dienone aldehyde with a hydroxyamine hydrochloride
solution, f) purifying by chromatography, g) drying.
2. The microparticles according to claim 1, where in the process
hydroxyestradienone is converted into nordienedione ketal by
ketalization with Lewis acids and either by chromic acid oxidation
or Oppenauer oxidation.
3. The microparticles according to claim 2, where in the process
either the hydroxyestradienone is first oxidized and then ketalized
or is first ketalized and then oxidized.
4. The microparticles according to claim 3, where the process
comprises carrying out the chromic acid oxidation first and a
selective ketalization subsequently or the ketalization first and
an Oppenauer oxidation subsequently.
5. The microparticles according to claim 3, where in the process
the chromic acid oxidation is carried out as two-phase reaction
between two liquid phases.
6. The microparticles according to claim 5, where in the process
water, is added to a solution of hydroxyestradienone in acetone in
such a way that a defined systemic water concentration, preferably
of 10-15% by weight, is set up, with the steroid concentration not
exceeding 8 g/l of acetone.
7. The microparticles according to claims 3 and 4, where the
ketalization is carried out first.
8. The microparticles according to claim 7, where in the process
the ketalization takes place in a bypass method.
9. The microparticles according to claim 3, where in the process
the Oppenauer oxidation takes place with catalysis by aluminium
diisopropoxide trifluoroacetate (DIPAT).
10. The microparticles according to claim 1, where in the process
nordienedione ketal is converted completely to trimethoxydiene via
the stages of nordienespirane and nordiene ether in three steps,
comprising a) producing nordienespirane in DMF in an initial phase
with addition of the reactants in a temperature range from 0 to
25.degree. C., and in an after-reaction phase between 20 to
40.degree. C.; b) the reaction product obtained in a) not being
isolated but being employed as solution of nordienespirane in
solvents; c) for conversion of the converting nordienespirane from
b) into the nordiene ether changing the solvent, optionally during
the reaction with sodium methanolate, or by azeotropic
distillation, and thus reaching reaction temperatures of 70.degree.
C. or more; d) crystallizing trimethoxydiene from methanol by
cooling the solution, to 20-35.degree. C., for about 1 to 2 hours,
and then cooling further to -5.degree. C. to -15.degree. C.
11. The microparticles according to claim 1, where in the process
the drying in g) takes place in such a way that contamination of
the dried asoprisnil microparticles with seed centers in the drying
device is greatly reduced.
12. The microparticles according to claim 11, where in the process
the drying takes place by a spray drying, a narrow particle size
range is achieved through geometrical and aerodynamic conditions in
the atomizing device, and wetting events by spray drops on surfaces
of the apparatus with which the product makes contact are
avoided.
13. The microparticles according to claim 12, in which the narrow
drop size range is generated by a high atomizing efficiency of the
spraying unit by maintaining a mass ratio of spraying gas employed
to sprayed solution of from 1.5 to 10, and a mass ratio of drying
gas employed to sprayed solution employed of at least 10, and with
a drying temperature of from 40.degree. C. to 90.degree. C.
14. The microparticles according to claim 13, where in the process
the high atomizing efficiency of the spraying unit is produced by a
high speed of rotation of a rotating disc or by a high atomizing
gas throughput through a twin-fluid nozzle.
15. The microparticles according to claim 11 wherein spray-dried
asoprisnil microparticles are subjected to an after-drying
procedure which takes place in vacuo and/or with flushing of the
asoprisnil microparticles with a solvent-free drying gas below
90.degree. C. for at least 12 h.
16. The microparticles according to claim 11, where in the process
the deposition of the asoprisnil microparticles after the spray
drying takes place on a product filter.
17. (canceled)
18. The microparticles according to claim 1 having an average
particle size d.sub.50 of less than 2.5 .mu.m, and a maximum
particle size d.sub.100 of less than 25 .mu.m.
19. The microparticles according to claim 1, having enthalpy of
fusion at 194.7.degree. C..+-.2.degree. C., determined by DSC with
a heating rate of 5 K/min, is of less than 20 J/g.
20. The microparticles according to claim 1, when heated at 20
K/min to 170.degree. C. and then cooled at 20 K/min to 90.degree.
C., having a number of crystallites visible by thermomicroscopy is
less than 10 000 per mg.
21. The microparticles according to claim 1, in the form of
medicaments.
22. In a medicament for the treatment of hormone-dependent
gynaecological disorders, endometriosis, fibroids or other
gynaecological dysfunctions, the improvement wherein the medicament
comprises microparticles of claim 21.
23. In a medicament for hormone replacement therapy (HRT) or for
female fertility control, the improvement wherein the medicament
comprises microparticles of claim 21.
24. A pharmaceutical composition comprising asoprisnil
microparticles according to claim 1 together with a
pharmaceutically acceptable excipient and/or carrier.
25. The pharmaceutical composition according to claim 24, in a
solid pharmaceutical form.
26. The pharmaceutical composition according to claim 25,
formulated for oral administration.
Description
[0001] This application claims the benefit of the filing date of
U.S. Provisional Application Ser. No. 60/792,643 filed Apr. 18,
2006, which is incorporated by reference herein.
[0002] The present invention relates to a method for the reliable
and reproducible preparation of
4-[17.beta.-methoxy-17.alpha.-methoxymethyl-3-oxoestra-4,9-dien-11.beta.--
yl]benzaldehyde (E)-oxime (asoprisnil) on the pilot and
manufacturing scale. Asoprisnil, which is prepared by this method,
is distinguished by a very good physical stability and is therefore
particularly suitable for the manufacture of solid pharmaceutical
forms (tablets, coated tablets, etc.) which even withstand ICH
accelerated conditions (40.degree. C., 75% r.h.).
[0003] The preparation of a asoprisnil on the laboratory scale is
described for example in DE 43 32 283 A1; further details on
asoprisnil can be found in EP 0571 15, DE 35 04 42, DE 100 56 675
A1 and DE 100 56 676 A1.
[0004] Intermediates for preparing asoprisnil, for example the
preparation of 3,3-dimethoxyestra-5(10),9(11)-diene-17-one
(nordienedione ketal) are described in French patent 151 4 086 and
in a publication in "Pharmazie 39, No. 7 (1984)" (B. Menzenbach, M.
