U.S. patent application number 14/688960 was filed with the patent office on 2016-04-07 for methods of preparing intermediate of fluticasone propionate.
The applicant listed for this patent is AMPHASTAR PHARMACEUTICALS INC.. Invention is credited to Song Chen, Yong Liu, Yinhua Qiu, Zhengyuan Wu, Haoning Zhang.
Application Number | 20160096863 14/688960 |
Document ID | / |
Family ID | 55588872 |
Filed Date | 2016-04-07 |
United States Patent
Application |
20160096863 |
Kind Code |
A1 |
Qiu; Yinhua ; et
al. |
April 7, 2016 |
METHODS OF PREPARING INTERMEDIATE OF FLUTICASONE PROPIONATE
Abstract
A method of preparing a thioic acid intermediate of fluticasone
propionate includes: treating a 17.beta.-[(N,N-dimethyl
carbamoyl)thio]carbonyl compound in a solution including an alcohol
and an alkali metal hydroxide, an alkaline-earth metal hydroxide,
or a mixture thereof to cleave an amide from the
17.beta.-[(N,N-dimethyl carbamoyl)thio]carbonyl compound; treating
the solution to separate an aqueous portion; and adding an acid to
the aqueous portion to obtain the thioic acid intermediate of
fluticasone propionate. A method of preparing fluticasone
propionate includes preparing the thioic acid intermediate of
fluticasone propionate, and alkylating the thioic acid intermediate
of fluticasone propionate to prepare the fluticasone
propionate.
Inventors: |
Qiu; Yinhua; (Nanjing,
CN) ; Wu; Zhengyuan; (Nanjing, CN) ; Liu;
Yong; (Nanjing, CN) ; Chen; Song; (Nanjing,
CN) ; Zhang; Haoning; (Nanjing, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMPHASTAR PHARMACEUTICALS INC. |
Rancho Cucamonga |
CA |
US |
|
|
Family ID: |
55588872 |
Appl. No.: |
14/688960 |
Filed: |
April 16, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62059786 |
Oct 3, 2014 |
|
|
|
Current U.S.
Class: |
552/610 |
Current CPC
Class: |
C07J 41/0038 20130101;
C07J 31/006 20130101; C07J 3/005 20130101; C07J 5/0076
20130101 |
International
Class: |
C07J 31/00 20060101
C07J031/00 |
Claims
1. A method of preparing a thioic acid intermediate of fluticasone
propionate, the method comprising: treating Compound 4,
17.beta.-[(N,N-dimethylcarbamoyl)thio]carbonyl-6.alpha.,9.alpha.-difluoro-
-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propionyloxyandrosta-1,-
4-diene in a solution comprising an alcohol and an alkali metal
hydroxide, an alkaline-earth metal hydroxide, or a mixture thereof
to cleave an amide from Compound 4; treating the solution to
separate an aqueous portion; and adding an acid to the aqueous
portion to obtain the thioic acid intermediate of fluticasone
propionate: ##STR00010##
2. The method of claim 1, wherein the thioic acid intermediate of
fluticasone propionate is Compound 1,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-propionyl oxyandrosta-1,4-diene-17.beta.-carbothioate:
##STR00011##
3. (canceled)
4. The method of claim 1, wherein the treating of the solution
removes impurities and comprises evaporating at least a portion of
the alcohol, adding water and an organic solvent, and stirring to
separate the aqueous portion from the solution.
5. The method of claim 1, wherein the adding of the acid comprises
adding the acid dropwise to the aqueous portion.
6. The method of claim 1, wherein the alkali metal hydroxide
comprises lithium hydroxide, sodium hydroxide, potassium hydroxide,
or a mixture thereof, and wherein the alkaline-earth metal
hydroxide comprises magnesium hydroxide, calcium hydroxide, or a
mixture thereof.
7. The method of claim 1, wherein the alkali metal hydroxide
comprises sodium hydroxide, and wherein the alkaline-earth metal
hydroxide comprises calcium hydroxide.
8. The method of claim 1, wherein the mole ratio of the total
amount of the alkali metal hydroxide and the alkaline-earth metal
hydroxide to the amount of Compound 4 is about 1:1 to about
5:1.
