U.S. patent application number 15/825697 was filed with the patent office on 2018-05-31 for methods for onapristone synthesis dehydration and deprotection.
The applicant listed for this patent is ARNO THERAPEUTICS, INC.. Invention is credited to Ferry Brands, Stefan Proniuk, Ulf Tilstam.
Application Number | 20180148471 15/825697 |
Document ID | / |
Family ID | 60703146 |
Filed Date | 2018-05-31 |
United States Patent
Application |
20180148471 |
Kind Code |
A1 |
Tilstam; Ulf ; et
al. |
May 31, 2018 |
METHODS FOR ONAPRISTONE SYNTHESIS DEHYDRATION AND DEPROTECTION
Abstract
Methods and systems for making onapristone (ONA) using acidic
hydrolysis and dehydration with sulfuric acid in an alcoholic
solution are provided.
Inventors: |
Tilstam; Ulf; (Hoegaarden,
BE) ; Proniuk; Stefan; (Austin, TX) ; Brands;
Ferry; (Berghem, NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ARNO THERAPEUTICS, INC. |
Flemington |
NJ |
US |
|
|
Family ID: |
60703146 |
Appl. No.: |
15/825697 |
Filed: |
November 29, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62428401 |
Nov 30, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07J 21/006 20130101;
C07J 41/0083 20130101 |
International
Class: |
C07J 41/00 20060101
C07J041/00; C07J 21/00 20060101 C07J021/00 |
Claims
1. A method of making onapristone comprising: reacting the compound
of Formula I: ##STR00006## with sulfuric acid in a solvent to
deprotect and dehydrate the compound of Formula I; maintaining the
reaction temperature below about 60.degree. C.; neutralizing the
reaction with an inorganic base to form a solution; and extracting
the compound of Formula II ##STR00007## from the solution.
2. The method of claim 1, wherein the sulfuric acid is diluted up
to 80% with water.
3. The method of claim 2, wherein the sulfuric acid is diluted from
30 to 60% with water.
4. The method of claim 3, wherein the sulfuric acid is diluted with
50% water.
5. The method of claim 1, wherein the solvent is selected from the
group consisting of methanol, ethanol, acetone, n-propanol and
isopropanol.
6. The method of claim 5, wherein the solvent is methanol.
7. The method of claim 1, wherein the temperature is maintained
between about -50 to about 60.degree. C.
8. The method of claim 7, wherein the temperature is maintained
between about -10 and 30.degree. C.
9. The method of claim 8, wherein the temperature is maintained
from about 0 to about 15.degree. C.
10. The method of claim 1, wherein the inorganic base is selected
from the group consisting of sodium hydrogen carbonate, sodium
phosphate or ammonia.
11. The method of claim 10, wherein the inorganic base is ammonia
with a concentration between about 5 and 30%.
12. The method of claim 11, wherein the inorganic base is 30%
ammonia.
13. The method of claim 1, wherein the reaction with the inorganic
base is performed at a temperature from about 0 to about 30.degree.
C.
14. The method of claim 13, wherein the reaction with the inorganic
base is performed at a temperature from about 0 to about 15.degree.
C.
15. The method of claim 1, wherein extraction of the compound of
Formula II is performed with ethyl acetate.
16. The method of claim 1, wherein extraction of the compound of
Formula II is performed by crystallization.
17. The method of claim 1, further comprising concentrating the
solution.
18. The method of claim 17, wherein the solution is concentrated by
vacuum distillation.
Description
[0001] This application claims benefit of U.S. Provisional
application No. 62/428,401, filed on Nov. 30, 2016. The priority of
this application is expressly claimed, and the disclosure is hereby
incorporated by reference in its entirety
[0002] All references cited herein, including but not limited to
patents and patent applications, are incorporated by reference in
their entirety.
BACKGROUND
[0003] Onapristone (ONA) is an anti-progestin drug and progesterone
receptor antagonist which was originally developed for
contraceptive use. However, it has demonstrated substantial
activity in advanced breast cancer. It is thought that ONA binds to
the progesterone receptor (PR), preventing the PR from binding to
DNA, thereby inhibiting or eliminating PR-induced transcription.
See, e.g., Klijn et al., Progesterone antagonists and progesterone
receptor modulation in the treatment of breast cancer, Steroids, v.
65, pp. 825-830 (2000); Jonat et al., The clinical efficacy of
progesterone antagonists in breast cancer, Endocrine Therapy of
Breast Cancer, pp. 117-124.
[0004] European Patent Number 0129499 (499 patent) refers to a
process for the deprotection and dehydration of the final
intermediate to obtain ONA as a crude mixture. According to the
'499 patent, any mineral or organic acid can be used for the
removal of the ketal in the 3-position, the dehydration of the
5-hydroxy group, and the removal of the protecting group on the
primary hydroxyl group at C23. Solvents for the process should be
aqueous methanol, ethanol, or acetone, and the mineral acids should
be used in catalytic amounts, according to the '499 patent.