Hubner, R. Sahm, K. Ponsold: "Synthese potentieller Metaboliten der
STS 557 (Dienogest)"), the preparation of
3,3,17.beta.-trimethoxy-17.alpha.-methoxymethylestra-5(10):9(11)-diene
(trimethoxydiene) from nordienedione ketal in EP 0 648 779, EP 0
648 778, EP 0 411 733, DD 289539, DE 100 56675, and the preparation
of dienone aldehyde and asoprisnil in DE 43 32 283. EP 129 26 07
describes novel solid forms of asoprisnil, in particular a
high-purity and stable amorphous or highly crystalline form
(ansolvate/anhydrate), a method for the preparation, and the use in
pharmaceutical compositions. The solid forms are distinguished in
particular by high stability.
[0005] These preparation methods describe the principle of the
preparation of the various intermediates and of the target product,
the active ingredient
4-[17.beta.-methoxy-17.alpha.-methoxymethyl-3-oxoestra-4,9-dien-11.beta.--
yl]benzaldehyde (E)-oxime (asoprisnil) on the laboratory scale.
Details of reaction conditions for preparing asoprisnil on the
pilot or even manufacturing scale are not disclosed in the
literature.
[0006] According to the details disclosed in the literature, it is
not possible to prepare the individual intermediates on the
manufacturing scale in such a way that the medicinally active
asoprisnil and its precursors can be obtained therefrom reliably
and reproducibly and having the analytical parameters required by
the authorities or by the legislation pursuant to ICH Q6A Guidance,
2000, such as byproduct profile, content of active ingredient,
chemical and physical purity, and stability. Thus, although the
amorphous solid form described in EP 129 26 07 shows good stability
as pure active ingredient, in the solid pharmaceutical form there
is partial to complete recrystallization under ICH accelerated
conditions (40.degree. C., 75% r.h.). The suitability of the
asoprisnil obtainable by this method for a solid pharmaceutical
form is accordingly low.
[0007] It is therefore an object of the present invention to
provide a productive and reliable method for preparing asoprisnil
with which the active ingredient can be prepared reproducibly in
high purity and yield on the pilot and manufacturing scale. By
purity is meant the physical and chemical purity of the active
ingredient.
[0008] This object is achieved by the present multistage method for
preparing asoprisnil. It consists of the following stages (see FIG.
1):
##STR00001##
[0009] In the first stage of the method (see FIG. 2), the synthesis
of 3,3-dimethoxyestra-5(10),9(11)-dien-17-one (nordienedione ketal)
from 17.beta.-hydroxyestra-4,9-dien-3-one (hydroxyestradienone),
the nordienedione ketal is obtained either [0010] by oxidation of
17.beta.-hydroxyestra-4,9-dien-3-one (hydroxyestradienone) to
estra-4,9-diene-3,17-dione (nordienedione) and subsequent selective
ketalization to 3,3-dimethoxyestra-5(10),9(11)-diene-17-one
(nordienedione ketal) or [0011] by ketalization of
hydroxyestradienone to
17.beta.-hydroxy-3,3-dimethoxyestra-5(10),9(11)-diene (hydroxy
ketal) and subsequent oxidation to nordienedione ketal.
[0012] The second stage of the method, the preparation of
3,3,17-trimethoxy-17.alpha.-methoxymethylestra-5(10),9(11)-diene
(trimethoxydiene) from nordienedione ketal takes place in three
steps via the stages
3,3-dimethoxyestra-5(10),9(11)-diene-17.beta.-spiro-1',2'-oxirane
(nordienespirane) and
3,3-dimethoxyestra-5(10),9(11)-dien-17.beta.-ol (nordiene
ether).
[0013] In a third stage, trimethoxydiene is converted into the
corresponding 5.alpha.,10.alpha.-epoxide (enepoxide) and, in a
subsequent Cu(I)-catalyzed Grignard reaction with
4-bromobenzaldehyde dimethyl ketal, converted into the so-called
dimethoxy acetal
(3,3,17.beta.-trimethoxy-11.beta.-[4-(dimethoxymethyl)phenyl]-17.alpha.-m-
ethoxy-methylestr-9-en-5.alpha.-ol). Reaction of the dimethoxy
acetal with acids such as, for example, with 85 to 95% strength
acetic acid affords
4-[17.beta.-methoxy-17.alpha.-methoxymethyl-3-oxoestra-4,9-dien-11.beta.--
yl]benzaldehyde (dienone aldehyde).
[0014] The procedure reduces the formation of byproducts and thus
ensures the reproducibility and validatability of each individual
step in this stage of the method. The resulting product has a
purity which is proved by specified individual analytical
assessments (HPLC purity, UV content), and whose preparation
reliably and reproducibly reduces the amounts of impurities such
as, for example, byproducts of the Grignard reaction (Wurtz
products), 11.alpha.-aldehyde and 5.alpha.-OH aldehyde.
[0015] For the final stage, the synthesis of
4-[17.beta.-methoxy-17.alpha.-methoxymethyl-3-oxoestra-4,9-dien-11.beta.--
yl]benzaldehyde (E)-oxime-asoprisnil-dienone aldehyde is reacted
with hydroxyamine hydrochloride in organic solvents such as, for
example, pyridine or methylene chloride as described in DE 43 32
283.
[0016] The product is subsequently worked up and purified by
methods known to the skilled person, such as, chromatography,
fractional filtration or crystallization, and subjected to a spray
drying. It is particularly important in this connection to prepare
amorphous asoprisnil microparticles which have a high and, in
particular, reproducible physical purity and stability in the solid
pharmaceutical form. It is known that there is a high risk of
recrystallization in the preparation of pure amorphous forms of
active ingredients by spray drying, which recrystallization may
occur in the active ingredient alone or through contact with
excipients of the pharmaceutical form (Nurnberg, Acta Pharmaceutica
Technologica, 26, 1980).
[0017] Both the crystalline and the amorphous form of asoprisnil
described in EP129 26 07 satisfy the requirements to be met by the
stability as active ingredient and for pharmaceutical processing.
However, the asoprisnil microparticles must additionally show
sufficient stability as active ingredient (Drug Substance) in the
solid pharmaceutical form itself under ICH accelerated conditions.
This makes special demands on the physical purity, which in
amorphous structures has a direct effect on the stability thereof
in relation to recrystallization. It is therefore indispensable for
no detectable recrystallization of these microparticles to occur
both during storage of the solid pharmaceutical form under normal
conditions (25.degree. C., 60% r.h.) and under accelerated
conditions (40.degree. C., 75% r.h.). The reliable and, in
particular, reproducible preparation of these microparticles makes
special demands on the purification and drying of asoprisnil.