9. The method of claim 8, wherein the mole ratio of the total
amount of the alkali metal hydroxide and the alkaline-earth metal
hydroxide to the amount of Compound 4 is about 1.5:1.
10. The method of claim 1, wherein the alcohol comprises methanol,
ethanol, propanol, butanol, or a mixture thereof.
11. The method of claim 10, wherein the alcohol comprises
methanol.
12. The method of claim 10, wherein a volume to weight ratio of the
alcohol to Compound 4 is about 5:1 to 30:1 v/w.
13. The method of claim 12, wherein the volume to weight ratio of
the alcohol to Compound 4 is about 15:1 v/w.
14. The method of claim 1, wherein the treating of Compound 4 is
performed at a reaction temperature of about 0.degree. C. to about
50.degree. C.
15. The method of claim 14, wherein the reaction temperature is
about 25.degree. C. to about 30.degree. C.
16. The method of claim 4, wherein the organic solvent comprises an
ester, an ether, an alkane, an aromatic hydrocarbon, a
halohydrocarbon or a mixture thereof.
17. The method of claim 16, wherein the ester comprises ethyl
acetate, methyl acetate, butyl acetate, or a mixture thereof.
18. The method of claim 16, wherein the ether comprises diethyl
ether, methyl tert butyl ether, or a mixture thereof.
19. The method of claim 16, wherein the organic solvent comprises
toluene, dichloromethane, chloroform, or a mixture thereof.
20. The method of claim 16, wherein the aromatic hydrocarbon
comprises toluene.
21. The method of claim 1, wherein the acid comprises an organic
acid, an inorganic acid, or a mixture thereof.
22. The method of claim 21, wherein the inorganic acid comprises
hydrochloric acid, phosphoric acid, sulphuric acid, or a mixture
thereof, and wherein the organic acid comprises acetic acid, formic
acid, propionic acid, or a mixture thereof.
23. The method of claim 21, wherein the acid is added to the
aqueous portion to obtain a pH of 1 to 5.
24. The method of claim 23, wherein the pH is 2 to 3.
25. A method of preparing fluticasone propionate, the method
comprising: preparing the thioic acid intermediate of fluticasone
propionate according to the method of claim 1; and alkylating the
thioic acid intermediate of fluticasone propionate to prepare the
fluticasone propionate.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to and the benefit of
related U.S. Provisional Application Ser. No. 62/059,786, filed in
the U.S. Patent and Trademark Office on Oct. 3, 2014, the entire
content of which is incorporated herein by reference.
BACKGROUND
[0002] The structure of fluticasone propionate is illustrated as
follows:
##STR00001##
[0003]
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo--
17.alpha.-propionyloxyandrosta-1,4-diene-17.beta.-carbothioate
(Compound 1) is utilized as an intermediate (or a key or important
intermediate) in the synthesis of fluticasone propionate. The
structure of Compound 1 is illustrated as follows:
##STR00002##
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-propionyloxyandrosta-1,4-diene-17.beta.-carbothioate (Compound
1)
[0004] Fluticasone propionate may be synthesized by way of the
oxidation of flumethasone to yield Compound 1, which may be reacted
to obtain fluticasone propionate. The synthetic route for the
foregoing synthesis may be generally illustrated as follows:
##STR00003##
[0005] Dimethylthiocarbamoyl chloride may be used as a sulfation
agent in the above-identified process. Then, the resultant product
may be decomposed by refluxing to obtain diethylamine and the
thioic acid, Compound 1. However, pollution is generated by that
method due, at least in part, to the relatively high consumption of
reagents. Additionally, the yield obtained by using diethylamine is
low. Diethylamine may also be used as a decomposing agent, but the
generation of pollution and low yield have also been observed when
diethylamine is used as the decomposing agent.
[0006] To facilitate the discussion of the subject matter disclosed
herein, Compound 2 is defined herein as
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxoandrost-
a-1,4-diene-17.beta.-carboxylic acid, Compound 3 is defined herein
as
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-propionyloxyandrosta-1,4-diene-17.beta.-carboxylic acid, and
Compound 4 is defined herein as 17.beta.-[(N,N-dimethyl
carbamoyl)thio]carbonyl-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.al-
pha.-methyl-3-oxo-17.alpha.-propionyloxyandrosta-1,4-diene.