[0005] The '499 patent discloses that heating the precursor to ONA
in 70% acetic acid at 50.degree. C. for 3 hours is the best process
for the removal of the protecting groups and the dehydration of the
5-OH group. The '499 patent further teaches that (1) the reaction
mixture is diluted with water, (2) neutralized with aqueous ammonia
to pH 10.2, (3) extracted with ethyl acetate, and (4) after removal
of the solvent, the reaction mixture is chromatographically
purified to crystallize the ONA with a 70% yield of 70%.
[0006] The same method was disclosed in Neef, G., Steroids, 1984,
44, 349. The authors reported no yield from the reaction. Chen, G.
et al. Zhogguo Yaoke Daxue Xuebao, 1992, 23, 209 described the use
of the same method at 50.degree. C., but shortened the reaction
time to 1 hour. After workup and chromatographic purification, the
authors isolated ONA with a yield of 56% through crystallization.
The THP protected 17.beta.-OH intermediate was isolated from the
reaction mixture. This intermediate is formed during the reaction
due to a rearrangement of the THP protecting group from the primary
alcohol to the tertiary alcohol in the 17 position. THP protected
17.beta.-OH has been found to be the most stable with respect to
hydrolytic conditions.
[0007] Other reaction methods include the use of P-Toluenesulfonic
acid for hydrolysis of the ketal in C3, and dehydration of C5-OH
(U.S. Pat. No. 5,693,628); sulfuric acid in methanol for the
hydrolysis of ketals and dehydration of C5-OH (WO 2013016725);
sulfuric acid in acetone (WO 1998031702); sulfuric acid in ethanol
for the hydrolysis ketals and for the dehydration of C5-OH (U.S.
Pat. No. 6,900,193) and HCl in methanol for the hydrolysis of the
ketal and dehydration of the C5-OH (Gao, G. et al, Faming Zhuanti
Shenqing Gonkai CN1087090). In each of the above cases,
chromatographic purification prior to crystallization was
necessary, and the structures of the starting material contained
the C13 .beta. methyl group.
SUMMARY
[0008] In one aspect, methods are described herein for the
deprotection and dehydration of the compound of Formula I:
##STR00001##
[0009] to the compound of Formula II:
##STR00002##
[0010] In one aspect, the compound of Formula I is the precursor of
Formula II onapristone (ONA). The compound of Formula I is also
referred to herein as Steroid 1.
[0011] In another aspect, the compound of Formula II is the final
product, onapristone (ONA).
##STR00003##
DETAILED DESCRIPTION
[0012] Before describing an exemplary aspect described herein, it
is to be understood that the invention is not limited to the
details of construction or process steps set forth in the following
description. The aspect described herein is capable of being
practiced or being carried out in various ways.
[0013] Aspects described herein provide methods of making
onapristone by reacting the compound of Formula I:
##STR00004##
with sulfuric acid in a solvent to deprotect the compound of
Formula I. In this aspect, the reaction temperature is maintained
below about 60.degree. C.; the reaction is neutralized with an
inorganic base to form a solution; and the compound of Formula II
(onapristone) is extracted from the solution.
##STR00005##
[0014] In another aspect, the sulfuric acid is diluted up to 80%
with water. In yet another aspect, the sulfuric acid is diluted
from 30 to 60% with water. In a further aspect, the sulfuric acid
is diluted with 50% water.
[0015] The solvent can be selected from the group consisting of
methanol, ethanol, acetone, n-propanol and isopropanol. In another
aspect, the solvent is methanol.
[0016] In a further aspect, the reaction temperature is maintained
between about -50 to about 60.degree. C., -10 and 30.degree. C., or
from about 0 to about 15.degree. C.
[0017] In yet another aspect, the inorganic base is selected from
the group consisting of sodium hydrogen carbonate, sodium phosphate
or ammonia. In a further aspect, the inorganic base is ammonia with
a concentration between about 5 and 30%. In a further aspect, the
inorganic base is 30% ammonia.
[0018] In another aspect, the reaction with the inorganic base is
performed at a temperature up to about 30.degree. C., and at a
temperature from about 0 to about 15.degree. C.
[0019] In yet another aspect, the compound of Formula II is
extracted from the reaction solution with ethyl acetate.
[0020] In another aspect, the compound of Formula II (onapristone)
is extracted from the reaction solution by allowing onapristone to
crystallize.
[0021] In a further aspect, the reaction solution containing
onapristone can be concentrated (e.g., increasing the amount of
onapristone in the solution using vacuum distillation).
[0022] Previously described acetic acid methods of making
onapristone provided poor yields of onapristone, for example, 51%
yield after treatment of steroid 1 with 70% acetic acid at
60.degree. C. (data not shown). In addition, the acetic acid method
reaction is slow, requiring extension from one to two hours.
Moreover, purifying onapristone from acetic acid method reaction
did not improve the quality of the product. For example, new
impurities were formed due to reactions with the C17-OH group.
[0023] The main products from the acetic acid method side reactions
include C17 OAc and C17 ether, resulting from rearrangement. These
by-products are difficult to remove, and prevent crystallization of
the crude ONA resulting in the low yields of the reaction after
purification.
