Note: Descriptions are shown in the official language in which they were submitted.
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Process for preparing (1113, 16a)-9-fluoro-11-hydroxy-16,17-[1-methyl-
ethylidenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-
dien-3,20-dione
Field of the invention
This invention relates to a new process for the preparation of the
compound (1113, 16a)-9-fluoro-11-hydroxy-16,17-[1-methyl-
ethylidenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-
3,20-dione, used as a topic anti-inflammatory drug.
Background art
Compound (11 16a)-9-fluoro-11-hydroxy-16,17-[1-methyl-
ethylidenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-
3,20-dione with formula (I) is a corticosteroid previously described in
application W02007025632 (Example 1). This compound is especially useful
in the treatment of certain inflammatory diseases such as corticosteroid-
sensitive dermatosis, atopic dermatitis, contact dermatitis, psoriasis and
seborrhoeic dermatitis.
0
O O CH3
a`O CH3
HO O
O2N
F
(I)
Said compound is applied topically, preferably using creams, ointments,
lotions and gels and similar formulations.
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The compound of formula (I) is obtained in example 1 of application
W02007025632 by the reaction of triamcinolone acetonide (II) with 4-
(nitrooxymethyl)benzoic acid (III) in the presence of 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (IV) and 4-dimethylaminopyridine (V)
according to Diagram 1.
COOH C2H5
HO N H3C1-1 N CH3
CH3
O
CH3 N
HO
NOZ CH3
N N
0-1
/ (III) (IV)
CH3 (V)
F H
O
(II)
0
O O CH3
a`O CH3
HO O
O2N
F H
(I)
Diagram I
The yield of this reaction is of 34.4%, which makes it industrially
unviable. Also, the price of the diimide used (IV) is also a drawback for use
in
industrial processes.
It is therefore necessary to find a different process for the industrial
production of compound (I) with a high yield and using cheaper starting
products.
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The authors of the present invention have achieved a new industrial
process to obtain (I) that produces the product with a much higher yield and
also replaces diimide (IV) with N,N'-diisopropylcarbodiimide (VI), which is
cheaper. On the other hand, we have found that the resulting product is of
very high purity. Moreover, the new process also comprises a final step of
controlled precipitation, which provides the end product with a suitable
particle
size for the preparation of topical formulations.
Summary of the invention
In a single aspect, the invention provides a new industrial process for
preparing (11P, 16a)-9-fluoro-11-hydroxy-16,17-[1-methyl -ethyl idenebis(oxy)]-
21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione (I) with a
good yield, starting from cost effective products and providing an end product
with suitable purity and particle size.
Detailed description of the invention
The process for preparing 11P, 16a)-9-fluoro-11-hydroxy-16,17-[1-
methyl-ethyl idenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-
dien-3,20-dione (I), which is the single aspect of the invention, comprises
the
following steps:
(i) reaction of triamcinolone acetonide (II)
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HO
O CH3
.`O CH3
HO
F H
O
(II)
with 4-(nitrooxymethyl)benzoic acid (III), 4-dimethylaminopyridine (V)
and N,N'-diisopropylcarbodiimide (VI)
COOH H3C'~' CH ,CH3
H3CI-I CH3
N
11
N
61w~/NO2 N H
O
H3C CH3
(III) (V) (VI)
in an inert solvent, followed by the elimination by filtration or
centrifuging of the solid formed, which consists mainly of N,N'-
diisopropylurea, acidification of the liquid phase, neutralising and
washout thereof with water, adding an inert anti-solvent to the organic
phase and separating the compound (I) thus formed by filtration or
centrifuging;
(ii) crystallisation of compound (I) formed in step (i) in a mixture of a
solvent and an anti-solvent; and
(iii) precipitation of the compound (I) crystallised in step (ii) in a mixture
of a solvent and an anti-solvent.
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In a preferred embodiment, the solvent of step (i) is chosen from the
group consisting of halogenated hydrocarbons such as dichloromethane,
amides such as dimethylformamide and dimethylacetamide, cyclic ethers such
as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone,
5 esters such as ethyl acetate and isopropyl acetate, nitriles such as
acetonitrile,
sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures
thereof. The solvent is preferably dichloromethane.
In another preferred embodiment, the acidification is performed with an
acid chosen from the group consisting of mineral acids such as hydrochloric
acid, sulphuric acid, phosphoric acid and hydrobromic acid, carboxylic acids
such as acetic acid, trifluoroacetic acid and formic acid, sulphonic acids
such
as methane sulphonic acid, trifluoromethane sulphonic acid and p-toluene
sulphonic acid and other similar acids and mixtures thereof. The acid is
preferably hydrochloric acid.
In another preferred embodiment, the neutralisation is performed with a
base chosen from the group consisting of alkaline bicarbonates such as
sodium bicarbonate and potassium bicarbonate and alkaline carbonate such
as sodium carbonate and potassium carbonate. The base is preferably
sodium bicarbonate.