Compounds 2-4 are illustrated as follows:
##STR00004##
[0007] Compound 1 may be generated by reacting Compound 3 with
dimethylthiocarbamoyl chloride and sodium iodide in 2-butanaone to
obtain Compound 4, which may then be reacted with a hydrolyzing
agent, such as sodium hydrosulfide or sodium thiomethoxide, to
generate the sodium salt of Compound 1. The sodium salt of Compound
1 may be alkylated in-situ with chlorofluoromethane to yield
fluticasone propionate, or the sodium salt of Compound 1 may be
acidified to obtain Compound 1, which may also be isolated and
converted to fluticasone propionate by alkylation with
chlorofluoromethane. When Compound 4 is hydrolyzed by utilizing
sodium hydrosulfide or sodium thiomethoxide, however, excess sodium
hydrosulfide or sodium thiomethoxide may generate toxic hydrogen
sulfide or methyl mercaptan. If the alkylation of the sodium salt
of Compound 1 is direct, excess sodium hydrosulfide may react with
chlorofluoromethane, and thus, more chlorofluoromethane may be
required (e.g., to compensate for the chlorofluoromethane that
reacts with the excess sodium hydrosulfide). Further, the resultant
impurity of such processes is difficult to remove, thereby
affecting (or reducing) the quality (or purity) of the final
product.
SUMMARY
[0008] Aspects of embodiments of the present disclosure generally
relate to a process for the preparation of a reaction intermediate
of fluticasone propionate. An embodiment of the reaction
intermediate includes
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-o-
xo-17.alpha.-propionyloxyandrosta-1,4-diene-17.beta.-carbothioate.
Fluticasone propionate is a corticosteroid derived from fluticasone
and may be used to treat asthma and allergic rhinitis. Fluticasone
propionate may also be used to treat eosinophilic esophagitis.
[0009] According to an embodiment of the present disclosure, a
method of preparing a thioic acid intermediate of fluticasone
propionate includes: treating a 17.beta.-[(N,N-dimethyl
carbamoyl)thio]carbonyl compound in a solution including an alcohol
and an alkali metal hydroxide, an alkaline-earth metal hydroxide,
or a mixture thereof to cleave an amide from the
17.beta.-[(N,N-dimethyl carbamoyl)thio]carbonyl compound; treating
the solution to separate an aqueous portion; and adding an acid to
the aqueous portion to obtain the thioic acid intermediate of
fluticasone propionate.
[0010] The thioic acid intermediate of fluticasone propionate may
include Compound 1,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-propionyloxyandrosta-1,4-diene-17.beta.-carbothioate, or a
derivative thereof:
##STR00005##
[0011] The 17.beta.-[(N,N-dimethyl carbamoyl)thio]carbonyl compound
may include Compound 4,
17.beta.-[(N,N-dimethylcarbamoyl)thio]carbonyl-6.alpha.,9.alpha.-difluoro-
11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propionyloxyandrosta-1,4-
-diene, or a derivative thereof:
##STR00006##
[0012] The treating of the solution may remove impurities and may
include evaporating at least a portion of the alcohol from the
solution, adding water and an organic solvent, and stirring to
separate the aqueous portion from the solution.
[0013] The adding of the acid may include adding the acid dropwise
to the aqueous portion.
[0014] The alkali metal hydroxide may include lithium hydroxide,
sodium hydroxide, potassium hydroxide, or a mixture thereof, and
the alkaline-earth metal hydroxide may include magnesium hydroxide,
calcium hydroxide, or a mixture thereof.
[0015] The alkali metal hydroxide may include sodium hydroxide, and
the alkaline-earth metal hydroxide may include calcium
hydroxide.
[0016] A mole ratio of the total amount of the alkali metal
hydroxide and the alkaline-earth metal hydroxide to the amount of
the 17.beta.-[(N,N-dimethyl carbamoyl)thio]carbonyl compound may be
about 1:1 to about 5:1.