[0018] The method according to the invention therefore also
includes a step for drying asoprisnil in which a contamination of
the microparticles with seed centres is greatly reduced through a
suitable procedure.
[0019] In every spraydrying system dried particles are deposited to
a greater or lesser extent on hot inner surfaces of the apparatus,
e.g. on the tower wall. It has surprisingly been found that wetting
events resulting from incompletely vaporized drops which are
associated with an only brief and localized increase in the ethanol
concentration in the particle layer cause the formation of
so-called seed crystals within a few seconds. By seed crystals are
meant microscopic or submicroscopic crystallites or crystalline
clusters which are thermodynamically stable and are the starting
point for recrystallization processes (I. Gutzow, J. Schnelzer,
`The Vitreous State`, Springer Verlag 1995, Chapter 9, page
221).
[0020] In the present method according to the invention, the
spray-drying process is characterized in that the largest drops in
the spray cone produced by the atomizing device are vaporized so
rapidly that even isolated wetting events on surfaces of the
apparatus with which the product makes contact are very
substantially decreased or, better, precluded. This wetting effect
is reduced or even precluded to a distinctly higher degree than
usual in conventional spray drying.
[0021] The size distribution of the drops generated in the
atomizing unit depends on the atomizing device (pressure nozzle,
rotating disc, twin fluid nozzle), the geometry thereof, and on the
atomization parameters. The twin fluid nozzle generates, for
example by comparison with other atomizing devices, a very fine but
very broad range of drop sizes. The rotating disc by contrast a
coarser but, on the other hand, narrower range of drop sizes. The
particle size distribution of the dried particles is determined by
the range of drop sizes.
[0022] For use of asoprisnil as drug substance for example in oral
low-dose forms it is crucial to generate a particular particle size
distribution. On the one hand, the uniformity of content
(CUT--Content Uniformity) and, on the other hand, especially for
hydrophobic substances of poor solubility like asoprisnil, the
kinetics of dissolution of the active ingredient from the
pharmaceutical form must be ensured. Traditionally, a technology
with which the dried active ingredient is subsequently micronized
is generally usual. This takes place preferably in jet mills and
means an additional method step associated with high risks for the
stability of solids and the purity of phases. The high energy input
frequently leads to phase transformations or to the generation of
seed centres for phase transformations.
[0023] It is known that amorphous substances like asoprisnil often
dry from solutions to form a solid film on the surface of drops.
Only subsequently and distinctly more slowly do the liquid contents
of the globule vaporize from a blow-out orifice or by diffusion.
The measured particle sizes are therefore insubstantially smaller
than the drops from which they are formed. This second phase of
drying delays the kinetics of drying of large drops even further.
Whether a drop can be completely vaporized and dried to a particle
during the spray drying depends not only on its size but also on
the geometric and aerodynamic conditions in the drying tower, e.g.
on the length of the flight path available and the velocity
(Nurnberg, Acta Pharmaceutica Technologica, 26, 1980; Bauckhage,
Chem. Ing. Technik 62 (1990), No. 8; Zbicinski, Chemical
Engineering Journal 86, 2002, pp. 207-216).
[0024] A further advantageous configuration of the method according
to the invention therefore consists of obtaining the active
ingredient asoprisnil after the spray drying in the form of
amorphous microparticles with a particular particle size
distribution in one method step without subsequent
micronization.
[0025] Particularly preferred embodiments of the method according
to the invention are described below, consisting of the following
stages:
hydroxyestradienone.fwdarw.nordienedione
ketal.fwdarw.trimethoxydiene.fwdarw.dienone
aldehyde.fwdarw.asoprisnil (see FIG. 1).
[0026] The hydroxyestradienone starting material of the method
according to the invention can be obtained by methods known to the
skilled person (Menzenbach, Bernd; Huebner, Michael, Zeitschrift
fur Chemie (1986), 26(10), 371ff).
1. Nordienedione Ketal
1.1. Nordienedione Ketal Via Nordienedione
(Hydroxyestradienone.fwdarw.Nordienedione.fwdarw.Nordienedione
Ketal)
Chromic Acid Oxidation of Hydroxyestradienone
[0027] The carrying out of chromic acid oxidations in the synthesis
of steroid active ingredients is a synthesis stage which is widely
used and described in detail in the specialist literature.
Steroidal alcohols are oxidized to ketones using a mixture of
chromic acid and sulphuric acid (Jones' reagent, J. Chem. SOC.
1946, 39 and J. Chem. Soc. 1953, 2548). This chromic acid oxidation
is carried out in various solvents such as acetone, DMF,
dichloromethane and chloroform. DMF and chloroform may in many
cases be replaced by the less physiologically and ecologically
objectionable acetone. Disadvantages of this replacement of DMF and
chloroform by acetone are the incomplete and non-reproducible
conversion of the starting material. For example, unreacted
hydroxyestradienone can be removed only with great difficulty and
is therefore "carried over" as impurity throughout the synthesis of
the active ingredient, thus greatly impairing the quality of the
synthesized product.
[0028] Complete and reproducible chromic acid oxidation of
hydroxyestradienone is carried out according to the invention in
acetone by managing the reaction as two-phase reaction between
liquid phases. To this end, a certain amount of water is added to a
solution of hydroxyestradieneone in acetone in such a way that the
water content of the organic phase passes through a minimum in the
distribution equilibrium of the water between organic phase and the
aqueous chromic acid phase. This minimum arises through the
surprising occurrence of a phase change in the inorganic chromic
acid phase, which extracts water from the inorganic phase despite
an increase in total water content of the reaction solution. The
result of this is that [0029] 1. the solubility of the organic
phase for the steroid is improved, [0030] 2. the chromium sludge
cannot trap any starting material because its viscosity can be
instantaneously reduced and [0031] 3. thus a very large mass
transfer area can be created by the agitator.
[0032] This minimum is influenced by the temperature and
concentration conditions in the chromic/sulphuric acid. The optimum
of these parameters can be determined experimentally by the skilled
person.