In another embodiment preferred, the anti-solvent of step (i) is chosen
from the group consisting of C1-C4 alkanols such as ethanol, methanol and
isopropanol, aromatic hydrocarbons such as toluene and xylenes, as well as
water and other similar anti-solvents and mixtures thereof. The anti-solvent
is
preferably ethanol.
In another preferred embodiment, the solvent of step (ii) is chosen from
the group consisting of halogenated hydrocarbons such as dichloromethane,
amides such as dimethylformamide and dimethylacetamide, cyclic ethers such
as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone,
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esters such as ethyl acetate and isopropyl acetate, nitriles such as
acetonitrile,
sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures
thereof. The solvent is preferably dichloromethane.
In another preferred embodiment, the anti-solvent of step (ii) is chosen
from the group consisting of C1-C4 alkanols such as ethanol, methanol and
isopropanol, aromatic hydrocarbons such as toluene and xylenes, as well as
water and other similar anti-solvents and mixtures thereof. The anti-solvent
is
preferably ethanol.
In another preferred embodiment, the solvent of step (iii) is chosen from
the group consisting of esters such as ethyl acetate and isopropyl acetate,
amides such as dimethylformamide and dimethylacetamide, cyclic ethers such
as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone,
nitriles such as acetonitrile, halogenated hydrocarbons such as
dichloromethane and sulphoxides such as dimethyl sulphoxide and similar
solvents and mixtures thereof. The solvent is preferably ethyl acetate.
In another preferred embodiment, the anti-solvent of step (iii) is chosen
from a group consisting of C6-C9 aliphatic hydrocarbons such as heptane,
aliphatic ethers such as isopropyl ether and ethyl ether, the group consisting
of C1-C4 alkanols such as ethanol, methanol and isopropanol, and similar anti-
solvents and mixtures thereof. The anti-solvent is preferably heptane.
Examples
Example 1
Synthesis of (1113, 16a)-9-fluoro-11-hydroxy-16,1741-methyl-
ethyl idenebis(oxy)1-21-f1-oxo-[4-(nitrooxymethyl)benzoxyllpregna-1,4-dien-
3,20-dione (I)
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COOH H3C'~' CH /CH,
HO H3CINCH3
O CH3 \
~.O CH3
HO N
N O2 CIH
H3C CH3
(III) (VI) (V)
F H
(II)
0
O O CH3
a`O CH3
HO O
O2N
F H
O
(I)
Diagram 2
(i) Reaction
12.92 Kg of triamcinolone acetonide (II), 6.50 Kg of 4-(nitrooxymethyl)benzoic
acid (III), 401 g of 4-dimethylaminopyridine (V) and 5.8 I of N,N'-
diisopropylcarbodiimide (VI) were added to 284 I of dichloromethane. The
solution was placed at ambient temperature and maintained with stirring until
the reaction was completed. 13 I of dichloromethane were added.
The solid formed (N,N'-diisopropylurea) was removed by filtration and the
filter
was washed with dichloromethane.
The dichloromethane extracts were placed together and 203 I of 0.5 N HCI
were added. 203 1 of 0.5 N HCI were added to the organic phase, followed by
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129 I of 0.25 N NaHCO3. It was washed with water until the pH of the aqueous
phase was similar to that of the water added.
465 I of absolute ethanol were added to the organic phase and it was distilled
at atmospheric pressure to a final volume of between 465 I and 504 I, and it
was left to reach room temperature.
The suspension was filtered and the wet solid was washed with ethanol.
The wet solid was dried under vacuum, producing 15.59 Kg of compound (I).
Yield = 85.5%. HPLC Purity = 98.41 %.
(ii) Crystallisation
15.56 Kg of the solid obtained in the previous step were added to 467 I of
dichloromethane. This was heated to reflux and distilled at atmospheric
pressure to a final volume of 47 I. It was left to reach ambient temperature
and
560 I of ethanol were added.
The suspension was filtered and the wet solid was washed with ethanol.
The wet solid was dried under vacuum.
(iii) Precipitation
11.21 Kg of the solid obtained in the previous step were added to 516 I of
ethyl acetate. It was heated to reflux and stirred until solution. It was
cooled to
40-50 C. 538 I of heptane were added and it was taken to ambient
temperature. The solution was filtered through a 0.2 pm filter. It was washed
with ethyl acetate and stirred at least for 3 hours at ambient temperature.
The suspension was filtered and the wet solid was washed with heptane.
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The wet solid was dried under vacuum.
Example 2
Particle size distribution for (I)
The particle size distribution of the product obtained in the final step of
Example 1 showed a Gaussian distribution characterised by values d(0.9) _
10.79 pm; d(0.5) = 5.26 pm; and d(0.1) = 2.34 pm.