[0017] The mole ratio of the total amount of the alkali metal
hydroxide and the alkaline-earth metal hydroxide to the amount of
the 17.beta.-[(N,N-dimethyl carbamoyl)thio]carbonyl compound may be
about 1.5:1.
[0018] The alcohol may include methanol, ethanol, propanol,
butanol, or a mixture thereof.
[0019] The alcohol may include methanol.
[0020] A volume to weight ratio of the alcohol to the
17.beta.-[(N,N-dimethyl carbamoyl)thio]carbonyl compound may be
about 5:1 to 30:1 v/w.
[0021] The volume to weight ratio of the alcohol to the
17.beta.-[(N,N-dimethyl carbamoyl)thio]carbonyl compound may be
about 15:1 v/w.
[0022] The treating of the 17.beta.-[(N,N-dimethyl
carbamoyl)thio]carbonyl compound may be performed at a reaction
temperature of about 0.degree. C. to about 50.degree. C.
[0023] The reaction temperature may be about 25.degree. C. to about
30.degree. C.
[0024] The organic solvent may include an ester, an ether, an
alkane, an aromatic hydrocarbon, a halohydrocarbon, or a mixture
thereof.
[0025] The ester may include ethyl acetate, methyl acetate, butyl
acetate, or a mixture thereof.
[0026] The ether may include diethyl ether, methyl tert butyl
ether, or a mixture thereof.
[0027] The organic solvent may include toluene, dichloromethane,
chloroform, or a mixture thereof.
[0028] The aromatic hydrocarbon may include toluene.
[0029] The acid may include an organic acid, an inorganic acid, or
a mixture thereof.
[0030] The inorganic acid may include hydrochloric acid, phosphoric
acid, sulphuric acid, or a mixture thereof, and the organic acid
may include acetic acid, formic acid, propionic acid, or a mixture
thereof.
[0031] The acid may be added to the aqueous portion to obtain a pH
of 1 to 5.
[0032] The pH may be 2 to 3.
[0033] A method of preparing fluticasone propionate includes:
preparing the thioic acid intermediate of fluticasone propionate;
and alkylating the thioic acid intermediate of fluticasone
propionate to prepare the fluticasone propionate. The alkylating of
the thioic acid intermediate of fluticasone propionate may include
alkylating the thioic acid intermediate of fluticasone propionate
with a halohydrocarbon. The halohydrocarbon may include a
chlorofluorocarbon. The chlorofluorocarbon may include
chlorofluoromethane.
DETAILED DESCRIPTION
[0034] The following detailed description is provided only for
purposes of illustration of embodiments of the present disclosure
and not for purposes of limiting the scope of the present
invention. Alternate embodiments will be readily apparent to those
of skill in the art and are intended to be included within the
scope of the present invention. Also, in the context of the present
application, the term "thioic acid intermediate of fluticasone
propionate" is used in a broad sense and encompasses any thioic
acid intermediate that can be used to form fluticasone propionate.
For example, as used herein, the term "thioic acid intermediate of
fluticasone propionate" encompasses Compound 1 and derivatives
thereof (e.g., substituted
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-propionyloxyandrosta-1,4-diene-17.beta.-carbothioate). As used
in the context of the present application, the term
"17.beta.-[(N,N-dimethyl carbamoyl)thio]carbonyl compound" is used
in a broad sense and encompasses any 17.beta.-[(N,N-dimethyl
carbamoyl)thio]carbonyl compound that can be used to form the
thioic acid intermediate of fluticasone propionate. For example, as
used herein, the term "17.beta.-[(N,N-dimethyl
carbamoyl)thio]carbonyl compound" encompasses Compound 4 and
derivatives thereof (e.g., substituted 17.beta.-[(N,N-dimethyl
carbamoyl)thio]carbonyl-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.al-
pha.-methyl-3-oxo-17.alpha.-propionyl oxyandrosta-1,4-diene).
[0035] Embodiments of the present disclosure provide a facile,
efficient, economical, and simple to industrialize process for
producing an intermediate (or a key or important intermediate) of
fluticasone propionate. The intermediate may include a thioic acid
intermediate of fluticasone propionate including Compound 1
(6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.al-
pha.-propionyloxyandrosta-1,4-diene-17.beta.-carbothioate).