[0024] Other methods (e.g., hydrochloric acid, oxalic acid or
p-toluenesulfonic) produced either highly impure material or an
incomplete reaction. Use of these acid catalysts are reported to be
efficient for removal of the protecting group in the C3 position
and the dehydration of the C5 OH group. However, these methods are
not suitable for compounds having a THP-ether protecting group.
[0025] In one aspect, the reaction can be performed in aqueous
solvent (methanol, ethanol, acetone, n-propanol or isopropanol) or
in neat alcohol with concentrated or diluted sulfuric acid. In
another aspect, the reaction is preferably run in methanol or
ethanol. In yet another aspect, the most preferable solvent is neat
methanol.
[0026] The amount of sulfuric acid has an influence of the reaction
time. In one aspect, the reaction can be run with 0.1 equivalents
to 10 equivalents of sulfuric acid either diluted with water or
neat. In another aspect, the reaction is preferably run with
diluted sulfuric with 10-90% sulfuric acid in water with 1-5
equivalents of sulfuric acid. In yet another aspect, the reaction
performs best with 3 equivalents of sulfuric acid diluted 1:1 with
water.
[0027] The temperature and the reaction time are important
parameters for the reaction. The lower the temperature, the slower
the reaction. In one aspect, the reaction can be run at about -50
to about 60.degree. C. for about 10 minutes to about 10 hours. In
another aspect, the reaction can be run at -10 to about 30.degree.
C. for about 30 minutes to about 5 hours. In another aspect, the
reaction can be run at about 0-15.degree. C. for about 1-2
hours.
[0028] The workup can be performed, for example, through the
addition of aqueous inorganic bases (e.g., sodium bicarbonate,
sodium phosphate, or ammonia). The temperature can be controlled to
minimize the formation of impurities.
[0029] In another aspect, the inorganic base is added slowly to the
acidic reaction mixture under temperature controlled conditions
(e.g., 0-50.degree. C., or 0-15.degree. C.).
[0030] In another aspect, the temperature can be controlled from
0-50.degree. C.
[0031] Acid hydrolysis to dehydrate position 5 and remove
protecting groups to yield onapristone (ONA).
[0032] In another aspect, methods described herein provide about an
80% yield and about 88.9%) purity. The described methods omit the
need for chromatographic purification as the crude ONA product is
directly crystallized.
EXAMPLES
[0033] The following non-limiting example illustrate aspects
described herein. Not every element described herein is required.
Indeed, a person of skill in the art will find numerous additional
uses of and variations to the methods described herein, which the
inventors intend to be limited only by the claims. All references
cited herein are incorporated by reference in their entirety.
Example 1--Deprotection and Dehydration
[0034] 24 kg of a methanol solution containing 6.21 kg of
AR-18-1109 and 4 L THF was concentrated in a vacuum. 20 L methanol
and 20 mL pyridine was added to the residue, and the mixture was
concentrated in a vacuum. 20 L methanol and 20 mL pyridine were
added to the resulting residue, and this mixture was concentrated
in a vacuum. 6 L methanol and 19 mL pyridine was added to the
resulting residue, and the solution was cooled to 5.degree. C.
under a nitrogen atmosphere.
[0035] 50% sulfuric acid was added slowly to the resulting solution
while maintaining the temperature between 5-10.degree. C. The
reaction was allowed to proceed for 1 hour. Next, a solution of 5.0
L water and 5.0 L ammonia (28-30%) was slowly added to the
solution, while maintaining the temperature below 15.degree. C.,
resulting in formation of a suspension.
[0036] Next, 20 L of water and 20 L of ethyl acetate were added.
After stirring, the phases were allowed to settle and separate. The
aqueous layer was extracted twice with 20 L ethyl acetate. The
combined organic phases were washed with 3.5 L water and 10.5 L
water. Washing was continued with 2.5 L brine and 7.5 L of water.
The organic layer contained about 4.7 kg of crude ONA (88.9% a/a).
This material was pooled with 4.8 kg of crude material (89.9% a/a)
obtained with the same procedure performed with another batch of
starting material.
[0037] The resulting solution of pooled product was concentrated
until crystallization occurred. The crystallized solids were
isolated, yielding 5.3 kg (96.1%) of onapristone. After allowing
the filtrate to stand overnight, the solids formed yielded another
0.78 kg of onapristone upon additional filtration. The mother
liquor contained another 2.46 kg of onapristone which was collected
as described below.
[0038] 15.1 L THF and 15.2 L isopropyl acetate were added to the
6.07 kg of crude onapristone. The mixture was stirred at 54.degree.
C. until all material had dissolved. The THF was removed by vacuum
distillation and addition of subsequent lots of isopropyl acetate.
During distillation, onapristone started to crystallize yielding
5.12 kg of AR-18-1110 (purity 97.2% a/a). The mother liquor
contained about 0.97 kg of material (purity 84.9% a/a) from which
0.78 kg of ONA was obtained.
* * * * *