[0033] The complete and, in particular, reproducible reaction is
achieved by adding water, preferably 2-10% by weight based on
acetone, to a solution of hydroxyestradienone in acetone in such a
way that a defined systemic water concentration (added water plus
water from the chromic/sulphuric acid), preferably of 10-15% by
weight, is adjusted, with the steroid concentration not exceeding 8
g/l of acetone. The subsequent selective monoketalization of the
diketone nordienedione is carried out according to the invention
with Lewis acids according to the following variants: [0034] 1.
Selective ketalization with silicon tetrachloride and methanol
[0035] a) silicon tetrachloride is put into a mixture of methanol
and n-hexane solvents, with the addition taking place in a
temperature range from -5 to 15.degree. C., preferably 2 to
10.degree. C.; [0036] b) rapid addition of nordienedione is in the
aforementioned temperature range from -5 to 15.degree. C.,
preferably 2.degree. C. to 10.degree. C.; [0037] c) stirring during
crystallization, where the solution obtained in b) is preferably
stirred at 5.degree. C. to 15.degree. C., particularly preferably
10.degree. C., for 60 to 100 minutes, and then at -8.degree. C. to
0.degree. C. to complete the crystallization; [0038] d) the
resulting crystals are isolated using a solid/liquid separating
device and are then washed alternately with methanol and hexane or
methanol/aqueous ammonia [0039] e) drying of the resulting
nordienedione ketal or [0040] 2. selective ketalization with acetyl
chloride and methanol using a solution of the crude product from
the chromic acid oxidation.
[0041] The described variants of a specific procedure for the
selective ketalization of nordienedione are distinguished by the
formation of byproducts being greatly reduced. The said methods
afford a product which makes specified individual analytical
assessments reliably and reproducibly possible and satisfies high
quality demands.
1.2. Nordienedione Ketal Via Hydroxy Ketal
[0042] In this variant, firstly
17.beta.-hydroxyestra-4,9-dien-3-one (hydroxyestradienone) is
ketalized to give the intermediate
17.beta.-hydroxy-3,3-dimethoxyestra-5(10),9(11)-diene (hydroxy
ketal). This is followed by oxidation to a nordienedione ketal by
Oppenhauer oxidation:
hydroxyestradienone.fwdarw.hydroxy ketal.fwdarw.nordienedione
ketal
[0043] Purification takes place by usual methods known to the
skilled person, for example by chromatography or fractional
filtration. Examples thereof which may be mentioned are the
following solvents such as methanol, heptane, cyclohexane, methyl
tert-butyl ether as well as combinations thereof, and mixtures of
solvents such as, for example, methyl tert-butyl ether/heptane,
cyclohexane/methyl tert-butyl ether, isopropanol/water.
Cyclohexane/methyl tert-butyl ether are particularly suitable.
[0044] The support material used for a purification by
chromatography is for example aluminium oxide.
[0045] The ketalization with trialkyl orthoformates in methanol is
described in detail for steroid active ingredients in the
specialist literature (Byer, Walter, Lehrbuch der organischen
Chemie, 21.sup.st Edition, S. Hirzel Verlag Stuttgart, p. 216).
Steroids which have a keto function in position 3 are converted
into the corresponding dimethyl ketals by using trimethyl
orthoformate in mixtures of solvents containing methanol. In
conventional ketalization methods, sulphuric acid or sulphuric acid
derivatives such as, for example, p-toluenesulphonic acids are
added as catalysts. One disadvantage of the procedure mentioned is
that these catalysts must subsequently be removed by extraction.
Ketals are unstable under these aqueously acidic conditions.
[0046] The ketalization is therefore carried out according to the
invention on an acid-activated ion exchanger. The ion exchanger can
be put directly into the reaction solution. The advantage of this
is that the ion exchanger can easily be removed again by
filtration. A further variant of the configuration of the
ketalization consists according to the invention of passing the
reaction solution over the acid-activated ion exchanger in a
so-called bypass method. This means that removal of the ion
exchanger is no longer necessary.
[0047] Oppenhauer oxidation of steroids is likewise described in
detail in the specialist literature (Byer, Walter, Lehrbuch der
organischen Chemie, 21.sup.st Edition, S. Hirzel Verlag Stuttgart,
p. 216). Steroids with a 17-hydroxy function are oxidized to the
corresponding 17-ketones by using aluminium alcoholates and
cyclohexanone. However, it is not possible to carry out the
reaction hydroxy ketal.fwdarw.nordienedione ketal quantitatively
using conventional aluminium alcoholates such as, for example,
aluminium triisopropoxide. For this reason, the reaction is carried
out according to the invention with aluminium diisopropoxide
trifluoroacetate (DIPAT) as catalyst in the presence of
cyclohexanone. The hydroxy ketal is reacted virtually completely
through the use of DIPAT.
[0048] The nordienedione ketal product of the reaction results as
crude product. However, it is possible with conventional methods
such as, for example, recrystallization to achieve a purity of only
less than 90%. For this reason, the prepared nordienedione ketal is
dissolved according to the invention in methyl tertiary butyl
ether, filtered through aluminium oxide and then eluted with a
mixture of cyclohexane and methyl tertiary butyl ether. The product
is obtained with a purity of more than 95%.
2. Trimethoxydiene Via Nordienespirane and Nordiene Ether
[0049] Nordienespirane is prepared from nordienedione ketal
according to DE 100 56 675 with trimethylsulphonium iodide and
potassium tertiary butoxide in DMF. Nordienespirane is then
converted with sodium methanolate in methanol into nordiene ether.
A precondition for its further conversion to trimethoxydiene
according to the following sequence
nordienedione ketal.fwdarw.nordienespirane.fwdarw.nordiene
ether.fwdarw.trimethoxydiene is that the nordiene ether is isolated
and purified in a complicated manner.
[0050] On further processing in solution, for conversion to be as
quantitative as possible it is necessary to remove as completely as
possible from the nordiene ether solution the residues of water and
methanol originating from the precursors.
[0051] Virtually complete conversion to trimethoxydiene is achieved
according to the invention by [0052] a) carrying out at the
nordienespirane stage the reaction in DMF in an initial phase with
addition of the reactants in a temperature range from 0 to
25.degree. C., preferably between 0 to 20.degree. C. and in an
after-reaction phase between 20 to 40.degree. C., preferably
between 30 to 35.degree. C.; [0053] b) the reaction product
obtained in step a) not being isolated but being employed as
solution of nordienespirane in solvents, preferably in hexane, DMF
or in THF; [0054] c) for conversion of the nordienespirane from
step b) into the nordiene ether changing the solvent, preferably
during the reaction with sodium methanolate, particularly
preferably by azeotropic distillation, and thus reaching the
required reaction temperatures of 70.degree. C. or more; [0055] d)
at the trimethoxydiene stage crystallizing from methanol by cooling
a steroid solution, preferably a solution with 40-50% by weight
steroid, to 20-35.degree. C., preferably 25.degree. C., for about 1
to 2 hours, and then cooling further to -5.degree. C. to
-15.degree. C., preferably -10.degree. C.