Embodiments of the process provide an improved yield and a highly
purified product including the thioic acid intermediate of
fluticasone propionate (e.g., Compound 1). For example, according
to embodiments of the present disclosure, the percent yield of
Compound 1 is improved from 45% to 90%, and the purity of Compound
1 is >98%. Compound 1 is utilized as an intermediate product
(e.g., a reaction intermediate) in embodiments of a process of
preparing fluticasone propionate. Compound 1 is illustrated as
follows:
##STR00007##
[0036] According to an embodiment of the present disclosure, the
method of preparing a thioic acid intermediate of fluticasone
propionate includes: treating a 17.beta.-[(N,N-dimethyl
carbamoyl)thio]carbonyl compound (e.g., Compound 4,
17.beta.-[(N,N-dimethylcarbamoyl)thio]carbonyl-6.alpha.,9.alpha.-difluoro-
-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propionyloxyandrosta-1,-
4-diene or a derivative thereof) in a solution including an alcohol
and an alkali metal hydroxide, an alkaline-earth metal hydroxide,
or a mixture thereof to cleave an amide from the
17.beta.-[(N,N-dimethyl carbamoyl)thio]carbonyl compound; treating
the solution to separate an aqueous portion, and adding an acid to
the aqueous portion to obtain the thioic acid intermediate of
fluticasone propionate (e.g., Compound 1,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-propionyl oxyandrosta-1,4-diene-17.beta.-carbothioate, or a
derivative thereof). The amide may be cleaved from the
17.beta.-[(N,N-dimethyl carbamoyl)thio]carbonyl compound by
hydrolysis. The amide may include, for example,
(CH.sub.3).sub.2NCOOH. The treating of the solution may remove
impurities and may be followed by acid precipitation of the thioic
acid intermediate of fluticasone propionate. The adding of the acid
may include adding the acid dropwise (e.g., adding droplets of the
acid) to the aqueous portion. Embodiments of the present disclosure
are convenient and environmental friendly, and produce a final
product having high yield and high purity.
[0037] For example, according to embodiments of the present
disclosure a process of preparing Compound 1 includes: (a) treating
Compound 4 (i.e., 17.beta.-[(N,N-dimethyl
carbamoypthio]carbonyl-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alp-
ha.-methyl-3-oxo-17.alpha.-propionyl oxyandrosta-1,4-diene) in an
alkali metal hydroxide/alcohol or an alkaline-earth metal
hydroxide/alcohol to decompose amide (e.g., to cleave an amide from
Compound 4); (b) evaporating alcohol, adding water and organic
solvent, stirring (e.g., stirring thoroughly), obtaining a water
phase (e.g., an aqueous solution or aqueous portion) after removing
impurities; (c) obtaining Compound 1
(6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.al-
pha.-propionyloxyandrosta-1,4-diene-17.beta.-carbothioate) by
adding an acid (e.g., droplets of the acid) to the aqueous
solution. The organic solvent may include any suitable organic
solvent, such as an ester, an ether, an alkane, an aromatic
hydrocarbon, a halohydrocarbon, or a mixture thereof. For example,
the ester may include ethyl acetate, methyl acetate, butyl acetate,
or a mixture thereof. The ether may include diethyl ether, methyl
tert butyl ether, or a mixture thereof. The organic solvent may
include the halohydrocarbon (e.g., dichloromethane, chloroform, or
a mixture thereof), the aromatic hydrocarbon (e.g., toluene), or a
mixture thereof.
[0038] The alkali metal hydroxide may include lithium hydroxide,
sodium hydroxide, potassium hydroxide, or a mixture thereof, and
the alkaline-earth metal hydroxide may include magnesium hydroxide,
calcium hydroxide, or a mixture thereof. A mole ratio of the total
amount of the alkali metal hydroxide and the alkaline-earth metal
hydroxide to the amount of the 17.beta.-[(N,N-dimethyl
carbamoyl)thio]carbonyl compound may be about 1:1 to about 5:1. The
mole ratio of the total amount of the alkali metal hydroxide and
the alkaline-earth metal hydroxide to the amount of the
17.beta.-[(N,N-dimethyl carbamoyl)thio]carbonyl compound may be
about 1.5:1. The alcohol may include any suitable alcohol, such as
methanol, ethanol, propanol, butanol, or a mixture thereof.