[0056] Since the water and solvent contents in the starting
material for conversion of nordienedione ketal into nordienespirane
play a substantial part, a virtually complete conversion is
achieved in this stage by limiting the amounts of methanol and
water, which are considerable as a result of the preparation, in
the nordienedione ketal. This is ensured when the water content is
less than 1%, preferably less than 0.6% and the methanol content is
less than 1%, preferably less than 0.8%, in the nordienedione
ketal.
[0057] Changing the solvent in the conversion of nordienespirane to
nordiene ether, for example from hexane to methanol, preferably by
azeotropic distillation, allows the synthesis to be continued
without high-loss and complicated intermediate isolation of the
nordienespirane.
[0058] Since the water and solvent contents in the starting
material for conversion of nordiene ether into trimethoxydiene play
an equally large part as in the abovementioned conversion of
nordienedione ketal into nordienespirane, in this case too complete
conversion to trimethoxydiene is guaranteed by reducing the amounts
of water and methanol derived from the nordiene ether stage,
preferably by azeotropic distillation, to below 0.8% water,
particularly preferably below 0.4% water. Removal of unreacted
nordiene ether is no longer possible later.
[0059] The specific temperature control has the effect of
distinctly reducing the formation of byproducts while, at the same
time, conversion is virtually complete and rapid. In particular,
the formation of the 17.alpha. epimers of nordienespirane and the
formation of 16-methyltrimethoxydiene are greatly minimized.
[0060] The specific management of the crystallization guarantees a
very good reduction in the amount of byproducts in the crystals. In
particular, unreacted nordiene ether and byproducts such as, for
example, the 17-oxetane compound of the nordiene ketal remain in
solution. The resulting product can very easily be filtered, washed
and dried.
3. Dienone Aldehyde Via Enepoxide and Dimethoxy Acetal
[0061] Trimethoxydiene is dissolved in dichloromethane and
pyridine. Hexafluoroacetone is added as catalyst for the subsequent
epoxidation. A hydrogen peroxide solution is metered in at 25 to
35.degree. C. After conversion has taken place, the phases are
separated. The organic phase is, after removal of the peroxides by
washing with water, sodium bicarbonate solution and sodium
thiosulphate solution, changed to THF by distillation. The
dimethoxy acetal is prepared by a Grignard reaction from enepoxide
and magnesium in THF with bromobenzaldehyde dimethyl acetal.
Bromobenzaldehyde dimethyl acetal is obtained by acetalization of
4-bromo-benzaldehyde with trimethyl orthoformate in organic solvent
such as, for example, methanol and THF in the presence of an acidic
catalyst, for example sulphuric acid derivatives (e.g.
p-toluenesulphonic acid). For this, the reaction is carried out as
described under 1.2. with an acid-activated ion exchanger, with the
ketalization taking place by a bypass method according to the
invention in a preferred variant of the method. As the skilled
person is aware, activation of the magnesium turnings for the
Grignard reaction, for example with dibromoethane or DIBAH, may be
necessary in some circumstances. A catalytic amount of copper(I)
chloride is added to the Grignard solution, which can be controlled
before use for example to a temperature of 10 to 20.degree. C.,
under inert conditions and with stirring. Subsequently, preferably
within less than 60 minutes, a solution of
17.alpha.-(methoxymethyl)-3,3-17.beta.-trimethoxy-5.alpha.,10.alpha.-epox-
yestr-9(11)-ene and THF is added to the stirred Grignard solution
at -10.degree. C. to 55.degree. C., maximally 45.degree. C., and
subsequently an after-reaction is carried out at the same maximum
temperature. Working up takes place by methods known to the skilled
person.
4. Asoprisnil
4.1. Synthesis
[0062] The stage for preparing asoprisnil as crude product is
composed according to the invention of the following individual
steps: [0063] a) a suspension or solution of dienone aldehyde, for
example in pyridine or methylene chloride, is mixed with a solution
of hydroxyamine-hydrochloride in pyridine [0064] b) the reaction
solution obtained in step a) is put at a temperature of
0-30.degree. C., preferably 20-25.degree. C., into a solvent,
preferably ethyl acetate, methylene chloride or toluene, which is
controlled at a temperature of 5-15.degree. C., with stirring, and
acidified with hydrochloric acid or sulphuric acid; [0065] c)
working up takes place by [0066] crystallization by adding methyl
tertiary butyl ether to the solution and thus obtaining a methyl
tertiary butyl ether solvate with 12-20% methyl tertiary butyl
ether and subsequently drying, or [0067] filtration, preferably
through silica gel, changing to methanol by distillation,
precipitation with water and drying of the solid obtained in this
way.
4.2. Working Up
[0068] The working up of the asoprisnil obtained from the synthetic
method described above takes place by HPLC purification and
subsequent spray drying, the procedure for which is described
below.
[0069] The HPLC purification can be carried out by methods known to
the skilled person.
[0070] A solution of asoprisnil in alcohol, preferably in lower
alcohols such as ethanol, methanol and isopropanol, is sprayed with
a specific temperature regime into a spray-drying system as
described in WO 01/90137. This regime is such that the outlet
temperature of the drying gas is kept at 40.degree. C. to
90.degree. C., preferably 75.degree. C. to 90.degree. C. Moreover,
the mass ratio of spraying gas employed to sprayed solution is 1.5
to 10, preferably from 2.5 to 5, and the mass ratio of drying gas
employed to sprayed solution employed is at least 10, preferably at
least 20. Moreover, the dried asoprisnil particles are separated
from the drying gas on a product filter and deposited virtually
completely in a collecting vessel. It has been found that the
otherwise usual deposition of spray-dried particles via a cyclone
surprisingly leads to distinctly more unstable products in the case
of asoprisnil. The deposition of the spray-dried asoprisnil
particles on a product filter is therefore a particularly
advantageous embodiment of the invention. The use of fresh, unused
filter surfaces for each production run is a further advantageous
configuration of the invention, since a product with the desired
stability properties is prepared in this way. Even a few ppm of
crystalline asoprisnil particles lead to a significant
destabilization of the amorphous product. It has emerged that
despite thorough purification with the usual solvents such as
ethanol or methanol surprisingly small residues of crystalline
substances remain in the material on the filter which contaminate
the amorphous product with crystal seeds. The spray drying is
followed by an after-drying. In this procedure, the microparticles
are treated under vacuum of <100 mbar, preferably less than 10
mbar, and at a temperature of less than 90.degree. C., preferably
less than 50.degree. C., and/or with flushing with a solvent-free
drying gas for a lengthy period until the alcohol content is less
than 1%, preferably less than 0.5%, in order to stabilize the
amorphous structure further.
[0071] The described procedure results in physically pure and
stable amorphous asoprisnil microparticles
[0072] The term "physical purity" refers here, in accordance with
the literature (A. Burger, Pharmazie in unserer Zeit 26, 1997, 93),
to a chemically pure substance which essentially comprises
impurities of the same chemical substance but in a different solid
state (polymorphous, amorphous, pseudopolymorphous) only in small
amounts. Depending on the type of substance, these physical
impurities can be measured quantitatively by thermomicroscopy,
differential scanning calorimetry (DSC), x-ray powder
diffractometry or other methods.
[0073] The present invention accordingly relates to a method for
the reliable and reproducible preparation, working up and
purification of amorphous asoprisnil, which can be carried out on
the manufacturing scale. The method according to the invention
makes it possible to prepare asoprisnil on the pilot and/or
manufacturing scale in high purity with an overall yield of crude,
i.e. not yet purified, asoprisnil of 58% (gross). Taking account of
the active ingredient content in the asoprisnil final product, a
yield of 47% (net) is achieved.
[0074] Methods previously disclosed for preparing asoprisnil on the
laboratory scale, as published in DE 433 2283, WO 02/38582 and WO
02/38581, disclose yields of between 5 and 23%. Comparison of the
yields achieved is possible only with provisos because the
syntheses start from different starting materials and/or take place
by different routes. Compared with the methods described in DE 433
2283 and WO 02/38582, which start at a substantially later point,
namely 3,3-dimethoxy-5.alpha.,10.alpha.-epoxyestr-9(11)-en-17-one,
and compared with the method described in WO 02/38581, which starts
from a likewise later starting
material--3,3-dimethoxyestra-5(10),9(11)-dien-17-one-, the method
according to the invention, starting from
17.beta.-hydroxyestra-4,9-dien-3-one (hydroxyestradienone) via the
following stages
##STR00002##
achieves a distinct increase in the yield to 47 or 58%. The method
according to the invention surprisingly achieves an improvement in
the yield despite conversion of far larger quantities, i.e. on the
pilot or manufacturing scale, than described in the laboratory
methods previously published. A further advantage of the method
according to the invention is that each individual stage of the
method can be carried out reliably and reproducibly on the pilot
and manufacturing scale.
[0075] The method according to the invention for preparing
asoprisnil can be carried out in accordance with the following
examples, these serving for detailed explanation without
restricting the invention.
[0076] The method can be carried out by employing the agitated
reactors, distilling apparatuses, crystallizers, centrifuges and
dryers customary in batch-oriented chemical practice.
1. Nordienedione Ketal
1.1. Nordienedione Ketal Via Nordienedione
Variant A
[0077] 12 kg of hydroxyestradienone are dissolved in 180 l of
acetone and then 7.5 l of water are added. Chromic/sulphuric acid
for oxidation is prepared from 50 l of water, 18 kg of chromium
trioxide and 12 l of sulphuric acid. At 15.degree. C., 17.5 l of
this chromic/sulphuric acid with 260-270 mg of chromium trioxide/ml
are added over the course of one hour and then reaction is
continued at 22-25.degree. C. for 1 hour. Working up takes place by
the usual methods known to the skilled person (Cr.sup.6+ reduction
with bisulphite, concentration and crystallization from
acetone/water mixtures).
[0078] 33 l of methanol and 46 l of n-hexane are controlled at a
temperature of 2-10.degree. C. To them are added firstly 1.2 kg of
SiCl.sub.4 and then 10 kg of nordienedione with stirring. After
crystallization starts, the mixture is stirred at 5-15.degree. C.
for 1 hour to 1.5 hours and then cooled to 0 to -8.degree. C. and
filtered with suction. If crystallization does not start unaided,
seeding is also possible in a conventional way. The crystals are
washed on a fit with hexane and ammoniacal methanol. Drying results
in 80-109% of expected. The qualities which can reliably be
achieved are set forth in the specification and are achieved with
the method according to the invention, including purity 95 A %
(HPLC), proportion of unreacted nordienedione=0.2 A %, largest
unspecified byproduct=1.0 A %.
Variant B
[0079] 100 g of hydroxyestradienone are introduced into 400 ml of
acetone and 20 ml of water. A chromic/sulphuric acid solution
prepared from 101 ml of water, 35.6 g of chromium trioxide and 32
ml of sulphuric acid is metered in at an internal temperature of
12.degree. C. in such a way that 3/4 is metered in in two hours and
the remainder in a further 2 hours. After stirring for 30 minutes,
excess chromic acid is decomposed by adding 26 ml of isopropanol.
The change to water is then effected by distillation in vacuo at an
internal temperature of 60.degree. C. About 400 ml of water are
required for this. The precipitated intermediate (nordienedione) is
filtered off with suction and washed with water until neutral.
[0080] Nordienedione is then dissolved in 170 ml of methylene
chloride and stirred with 3.6 g of kieselguhr for 20 minutes.
Kieselguhr is filtered off and the filtrate is washed 2.times. with
50 ml of water each time to remove chromium salts. The organic
phase is changed to methanol by distillation in vacuo and
concentrated to 300 ml. 440 ml of hexane are added at an internal
temperature of 20.degree. C. The suspension is cooled to 5.degree.
C. Over the course of one minute, 26 ml of acetyl chloride are
added and then washed with 37 ml of methanol. The starting material
dissolves, and the product then precipitates. If necessary, seeding
with nordienedione ketal takes place after 3 minutes.