[0039] The acid may include any suitable acid, such as an organic
acid, an inorganic acid, or a mixture thereof. The inorganic acid
may include hydrochloric acid, phosphoric acid, sulphuric acid, or
a mixture thereof. The organic acid may include acetic acid, formic
acid, propionic acid, or a mixture thereof. The acid may be added
to the aqueous portion to obtain a pH of 1 to 5. For example, the
acid may be added to the aqueous portion to obtain a pH of 2 to
3.
[0040] The treating of the 17.beta.-[(N,N-dimethyl
carbamoyl)thio]carbonyl compound (e.g., Compound 4) may be
performed at a reaction temperature of about 0.degree. C. to about
50.degree. C. For example, the reaction temperature may be about
25.degree. C. to about 30.degree. C. A volume to weight ratio of
the volume of the alcohol to the weight of the
17.beta.-[(N,N-dimethyl carbamoyl)thio]carbonyl compound (e.g.,
Compound 4) may be about 5:1 to 30:1 v/w. For example, the volume
to weight ratio of the alcohol to the 17.beta.-[(N,N-dimethyl
carbamoyl)thio]carbonyl compound may be about 15:1 v/w.
[0041] In other processes in which Compound 4 is decomposed to form
diethylamine and a thioic acid (Compound 1), diethylamine functions
as a solvent and a reagent. After the reaction (the decomposition),
hydrochloric acid is added for neutralization, which generates
substantial amounts of organic waste water containing diethylamine,
and the percent yield (actual yield theoretical yield) of the final
product yield is only about 40%. Therefore, the addition of more
agents (e.g., diethylamine) results in more pollution and the yield
of such a diethylamine based process is low, as compared to
embodiments of the present disclosure.
[0042] Embodiments of the present disclosure utilize methane as a
solvent. Methane may be distilled for recycling, which may
effectively reduce the amount of organic waste (or organic
wastewater) produced. Additionally, according to embodiments of the
present disclosure, the percent yield of Compound 1 is improved by
up to 100% (i.e., from 45% to 90%), as compared to other processes.
Therefore, embodiments of the process disclosed herein utilize
fewer agents (or smaller amounts of agents) and are relatively
environmentally friendlier. Additionally, the yield of fluticasone
propionate is greatly increased.
[0043] In methods that utilize a hydrolyzing agent, such as sodium
hydrosulfide or sodium thiomethoxide, an excess amount of the
hydrolyzing agent may generate toxic hydrogen sulfide or methyl
mercaptan. If the alkylation of the sodium salt of Compound 1 is
direct, excess sodium hydrosulfide may react with
chlorofluoromethane, and thus, more chlorofluoromethane may be
required (e.g., to compensate for the chlorofluoromethane that
reacts with the excess sodium hydrosulfide). Further, the resultant
impurity of such processes is difficult to remove, which may affect
(or reduce) the quality (or purity) of the final product.
Embodiments of the present disclosure avoid or reduce the
generation of toxic hydrogen sulfide or methyl mercaptan, the need
for additional chlorofluoromethane, and the generation of
difficult-to-remove impurities.
[0044] Embodiments of the presently disclosed method do not
generate the impurity carboxylic acidmethyl ester, thereby
rendering the treatment simpler and the purity of Compound 1
relatively higher (e.g., higher than 98%).
[0045] A synthesis route according to an embodiment of the present
disclosure is shown in Reaction Scheme 1:
##STR00008## ##STR00009##
[0046] In Reaction Scheme 1, Compound 2 is prepared by the
oxidation of flumethasone with an oxidizing agent. The oxidizing
agent may include per-iodic acid (e.g., orthoperiodic acid
(H.sub.5IO.sub.6), metaperiodic acid (HIO.sub.4), or mixture
thereof) in tetrahydrofuran (THF). Compound 2 is then reacted to
form Compound 3, for example, by reacting Compound 2 in the
presence of or with propionyl chloride and catalysts (e.g.,
triethylamine and/or dimethylamine in acetone) to aminolyze
Compound 2 and obtain Compound 3. Compound 3 is then reacted to
obtain Compound 4. For example, Compound 3 may be reacted in the
presence of or with N,N-dimethylthiocarbamoyl chloride, sodium
iodide and triethylamine as catalysts in tetrahydrofuran to obtain
Compound 4. Compound 4 is reacted with an alkali metal hydroxide,
such as sodium hydroxide, and/or an alkaline-earth metal hydroxide,
such as calcium hydroxide, in alcohol, such as methanol, to obtain
Compound 1.
[0047] A process of using alkali metal carbonate/alcohol has also
been used for the preparation of Compound 1. Although such a method
can provide an improved yield of Compound 1, a methyl ester
impurity is generated by that method, and the methyl ester impurity
is difficult to remove, which affects (or reduces) the quality (or
purity) of the final product. A process of using alkali metal
phosphate/alcohol has also been used, but it too has been observed
to produce a difficult-to-remove impurity in the process.
EXAMPLES
[0048] The following examples provide further details of certain
embodiments of the current disclosure. The examples are provided to
illustrate embodiments of the present disclosure, but the present
invention is not limited thereto. Certain features of Reaction
Scheme 1 are embodied in the following examples:
Example 1
[0049] Compound 2, i.e.,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxoandrost-
a-1,4-diene-17.beta.-carboxylic acid, was prepared as follows.
[0050] A solution of per-iodic acid (36.2 g) in water (72 ml) was
prepared. This solution was added dropwise to a stirred suspension
of flumethasone (30 g) in tetrahydrofuran (150 ml) at a temperature
of 0 to 10.degree. C. to form a reaction solution. After completion
(or substantial completion) of the addition of the solution of
per-iodic acid, the reaction solution was stirred further for 2
hours. Tetrahydrofuran was then evaporated (at least a substantial
portion of the tetrahydrofuran was evaporated), the resultant
solution was cooled to a temperature of 0 to 10.degree. C., and the
resultant solution was maintained at a temperature of 0 to
10.degree. C. for 2 hours and then filtered to obtain a filtered
product. The filtered product was washed with water and dried at
50.degree. C. to obtain a final product. 28.3 g of the final
product having a purity of 99.5% (the final product included 99.5
wt % of Compound 2 based on the total weight of the final product)
was obtained. The percent yield of Compound 2 was 98.2%. The
percent yield of Compound 2 was calculated as shown in Equation 1.
The percent yield in each of Examples 2 to 5 was calculated in a
similar manner.
Percent yield = ( Weight of Compound 2 / molecular weight of
Compound 2 ) * Purity % ( Weight of flumethasone / molecular weight
of flumethasone ) * Purity % Percent yield = ( 28.3 g / 396.42 g /
mol ) * 99.5 % ( 30 g / 410.45 g / mol ) * 99 % = 98.2 % Equation 1
##EQU00001##
Example 2
[0051] Compound 3, i.e.,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-propionyoxyandrosta-1,4-diene-17.beta.-carboxylic acid, was
prepared as follows.
[0052] 40 ml of triethylamine was added to a suspension including
Compound 2 (50 g, 99.5 wt %, in 250 ml of acetone) at a temperature
of 0 to 10.degree. C. to prepare a reaction solution. Then, 45.6 ml
of propionyl chloride was added to the reaction solution. After
completion (or substantial completion) of the addition, the
reaction solution was stirred for 1 hour. Diethylamine (50 ml) was
then added to the reaction solution, which was then stirred for 2
hours to form a reaction mixture. Thereafter, the reaction mixture
was acidified to a pH of about 1 to 2 by adding 2M hydrochloric
acid to form a precipitated product. The precipitated product was
filtered, washed with water, and dried at 50.degree. C. to obtain a
final product. 54.5 g of the final product having a purity of 99.2%
(the final product included 99.2 wt % of Compound 3 based on the
total weight of the final product). The percent yield of Compound 3
was 98.6%.
Example 3
[0053] Compound 4, i.e.,
17.beta.-[(N,N-dimethylcarbamoyl)thio]carbonyl-6.alpha.,9.alpha.-difluoro-
-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propionyloxyandrosta-1,-
4-diene, was prepared as follows.
[0054] A solution of Compound 4 (31 g, 99.2 wt %) in
tetrahydrofuran (240 ml) was stirred at room temperature, and
dimethylthiocarbamoyl chloride (18.3 g), sodium iodide (3.0 g) and
triethylamine (20 ml) were added thereto and the resultant was
stirred for 16 hours. Then, the resultant was treated with
N,N-dimethylformamide (90 ml) and water (600 ml) to prepare a
mixture. The mixture was cooled to a temperature of 0 to 10.degree.
C., and stirred for 2 hours. The resultant product was filtered,
washed with water and dried at 50.degree. C. to obtain a final
product. 36.1 g of the final product having a purity of 98.8% (the
final product included 98.8% of Compound 4 based on the total
weight of the final product) was obtained. The percent yield of
Compound 4 was 97.3%.
Example 4
[0055] Compound 1, i.e.,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-propionyloxyandrosta-1,4-diene-17.beta.-carbothioate, was
prepared as follows.
[0056] A suspension including 35 g of Compound 4 (98.8 wt %) and
3.9 g of sodium hydroxide in 525 ml of methanol was stirred at a
temperature of 25 to 30.degree. C. for 24 hours. The methanol was
then evaporated from the suspension (at least a substantial portion
of the methanol was evaporated). Thereafter, 140 ml of acetic ether
(ethyl acetate) and 350 ml water were added thereto, and the
resultant was stirred for 30 minutes and an aqueous solution was
separated therefrom. Thereafter, the aqueous solution was acidified
to a pH of about 2 to 3 by adding 2M hydrochloric acid dropwise to
the aqueous solution to obtain a precipitated product. The
precipitated product was filtered, washed with water, and dried at
50.degree. C. to obtain a final product. 29.2 g of the final
product having a purity of 98.5% (the final product included 98.5
wt % of Compound 1 based on the total weight of the final product)
was obtained. The percent yield of Compound 1 was 95.8%.
Example 5
[0057] A suspension including 30 g of Compound 4 (98.8 wt %), and
6.2 g of calcium hydroxide in 450 ml methanol were stirred at a
temperature of 25 to 30.degree. C. for 24 hours. The methanol was
then evaporated from the suspension (at least a substantial portion
of the methanol was evaporated). Thereafter, 120 ml of acetic ether
(ethyl acetate) and 300 ml water were added thereto, and the
resultant was stirred for 30 minutes and an aqueous solution was
separated therefrom. Thereafter, the aqueous solution was acidified
to a pH of about 2 to 3 by 2M hydrochloric acid to obtain a
precipitated product. The precipitated product was filtered, washed
with water, and dried at 50.degree. C. to obtain a final product.
25.1 g of the final product having a purity of 98.7% (the final
product included 98.7 wt % of Compound 1 based on the total weight
of the final product) was obtained. The percent yield of Compound 1
was 96.3%.
[0058] Compound 1 may then be utilized to obtain fluticasone
propionate according to any suitable method in the art. For
example, Compound 1 may be alkylated to obtain fluticasone
propionate. In some embodiments, Compound 1 is alkylated with a
halohydrocarbon. The halohydrocarbon may include a
chlorofluorocarbon. For example, the chlorofluorocarbon may include
chlorofluoromethane.
[0059] While the present invention has been described in connection
with certain embodiments, it is to be understood that the invention
is not limited to the disclosed embodiments, but, on the contrary,
is intended to cover various modifications and equivalent
arrangements included within the spirit and scope of the appended
claims, and equivalents thereof. Throughout the text and claims,
the terms "about" and "substantially" are used as terms of
approximation, not terms of degree, and reflect the inherent
variation associated with measurement, significant figures, and
interchangeability, all as understood by a person having ordinary
skill in the relevant art. Also, it is to be understood that
throughout this disclosure and the accompanying claims, even values
that are not preceded by the term "about" are also implicitly
modified by that term, unless otherwise specified.
* * * * *