[0081] After crystallization has started, the mixture is stirred
for 80 minutes, then controlled to 5.degree. C. and made alkaline
by adding 37 ml of 50% strength sodium hydroxide solution. The
product (nordienedione ketal) is isolated and washed firstly with a
mixture of 320 ml of methanol and 13 ml of aqueous ammonia and then
with 35 ml of hexane. It is sucked dry under a nitrogen atmosphere
and dried in vacuo. Yield: 82.4 g of nordienedione ketal.
1.2. Nordienedione Ketal Via Hydroxy Ketal
[0082] 66.7 kg of hydroxyestradienone are dissolved in 500 l of
toluene and 400 ml of methanol. Filtration through 3.4 kg of
activated carbon is carried out where appropriate. Addition of 51 l
of trimethyl orthoformate and a further 70 l of methanol is
followed by circulation by pump over 33.4 kg of activated ion
exchanger at 30.degree. C. until conversion to hydroxy ketal is
complete. Addition of 20 l of pyridine and 400 l of a sodium
carbonate solution is followed by stirring and separation of the
phases. The aqueous phase is back-extracted several times with 135
l of toluene. The combined organic phases are concentrated to 300 l
and changed to 300 l of toluene by distillation.
[0083] 40 kg of aluminium isopropoxide and 180 l of heptane are
introduced into a second reaction vessel. 14.7 l of trifluoroacetic
acid are metered in at a temperature of 50.degree. C. Addition of
6.7 l of pyridine is followed by removal of heptane by distillation
down to 95 l. After cooling to .ltoreq.25.degree. C., the organic
hydroxy ketal solution is added while stirring. Addition of a total
of 76 l of cyclohexanone, metered in part, is followed by stirring
for up to 6 hours until conversion is complete. Addition of 570 l
of a sodium hydroxide solution is followed by stirring and
separation of the phases. The aqueous phase is back-extracted
several times with 70 l of toluene. The combined organic phases are
washed several times with 70 l of water. The mixture is
concentrated to 270 l and changed to water by distillation. This
results in 270 l of a suspension of crude product and water. The
crude product is isolated and dissolved in 270 l of methyl
tert-butyl ether. The solution is washed with 70 l of water. The
aqueous phase is back-extracted with 70 l of methyl tert-butyl
ether. The combined organic phases are filtered and concentrated to
135 l. After addition of 540 l of cyclohexane, the solution is
filtered through 134 kg of aluminium oxide. The aluminium oxide is
washed with a mixture of a total of 270 l of cyclohexane and 100 l
of methyl tert-butyl ether. The product-containing fractions are
concentrated and changed to 200 l of heptane by distillation. The
heptane solution is cooled to -15.degree. C., whereupon the product
crystallizes. The product is isolated and washed with 35 l of
heptane and 35 l of water. The nordienedione ketal product is dried
at max. 40.degree. C. until the loss on drying is .ltoreq.0.5%.
2. Trimethoxydiene Via Nordienespirane and Nordiene Ether
[0084] 65.6 kg of nordienedione ketal and 50 kg of
trimethylsulphonium iodide are suspended in 150 l of
dimethylformamide (DMF) and cooled to 15.degree. C. A solution of
30 kg of potassium tert-butoxide in 65 l of DMF is metered in at
20.degree. C. The mixture is stirred at 30.degree. C. for 30
minutes and the conversion is checked by TLC. 200 l of water and
410 l of hexane are added at 30 to 40.degree. C. to transfer the
reaction product into the hexane phase. The aqueous DMF phase is
back-extracted four times with 50 l of hexane each time. The
combined organic phase is washed twice with 85 l of water. The
aqueous phase is back-extracted with 50 l of hexane. Subsequently
concentrated in vacuo to a volume of 150 l and mixed with 130 l of
methanol. About 250 l of sodium methanolate solution (30%) are
added to the methanolic solution, and distillate is taken off under
atmospheric pressure until at least 70.degree. C. is reached. The
mixture is then heated under reflux for 1.5 hours until the
conversion is complete. Distillation is continued in vacuo with
continuous addition of 215 l of water. The nordiene ether obtained
in this way is taken up in 330 l of methyl tertiary butyl ether
(MtBE), the organic phase is separated off and the aqueous phase is
extracted twice with 100 l of methyl tertiary butyl ether each
time. The combined organic phases were extracted twice with 100 l
of water. The aqueous phases were back-extracted with 60 l of MtBE.
This is followed by concentration in vacuo and, at a volume of 165
l, water and methanol are removed azeotropically from the organic
phase with the addition of 165 l of methyl tertiary butyl ether to
maintain this volume. 27.2 l of methyl iodide and 10 l of MtBE are
added thereto. Then 70.5 kg of potassium tertiary butyl ether in
300 l of MtBE are metered in at 35.degree. C. Reaction is continued
for 1 to 2 hours, and the conversion is checked. After addition of
245 l of water, the organic phase is separated off and washed with
65 l of water. The aqueous phase is back-extracted with 65 l of
MtBE. This is followed by concentration to about 80 l in vacuo.
Distillation to change to methanol and concentration to a volume of
140 l are followed by stirring at 25.degree. C. for 1 to 2 hours.
The mixture is then cooled to below -10.degree. C. and stirred for
a further 2 hours. The product is subsequently isolated and washed
with 15 l of cold methanol. Trimethoxydiene is dried in vacuo at
40.degree. C.
3. Dienone Aldehyde Via Enepoxide and Dimethoxy Acetal
3.1. Enepoxide
[0085] 10.6 l of hexafluoroacetone are added to a solution of 80.6
kg of trimethoxy diene, 755 l of methylene chloride and 11 l of
pyridine. 81 l of a 35% strength hydrogen peroxide solution are
gradually added to this solution while stirring at a temperature of
30 to 40.degree. C. After the addition, the mixture is stirred at
30 to 40.degree. C. for 30 min and then a check of conversion is
carried out. The organic phase is separated off and washed twice
with 175 l of aqueous sodium bicarbonate solution. The organic
phase is subsequently washed with 250 l of sodium thiosulphate
solution. Finally, the organic phase is washed three to four times
with 160 l of water. The organic phase washed in this way is
concentrated in vacuo and at a temperature of 30.degree. C. and
changed to THF by distillation so that the final volume is 170
l.
3.2. Dimethoxy Acetal
[0086] The Grignard reagent is prepared from 13 kg of magnesium
turnings, 280 l of THF, 7.3 kg of DIBAH and 106 l of
bromobenzaldehyde dimethyl acetal. Bromobenzaldehyde dimethyl
acetal is prepared by acetalization of 4-bromo-benzaldehyde with
trimethyl orthoformate in methanol in the presence of acidic
catalysts, preferably acidic ion exchanger, preferably in a bypass
method. After addition of about 0.5 kg of copper(I) chloride, the
enepoxide solution is added, the mixture is stirred at 40.degree.
C. until conversion is complete. Excess Grignard reagent is
destroyed by metering in 490 l of ammonium chloride solution at
max. 10.degree. C. After addition of 142 l of dilute acetic acid,
the organic phase is washed 3 to 4 times with 122 l of ammonium
chloride solution. The aqueous phases are back-extracted three to
four times with 90 l of ethyl acetate. The combined organic phases
are washed with 170 l of sodium chloride solution and concentrated
to 220 l in vacuo at 40.degree. C.
3.3. Dienone Aldehyde
[0087] The dimethoxy acetal solution is mixed with 312 l of conc.
acetic acid and 35 l of water and heated at 90.degree. C. for about
30 min. After cooling, 680 l of water are metered in. The crude
product is isolated and stirred and washed several times with 170
l, 170 l and 110 l and 340 l of MtB ether at temperatures up to
50.degree. C. Dienone aldehyde is dried in vacuo at 30.degree. C.
to 40.degree. C.
4. Asoprisnil
4.1. Synthesis
Variant A
[0088] 15 kg of dienone aldehyde are suspended in 38 l of pyridine.
To this are added 42 l of a prepared hydroxyamine
hydrochloride/pyridine solution. After a successful check of
conversion and taking up in 88 l of ethyl acetate, 6N HCl is added
while monitoring the pH (2-4). After phase separation and
extraction of the organic phase with water, the organic ethyl
acetate phase is concentrated, distilled with toluene and
subsequently mixed with 50 l of methyl tertiary butyl ether.
Crystallization results in the target product. It is then
dried.
[0089] The following purities were achieved with the method
according to the invention after HPLC examination:
Oxime=92.9 area % Aldehyde=0.08 area %
Z-Oxime=3.1 A %
Dioxime=3.1 A %
Variant B
[0090] 50 kg of dienone aldehyde are dissolved in 250 l of
methylene chloride. A solution of 8.86 kg of hydroxyamine
hydrochloride in 130 l of pyridine is added at 20.degree. C. over
the course of 1 to 2 h. After a successful check of conversion,
about 280 l of sulphuric acid are metered in at <10.degree. C.
At 10.degree. C., the phases are separated and the aqueous phase is
back-extracted twice with 120 l of methylene chloride. The organic
phase is washed three times with 200 l of water, which are
back-extracted with 110 l of methylene chloride. The organic phase
is concentrated to 200 l in vacuo and filtered through silica gel.
The organic phase is washed with about 100 l of a sodium
bicarbonate solution. Distillation is carried out in vacuo to
change to a final volume of 200 l of methanol. The methanolic
product solution is added to 510 l of water, whereupon the crude
product precipitates. Asoprisnil (crude) is isolated and dried in
vacuo at 30 to 40.degree. C.
[0091] The crude product is purified by preparative high
performance liquid chromatography (HPLC). For this purpose, the
asoprisnil (crude) is dissolved in dichloromethane and applied to
silica gel. The substance is then eluted with a toluene/acetone
mixture. A mixed fraction is obtained in addition to the pure
fraction and can be rechromatographed to increase the yield. The
pure fraction is concentrated and isolated in the next process
step.
4.2. Working Up and Purification
EXAMPLE 1
[0092] 5.1 kg of asoprisnil are dissolved in 57 l of ethanol (DAB)
by heating to 60.degree. C. The clear solution is pumped with
minimal pulsation by a metering pump at 6 l/h to the twin-fluid
nozzle (d=0.8 mm) of a spray dryer, cylinder d=800.times.620 mm,
base cone 60.degree., co-current operation of heating and spraying
gas. The asoprisnil solution is maintained at a temperature of
65.degree. C. during this. The atomizing gas is adjusted at the
nozzle to 12 Nm.sup.3 N.sub.2/h. The heating gas throughput is 85
m.sup.3/h. The heating gas inlet temperature is adjusted so that
the outlet temperature at the dryer is 78.degree. C. to 85.degree.
C. The dried microparticles are deposited on fresh textile filters
with PTFE membrane of 1 m.sup.2. For this purpose, the surface of
the filter is periodically pulsed free with counter-current
nitrogen. After the spray-drying process, the asoprisnil powder is
subjected to an after-drying process. For this purpose, the drying
chamber is alternately subjected to a vacuum of 5 mbar and flushing
nitrogen heated to 45.degree. C. The vacuum and flushing phases
each last 45 min. The drying time is 12 h, and the final product
temperature reached is 35.degree. C. The asoprisnil microparticles
obtained in this way are analyzed and show the following
characteristics:
Residual solvent content: 0.36% ethanol Particle distribution:
d.sub.50=2.1 .mu.m, d.sub.100=21 .mu.m Enthalpy of fusion (DSC at
5K/min) 4.1 J/g (see FIG. 3) Number of crystallites at 170.degree.
C. 1187 crystallites per mg XRPD amorphous, no crystalline
reflections
EXAMPLE 2
[0093] 25 mg film-coated tablets in PVC-Al blister packs with
pharmaceutically customary excipients and with 16% active
ingredient according to example 1, which shows by DSC with a
heating rate of 5 K/min an enthalpy of fusion of 4.1 J/g and by
thermomicroscopy a crystallite number of 1187 per mg, are stored at
40.degree. C., 75% r.h. as specified in the ICH guideline.
Stability analysis with XRPD After 9 months at 40.degree. C., 75%
r.h.: amorphous
BRIEF DESCRIPTION OF DRAWINGS
[0094] FIGS. 1 and 2 show synthesis of the invention, and
[0095] FIG. 3 shows a DSC curve for a product.
[0096] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The preceding preferred
specific embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever.
[0097] In the foregoing and in the examples, all temperatures are
set forth uncorrected in degrees Celsius and, all parts and
percentages are by weight, unless otherwise indicated.
[0098] The entire disclosures of all applications, patents and
publications, cited herein and of corresponding U.S. Provisional
Application Ser. No. 60/792,643, filed Apr. 18, 2006, is
incorporated by reference herein.
[0099] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0100] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention
and, without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *