b FIELD OF THE INVENTION
The present invention relates to a process for the preparation of steroidal 17P-carboxylic
thioates. More particularly the present invention relates to a convenient and efficient
synthesis of fluticasone propionate.
BACKGROUND OF THE INVENTION
Anti-infammatory steroids are most typically of the corticoid type, i.e. are pregnane
derivatives. Certain androstane compounds containing a haloalkyl carbothioate grouping in
the 17P-position have particularly advantageous anti-inflammatory properties.
Fluticasone propionate I, an androstane compound chemically known as S-fluoromethyl-
6a,9a-difluoro-l l P-hydroxy-l6a-methyl- 1 7a-propionyloxy-3-0x0-androsta-1,4-diene1- 7 1)-
carbothioate, is represented below at Formula I.
Formula I
The original product patent of Fluticasone propionate has expired. There are several
processes known in the literature for fluticasone propionate, however, most of them are
associated with various difficulties. For instance, one of the processes that is con~monly
followed in the industries is disclosed in US patent 4335 121, the first published patent on this
product.
The starting material of US 4335121 is flumethasone, which is chemically known as 6a,9adifluoro-
11 P,1 7a,2 1 -trihydroxy- l6a-methyl-androsta-1,4-diene-3,20-dione. The starting
material is subjected to oxidative cleavage of the hydroxymethyl group on C-17 in by
periodic acid to obtain 6a,9a-difluoro- 1 1 P, 1 7a-dihydroxy- l6a-methyl-androsta-1,4-diene-3-
one- 17P-carboxylic acid (2).
The carboxyl group of compound (2) is then activated using N,N1-carbonyldiimidazole(C DI)
in dimethylformamide (DMF) and is subscrl~lently treated with H2S gave 6a,9a-diflooro- 1 1 1).
A 17a-dihydroxy-16a-methyl-3-oxo-androsta-l,4-diene-l7~-carbothiaociicd of formula 3, which
is esterified using propionyl chloride and triethylamine (TEA) to obtain 6a,9a-difluoro-l l phydroxy-
l6a-methyl- 17a-propionyloxy-3-oxo-androsta-1,4-dien1e 7-P -carbothioic acid, the
compound of formula 4. Alkylation of compound of formula 4 with bromochloromethane
using NaHC03 and dimethylacetarnide (DMAc) provides S-chloromethyl-6a,9a-difluoro-IP1-
hydroxy- 16a-methy1-17a-propionyloxy-3-oxo-androsta-1,4-dien1e7-p -carbothioate of formula
5, which when subjected to Halogen exchange with NaI in acetone provides the compound of
formula 6, namely, S-iodomethyl-6a,9a-difluoro-lip-hydrox1y6-a -methyl-l 7a-propionyloxy-
3-0x0-androsta-1,4-diene-17p-carbothioate.In the final step, the compound 6 is reacted with
silver fluoride (AgF) in acetonitrile to obtain fluticasone propionate of formula I. The
reaction is represented at scheme I below:
Scheme I: Process for synthesis of fluticasone propionate as disclosed in US 4335121
Periodic acid, THF
Flumethasone
CDI, DMF, H2S
F i
Propionyl chloride, TEA, DEA, Acetone,
3 MDC 4
r
DMAC, BrCH2CI, NaHCO,
F
Nal, Acetone
b
0 0
F F
AgF, Acetonitrile
6 Fluticasone propionate
A However there are certain disadvantages associated with US 4335 121. The yield of the said
process is low and the purity is also low. Notwithstanding, there are certain undesirable
impurities obtained from the said process.
Hence. there is a need to have a process with improved yield and purity and with decreased
content of undesirable impurities.
OBJECT OF THE INVENTION
An object of the invention is to provide an improved process for the synthesis of fluticasone
with improved yield and purity and reduce impurities.
SUMMARY OF THE INVENTION
The present invention discloses an improved process for the preparation of steroidal 178-
carboxylic thioate of Formula I,
FORMULA I
wherein R1 represents a fluoro- or chloro- or bromo- methyl group or a 2'-fluoroethyl group;
R2 represents a group COR6 where R6 is a CI-3 alkyl group; R3 represents a hydrogen atom,
a methyl group (which may be in either the a- or 8- configuration) or a methylene group; R4
represents a hydrogen, chlorine or fluorine atom and Rj represents a hydrogen or fluorine
atom.
comprising the steps of subjecting compounds of formula I1 to oxidation, esterification,
halogenation, reduction, deprotection and purification.
FORMULA I1
DETAILED DESCRIPTION OF THE INVENTION
The present invention discloses an improved process for the preparation of steroidal 17Pcarboxylic
thioate of Formula I,
FORMULA I
wherein R1 represents a fluoro- or chloro- or bromo-; methyl group or a 2'-fluoroethyl group;
RZ represents a group COR6 where R6 is a CI-3 alkyl group; R3 represents a hydrogen atom,
a methyl group (which may be in either the a- or P- configuration) or a methylene group; R4
represents a hydrogen, chlorine or fluorine atom and Rj represents a hydrogen or fluorine
atom.
The improved process of the present invention comprises the steps of subjecting compounds
of formula I1 to oxidation, esterification, halogenation. reduction, deprotection and
purification.
FORMULA I1
wherein Rj ; R4 and R5 has the same meaning as above.
In an embodiment, the present invention discloses an improved process for the preparation of
steroidal 17P-carboxylic thioate of Formula I,
wherein R1 represents a fluoromethyl group: R2 represents a group COR6 where R6 is an
ethyl group; R3 represents a methyl group; R4 represents a fluorine atom and Rs represents
fluorine atom,
wherein the improved process comprises the steps of:
1. subjecting compound of Markush structure I1 to oxidative cleavage to obtain
corresponding acid;
. .
11. reacting the acid obtained from step I with a coupling agent in the presence of
hydrogen sulfide to obtain thio acid;
...
111. esterifying the thio acid obtained from step ii;
iv. converting the product obtained from step iii to the desired product, 17P-carboxylic
thioate of Formula I in one or more steps by deprotection /halogen exchange;
v. optionally purifying the product obtained.
8
A In another embodiment, the present invention discloses an improved process for the
preparation of fluticasone propionate, S-iluoromethyl-6a,9u-diil~1oroP--lh1y droxy- 16umethyl-
17 a-propionyloxy-3-0x0-androsta-1,4-dien1e7-P -carbothioate
SCNF
HO .*fy -cocmcM f$" ',I!
01 y.
F
comprising the steps of:
wherein Fluticasone propionate, S-fluoromethyl-6a,9a-difluoro-l l P-hydroxy- l6a-methyl-
17a-propionyloxy-3-0x0-androsta-1,4-diene1-7 P-carbothioate is prepared by an improved
process comprising the steps of:
i. subjecting 6a,9a-difluoro- 1 1 p, 1 7a,2 1 -trihydroxy- 16a-methyl-androsta-1,4-diene-3.20-
dione to oxidative cleavage to obtain 6u,9a-difluoro- 1 1 P, 17u-dihydroxy- l6u-methylandrosta-
1,4-diene-3-one- 1 7P-carboxylic acid;
. .
11. converting 6a,9a-difluoro- 1 1 P, 1 7a-dihydroxy- 16a-methyl-androsta-l,4-diene-3-one-
17P-carboxylic acid to 6u,9a-difluoro- 1 1 P, 17a-dihydroxy-16a-methyl-3-0x0-
androsta-1,4-diene-l7P-carbothioic acid with a coupling agent and solvent in the
presence of Hydrogen sulfide;
. . .
111. converting 6a,9a-difluoro- 1 1 P, 17u-dihydroxy-16a-methyl-3-oxo-androsta-l,4-diene-
17P-carbothioic acid to S-chloromethyl-6a,9a-difluoro-1P1- hydroxy- l6a-methyl-17apropionyloxy-
3-oxo-androsta-1,4-diene-17~-carbothioabtye reacting with propionyl
halide, triethylamine, diethylamine, alkyl halide in the presence of Dimethyl
Acetamide;
iv. converting S-chloromethyl-6a,9a-difluoro-l l P-hydroxy- l6a-methyl-17apropionyloxy-
3-0x0-androsta-1,4-diene1- 7 P-carbothioate to S-iodomethyl-6a,9adifluoro-
llP-hydroxy- l6a-methyl- l7a-propionyloxy-3-oxo-androsta-1,4-dien1e7-P -
carbothioate by reacting with sodium Iodide in the presence of a polar solvent;
v. converting S-iodomethyl-6a,9a-difl~1oro-ll~-hyd1r 6oux-ym- ethyl- l7a-propionyloxy-
3-0x0-androsta-1.4-diene- 1 7P-carbothioate to Crude S-iluoromethyl-6a,9a-difl~1oro-
11 P-hydroxy- l6a-methyl- 1 7a-propionyloxy-3-0x0-androsta-1,4-dien1e7-0 -
carbothioate with Silver fluoride in the presence of Acetonitrile ;
& vi. optionally, purifying S-fluoromethyl-6a,9a-difluoro-l1~-hydroxy-l6a-methl7yla--
propionyloxy-3-0x0-androsta-1,4-diene1-7 0-carbothioate.
The scheme of the reaction of the present invention is provided at scheme 2.
Scheme 2: Reaction scheme of the present invention
Step 1
THF, MEOH, NalO,
Flumethasone
Step 2
-
F
2
Step 3
DMF, CDI, H2S, HCI
DMAC. TEA, PC, DEA, BCM
polar solvent, Nal
Fluticasone propionate
The improved process for synthesis of fluticasone propionate of the present invention
comprises the following steps.
Step 1: Subjecting Flumethasone, 6a19a-difluoro-1 1 ~117a,21-trihydroxy-16a-methvlandr0sta-
1~4-diene-3~2O-diontoe oxidative cleavage to obtain 6a,9a-difluoro-11 B,17adihydroxy-
16a-methyl-androsta-1,4-diene-3-one-l7-~arboxylaicci d,
This reaction may be conducted by subjecting flumethasone to an oxidizing agent, such as
sodium meta periodate, in a suitable solvent which may be selected from any of the following
classes such as alcohol, ketone, hydrocarbon, chlorinated solvents or their mixtures.
Preferably, the solvent is a mixture of methanol and tetrahydrofuran.,Tetrahydrofuran and
water, methanol and water, toluene, methanol and water, Tetrahydrofuran.toluene and water.
The oxidizing agent is taken in the range of 1 :2.1 to 1:3.1 with respect to the reactant and the
solvent is in the ratio of 1 :4.0 to 1 : 1 1 with respect to the reactant i.e Flumethasone.
b Preferably, methanol to tetrahydrofuran is taken in the ratio in the range of 1 :3 to 3:s.
Step 2: convert in^ 6u,9u-difluoro-11 B,17a-dihydroxv-l6u-methyl-androsta-44-diene-3-
one-17B-carboxylic acid (Flumethasone acid), to Flumethasone thio acid, 6u,9udifluoro-
1 1 B, 17a-dihydroxy-16u-methyl-3-oxo-androsta-l,4-diene-l7-carbothioiacc id
I This reaction may be conducted by subjecting flumethasone acid to a coupling agent. The
coupling agent may be dicyclohexane carbide and n,n carbonyl-di-imidazole. The coupling
agent added is in the range of 1 :1.2 to 1 :2.5 w.r.t to Flumethasone acid. The reaction may be
completed by the use of hydrogen sulphide gas. The reaction may be conducted in a suitable
solvent which may be selected from any of the following classes such as alcohol, ketone,
hydrocarbon, chlorinated solvents or their mixtures. The solvent can be selected from the
group of N, N, dimethyl fonnamide Or N,N-dimethyl acetamide The range of ratio of the
solvent added is 1:2.5 to 1:5.09 w.r.t to Flumethasone acid.
Step 3: Converting Flumethasone thio acid to Cloticasone propionate, S-chloromethvl-
6~,9a-difluoro-ll~-hydroxv-l6a-methvl-17a-propionvloxv-3-oxo-androsta-1,4-diene-l7~-
carbothioate
Flumethasone thio acid may be converted to cloticasone propionate by series of reaction
steps. The reaction is initiated by reacting Flumethasone thio acid with an activated derivative
of propionic acid such as its activated esters or preferably a propionyl halide such as
propionyl chloride.
Post to reaction with propionic acid the reaction may be further performed in the presence of
an unreactive organic base such as tri-n-propylamine, triethylamine, or tributylamine,
preferably triethylamine. Solvents for this process include substantially water immiscible
solvents such as ethyl acetate or methyl acetate or water miscible solvents such as acetone,
N,N-dimethylformamide or N,N-dimethylacetamide, especially acetone.
Step of addition of unreactive organic base is followed by step of addition of alkyl halides
containing one or more halogens. The alkylhalides may be organofluorine, organochlorine,
organobromine and organoiodine. Preferably, the alkyl halide is iodochloromethane or
bromochloromethane.
Preferably, propionyl halide is in the ratio 1 :3.1, triethylamine in the ratio of 1 :3.6,
diethylamine is in the ratio 1 :2.5, alkyl halide is in the ratio of 1 :2.1, Dimethyl Acetamide is
in the ratio of 1 : 10 and acetone is in the ratio 1 :4.0 w.r.t to Flumethasone thioacid.
The reaction is carried out at a temperature of 0°c*50c.
& Step 4: Converting Cloticasone propionate to Ioticasone propionate, S-iodomethvl-
6a,9a-difluoro-ll~-hydroxv-16a-methyl-l7a-propionyloxv-3-oxo-androsta-l,4-diene-l7Bcarbothioate
Cloticasone propionate may be converted to Ioticasone propionate by reacting with a sodium
halide such as sodium iodide in presence of a solvent. The solvent may be selected from any
of the following classes such as alcohol, ketone, hydrocarbon, chlorinated solvents or their
mixtures. Preferably, the solvent is a polar solvent such as Acetone, methyl isobutyl ketone.
Preferably, sodium iodide is in the ratio of 1:8.61 and the solvent is in the ratio of 1:24 with
respect to cloticasone propionate.
Step 5: Converting Ioticasone propionate to Fluticasone propionate, S-fluoromethvl-
Ioticasone propionate may be converted to Fluticasone propionate by reacting with a silver
halide such as silver fluoride in a suitable solvent which may be selected from any of the
following classes such as alcohol, ketone, hydrocarbon, chlorinated solvents or their
mixtures. Preferably, the solvent is Acetonitrile.
Step 6: Optionallv, purifying Fluticasone propionate.
If desired, the fluticasone propionate may be purified by crystallization or by column
chromatography techniques. The column chromatography may be carried out by using a
stationary phase such as silica and a mobile phase of a chlorinated solvent such as methylene
chloride, chloroform, Dibromochloromethane etc. or other chlorinated solvents. The
compound may also be purified by using a suitable solvent.
ADVANTAGES OF THE PROCESS OF THE PRESENT INVENTION
01. Uses less toxic sodium metaperiodate instead of highly toxic periodic acid
02. The conversion of formula 3 to 5 is a novel process, which process renders the
synthesis of fluticasone more efficient in terms of yield, time, solvent
consumption.
03. The process of the present invention has reduced dimer impurities (formed by the
oxidative dimerisation of the sulfur compounds, 4, 5 and 6 of the prior art) in
comparison with the process of prior art.
Without being limited by theory, it is submitted that the present invention uses a novel
process, which directly converts the compound [3] to compound [5] with or without the
b formation of compound [4], this novel process results in an improved process for the
synthesis of fluticasone with the stated advantages.
While the invention has been described and exemplified in sufficient detail for those skilled
in this art to make and use it, various alternatives, modifications, and improvements should
be apparent without departing from the spirit and scope of the invention. The examples
provided herein are representative of preferred embodiments, are exemplary, and are not
intended as limitations on the scope of the invention. Modifications therein and other uses
will occur to those skilled in the art. These modifications are encompassed within the spirit of
the invention and are defined by the scope of the claims.
Example 1: Process of preparation of fluticasone propionate as per US 4335121
Step 1: Preparation of 6a,9a-difluoro-l1~,17u-dihydroxy-16u-methyl-androsta-1,4-
diene-3-one-17P-carboxylic acid (Formula - 02)
~eribdica cid (0.4212 mol) aqueous solution is added to a solution of Flumethasone (0.1463
Mol) and 8 volumes of tetrahydrofuran. The mixture is then stirred at room temperature till
the reaction is complete as monitored by TLC. The end product is crystallized by adding
purified water. Wet material is isolated by filtration and dried at 75OC*5OC to obtain 6a,9adifluoro-
1 1P , 17a-dihydroxy- 16a-methyl-androsta-l,4-diene-3-onle7-P -carboxylic acid
(Yield =90.0 %, having HPLC purity = 99.18%)
Step 2: Preparation of 6a,9a-difluoro-ll~,l7u-dihydroxy-16a-methyl-3-oxo-androsta-l,4-
diene-17P-carbothioic acid (Formula-03)
N,N'-carbonyl di immadazole (0.3065) is added to a solution of Formula-02 (0.15 15 mol)
and N, N-dimethyl formamide(l250 ml) is then stirred at room temperature. Then, hydrogen
sulphide gas is purged in reaction mass till the completion of reaction which is monitored by
TLC. The material is crystallized by addition of 2N-hydrochloric acid at low temperature.
The desired product is isolated by filtration and washed with water till neutral pH and dried at
75OC*5OC to obtain 6a,9a-difluoro-11 P, 17a-dihydroxy-16a-methyl-3-0x0-androsta-1,4-
diene-17P-carbothioic acid. (Yield=95.58%, having HPLC purity =99.16 %)
Step 3: Preparation of 6u,9a-difluoro-ll~-hydroxy-16u-methyI-17a-propionyloxy-3-
0x0-androsta-l,4-diene-17P-carbothioca cid (formula-04)
A solution of formula-03 (0.12 13 mol) and tri ethyl amine (0.44 12 mol) in dichloromethane
(1400ml) is wash cooled with ice-salt and treated drop wise with propionyl chloride(0.5414
mol). The reaction mixture is stirred further at 0°C for 75min and washed successively with
2N-sodium carbonate, water, 2N-hydrochloric acid, water and brine. Then the solvent was
removed to give a white solid. The white solid is re-dissolved in acetone (1200 ml) and
diethyl amine (1.2083 mol) and stirred at room temperature for 60 min. The volume of the
reaction mixture is reduced and poured in to 2N hydrochloric acid containing ice and the
resulting precipitate is collected, washed with water and dried in vacuum to obtain a white
solid. The solid product is purified and crystallized with ethyl acetate. The crystallized
product is isolated by filtration and dried at 75OCh5"C to obtain dried 6a, 9a-difluoro-l lPhydroxy-
hydroxy- 16a-methyl- 17a-propionyloxy-3-0x0-androsta1-, 4-diene-1 7 P-carbothioc acid.
(Yield =102.40%, having HPLC purity = 92.49%)
Step 4: Preparation of S-chloromethyl-6a,9a-difluoro-l1~-hydroxy-16a-methyl-17a
propionyloxy-3-oxo-androsta-l,4-diene-l7~-carbothioat(Fe ormula-05)
Formula-04 (0.1068mol) is dissolved in N, N-dimethyl acetamide 368m1, wash treated with
sodium hydrogen carbonate (0.165 mol) and bromochloromethane (0.1696 mol) and stirred
continuously for 90 min. Ethyl acetate (3677 ml) is added to this mixture and the resultant
solution is washed successively with 2N-hydrochloric acid, water, sodium meta bi sulphite
solution, water, sodium bi carbonate solution, water and saturated sodium chloride solution,
then dried and the solution is concentrated to obtain crystals. The crystallized product is
purified by column chromatography using silica gel, with chloroform and acetone (9: 1) as the
mobile phase. The main band is subsequently eluted with ethyl acetate and crystallized with
ethyl acetate. The wet material is isolated after filtration and dried at 75OC k5"C to obtain
dried S-chloromethyl-6a,9a-difluoro- 1 1 P-hydroxy- l6a-methyl- l7a-propionyloxy-3-0x0-
androsta- 1,4-diene-17P-carbothioate( Yield =loo%, having HPLC purity = 89.47%).
Step 5: Preparation of S-Iodomethyl-6a,9a-difluoro-l1~-hydroxy-l6a-methyl-17apropionyloxy-
3-oxo-androsta-l,4-diene-l7~-carbothioat(Fe ormula 06)
Formula-5 (0.1162mol) is taken in acetone (20 volumes) at ambient temperature then to it is
added Sodium Iodide (0.4643 mol). Butylated hydroxyl toluene and hydroquinone is then
added to the mixture and refluxed for 24 hours.Reaction completion check is done by HPLC.
The material is then crystallized after adding 5% solution of NaHC03 . Wet material is then
isolated by filtration and is dried at a temperature of 75°C *5"C and purified in acetic acid
(20 vol) and ethyl acetate (10 volume) mixture at 80°C. It is then gradually cooled to -5OC, to
obtain S-Iodomethyl-6a,9a-difluoro- 1 1 P-hydroxy- l6a-methyl- 1 7a-propionyloxy-3-0x0-
androsta- 1,4-diene- 1 7P-carbothioate.
b Yield =85%, having HPLC purity=95.249%
Step 6: Preparation of S-Fluoromethyl-6a,9a-difluoro-l1~-hydroxy-l6a-methyl-17apropionyloxy-
3-oxo-androsta-1,4-diene-l7~-carbothioat(fel uticasone propionate crude)
A solution of mixed fluorides is obtained by refluxing silver fluoride (0.9868 mol) and
calcium fluoride (0.9868 mol) in acetonitrile at 90-95OC for 4 hours followed by filtration,
compound 6 (0.987 mol) is charged at -lO°C to -15OC into the solution obtained and the
reaction mixture is stirred for 36 hours at - 1 O°C to - 15OC than further silver fluoride (0.1974
mol) is added and the reaction mixture is stirred for a further 12 hours at -lO°C to -1 5OC.
Crude fluticasone propionate is isolated by aqueous extraction work up using ethyl acetate,
NaHC03, 2M HCl and water, distillation of ethyl acetate, followed by swapping with
diisopropyl ether gives colourless fluticasone propionate.Wet material is isolated after
filtration and dried at 75OC h5"C obtained crude S-fluoromethyl-6a,9a-difluoro-11 Phydroxy-
l6a-methyl- l7a-propionyloxy-3-oxo-androsta-l,4-dienle7-P -carbothioate.
Yield= 60%, having HPLC Purity = 91.08%
Step 7: Purification of S-Fluoromethyl-6a,9a-difluoro-l1~-hydroxy-16a-methyl-17apropionyloxy-
3-oxo-androsta-l,4-diene-l7~-carbothioat(fel uticasone propionate)
Crude fluticasone propionate (0.0939 mol) is dissolved in methanol (55 volume) at 60 to
65OC, Charcoal is then added and the mixture is filtered through hyflow bed. The filtrate
obtained is cooled down up to -5OC, filtered and washed with chilled methanol. Wet material
is dried at 50°C to 55OC under reduced pressure to obtain pure S-fluoromethyl-6a,9adifluoro-
1 1P -hydroxy- l6a-methyl- l7a-propionyloxy-3-0x0-androstal-,4 -diene- l7Pcarbothioate.
Yield=70%, having HPLC Purity= 99.6%.
Example 2: Preparation of Fluticasone propionate of the present invention
Step 1: Preparation of 6a,9a-difluoro-l1~,17a-dihydroxy-l6a-methyl-androsta-1,4-
diene-3-one-17P-carboxylic acid (Formula - 02)
Sodium meta per iodate (0.4488 mol) aqueous solution is added to a solution of
Flumethasone (0.1463 Mol) in 3 volumes of methanol and 8 volumes of terahydrofuran,
stirred at 40°h30C until the reaction is complete. The desired product is crystallized by
adding purified water. Wet material is isolated after filtration and dried at 75°Ch50C to obtain
b dried
(6a79a-difluoro-lip, 1 7a-dihydroxy- 16a-methyl-androsta-l,4-diene-3-on1e 7-8 -
carboxylic acid), Yield = 91.66%, having HPLC purity = 99.229%
Step 2: Preparation of 6a,9a-difluoro-ll P, 17a-dihydroxy-16a-methyl-3-oxoandrosta-1,
4-diene-l7P-carbothioic acid (Formula-03)
N,N-carbonyl di imidazole (0.3392 mol) were added in a solution of Formula -01 (0.1388
mol) and N, N-dimethyl formamide than stirred at 4O0+3"C until completion of reaction.
Hydrogen sulphide gas is purged in reaction mass at low temperature (20°C*2"C) till reaction
complete by TLC. The material is crystallized by adding the reaction mass in acidic water at
low temperature (18"C+2"C) Wet material is isolated after filtration and washed with water
till neutral pH and dried at 75"Cf5"C to obtain dried 6a,9a-difluoro-llp, 17a-dihydroxy-
16a-methyl -3-oxoandrosta-1, 4-diene-17P-carbothioic acid, Yield = 103.64%, having
HPLC purity = 99.266%
Step 3: Preparation of S-chloromethyl-6a,9a-difluoro-l1~-hydroxy-16a-methyl-17apropionyloxy-
3-oxo-androsta-l,4-diene-l7~-carbothioat(Fe ormula-05)
Formula-03 (0.1383mol) is dissolved in N, N-dimethyl acetamide, cooled to 0°C*5"C. To
this mixture, tri ethyl amine (0.4920mol) is added, and stirred at same temperature for one
hour, to this mixture propionyl chloride (0.4261) is added and stirred for 4 hours, before
adding bromochloromethane (0.2810mol) and subsequently aqueous diethyl amine
(1.378mol) at same temperature. Then this mixture is maintained at 40°Ch20C for one hour.
The desired material is crystallized by adding purified water at low temperature(30°C*5"C)
and filtered, washed with purified water till neutral pH at low temperature (20°C+5"C) and
purified in acetone at ambient temperature and dried at 75°C*50C to obtain dried Schloromethyl-
6a,9a-difluoro- 1 1 P-hydroxy- 1 6a-methyl- 1 7a-propionyloxy-3 -oxo-androsta- 1,
4-diene-l7P-carbothioate.Y ield =105.26%, having HPLC purity = 99.85%
Step 4: Preparation of S-Iodomethyl-6a,9a-difluoro-l1~-hydroxy-l6a-methyl-l7apropionyloxy-
3-oxo-androsta-l,4-diene-l7~-carbothioa(tFeo rmula-06)
Formula-5 (0.1162mol) is taken in acetone (20volume) at ambient temperature and added to
sodium iodide (1.0007mol) at ambient temperature, refluxed for 1 Shours, until completion of
reaction. Crystallization is effected by adding purified water at low temperature (35"C*5"C).
The wet material is isolated after filtration at low temperature (20°C&5"C) and purified in
acetone at ambient temperature and dried at 75OCf5"C to obtain S-Iodomethyl-6a,9a17
difluoro- 1 1 P-hydroxy- l6a-methyl- l7a-propionyloxy-3-0x0-androsta1-, 4-diene- l7P-
/
carbothioate.(Yield 102.10%, purity = 97.67%)
Alternatively, the reaction is conducted as below:
I
Formula-5 (0.1 162mol) is dissolved in acetone (20 volume) at ambient temperature and then I
added to sodium iodide (0.4643mol) at ambient temperature, followed by the addition of
butylated hydroxyl toluene and hydroquinone. This mixture is refluxed for 24hours and on
completion of the reaction, the desired product is crystallized by the addition of 5% solution
of NaHCO3. The retentate is dried at 75OC*5OC and purified by heating at 80°C in a mixture
I
of acetic acid (20 volume) and ethyl acetate (10volume) and gradually cooled to -5OC to
obtain S-Iodomethyl-6a,9a-difluoro- 1 1 P-hydroxy- l6a-methyl- l7a-propionyloxy-3-0x0-
androsta-1,4-diene- 17P-carbothioate (Yield =85%, purity = 95.249%)
I Step 5: Preparation of S-Fluoromethyl-6a,9a-difluoro-l l P-hydroxy-l6a-methyl-17apropionyloxy-
3-oxo-androsta-l,4-diene-l7~-carbothioate (Fluticasone propionate
crude)
Formula-6 (0.0987 mol) is dissolved in Acetonitrile (35 volume) at ambient temperature, to
this mixture silver fluoride (0.2284 mol) is added and maintained at 40°C*30C to complete
the reaction. The material is crystallized with purified water to obtained S-Fluoromethyl-6u,
9a-difluoro- 1 1P -hydroxy- l6a-methyl- 1 7a-propionyloxy-3-0x0-androsta1-, 4-diene-1 7Pcarbothioate.
(Yield =78.33%, having HPLC purity = 95.02%)
Alternatively, the reaction is conducted as below:
A solution of mixed fluorides is obtained by refluxing silver fluoride (0.9868mol) and
calcium fluoride (0.9868) in acetonitrile at 90-95OC for 4 hours, followed by filtration.
Compound 6 (0.0987 mol) is charged at -10 to 15OC into the reaction mixture and stirred for
36 hours at - 10 to -1 5OC. Further silver fluoride (0.1974mol) is added to the reaction mixture
i and again stirred for 12 hours at -10 to -15OC. Crude fluticasone propionate is isolated by
I aqueous extraction and ethyl acetate. Na2C03, 2M HC1 and water Distillation of the ethyl
I
acetate, followed by swapping with di isopropyl ether to give colorless fluticasone propionate
(S-Fluoromethyl-6u,9a-difluoro- 1 1 p-hydroxy- 16a-methyl- 17a-propionyloxy-3-0~0-
androsta- l,4-diene- l7P-carbothioate;Yield =60%, having HPLC purity = 9 1.08%)
I k Step 6:
Purification of S-Fluoromethyl-6a,9a-difluoro-11 P-hydroxy-l6a-methyl-
17apropionyloxy-3-oxo-androsta-l,4-diene-l7~-carbothioate(F luticasone propionate
Fluticasone propionate crude (0.0939mol) is dissolved in methanol (9.0 volumes) at ambient
temperature, refluxed and maintained at 65°Ck50C for 2 hours, filtration at ambient
temperature and dried at 75OC+5"C. The isolated material is dissolved in methylene chloride
and passed through silica column, with methylene chloride as solvent. The fraction
comprising the desired product is treated with sodium iodide and silver fluoride and again
extracted with acetone and water to obtain pure S-Fluoromethyl-6a, 9a-difluoro-11phydroxy-
16a-methyl-1 7apropionyloxy-3-0x0-androsta-1 , 4-diene- 17p-carbothioate. (Yield
=85.0%, purity = 99.69%)
I Alternatively, the purification is conducted as below:
Crude Fluticasone propionate(0.0939 mol) is dissolved in methanol (55 volumes) at 60 to
65°C , treated with charcoal and filtered through hyflow bed filtrate, cooled to -5°C filter and
washed with chilled methanol.(Yield =70%, purity = 99.60%)
Example-03: Comparative data of the process of the present invention against that of
I prior art.
The process as described in example 1 and example 2 were conducted. The yield was
calculated at the end of every step. In addition, the impurity profiling was conducted at every
step using HPLC. The particulars of HPLC are as below;
Column, 4.6mmx25cmcolumn that contains 5pm packing L1,
Dilution: All samples were diluted in mixture comprising 23ml acetonitrile and 77 ml
methanol
Mobile phase:
For formula 2 and 3: Methanol, 0.01M Monobasic ammonium phosphate buffer pH 3.5 and
acetonitrile (50:35: 15)
For formula 4 to 6 and crude fluticasone: Solution-A- mix 0.50 ml. of phosphoric acid in
1000ml of Acetonitrile, Solution-B- mix 0.50 ml. of phosphoric acid in 1000ml of Methanol
Solution-C- mix 0.50 ml. of phosphoric acid in lOOOml of Water ,Use solution-A, solution-B
and solution-C as gradient; two or more pump with concentration programming
Detection : At wavelength 239 nm, UV detector
flow rate -1 mll min
t The results of yield and purity stepwise are presented below at Table 1. From Table I, it is
clearly seen that present process is advantageous to the process of prior art with respect to
purity and yield.
Table 1: Comparison of purity and yield between the prior art process and process of
present invention
~ N AN-o t Applicable.
It can be clearly inferred from the above table that prior art process occurs in six steps.
i
Conversion of Flumethasone thio acid to Ioticasone propionate is a two step process in the
prior art whereas in the present process it occurs in a single step which saves time and solvent
consumption and still leads to a higher yield of fluticasone.
Further, product as synthesized by the present invention was compared with the product
obtained after varying reactants /reagents/solvents and conditions. The results of the same are
presented stagewise at Table 2.
Table 2: Purity and yield after changing the reaction conditions1 parameters
Results
White crystalline powder
HPLC purity=99.28%
Single impurity=0.05%
Total impurity=0.72%
White crystalline powder
HPLC purity=99.10%1
Single impurity=0.30%
Total impurity=0.9%
White crystalline powder
HPLC purity=99.03%
Single impurity=0.50%
Total impurity=0.97%
White crystalline powder
HPLC purity=97%1
Single impurity=2.609%
Total impurity=3%
Description:- White
crystalline powder
HPLC purity = 98.75%1
Single impurity= 0.6 12%
Total impurity = 1.25%
White crystalline powder
HPLC purity=99.15%
Single impurity=0.454%
Total impurity=0.85%
White crystalline powder
Yield
92%
85%1
85%1
82%1
80%1
78%1
85%
EXAMPLE
S.No
1.
I.
. . 11.
. . .
111.
iv.
v.
vi.
Input
1.0 gm
1 .O gm
1.0 gm
1.0 gm
1.0 gm
1.0 gm
1 .O gm
Output
0.92 gm
0.85 gm
0.85 gm
0.82 gm
0.80 gm
0.78 gm
0.85 gm
4:
Stage
1
Experimental Plan
THF, methanol,
Sodium meta per
iodate and Water=
THF, water
Sodium meta per
iodate
Methanol , water
Sodium meta per
iodate
Low volume of THF
and methanol, Water
& Sodium meta per
iodate
toluene, methanol
and water &
Sodium meta per
iodate
THF,Toluene and
water
Using potassium per
21
J. I I I magnate instead of HPLC purity = 99.0%
sodium meta per Single impurity=0.50%
iodate Total impurity = 1.00%
vii. Using low qty of 1.0 gm 0.75 gm 75%J, White crystalline powder
sodium meta per HPLC purity=96.65%i
iodate Single impurity= 1.874%
Total impurity=3.35%
viii. At low temperature 1.00 0.79gm 79%J, Description:-White
gm crystalline powder
HPLC purity = 98.8 l%i
Single impurity= 0.242%
Total impurity = 1.19%
ix. At high temperature 1.00 O.SOgm 80%i Description:-White
gm crystalline powder
HPLC purity = 96.45%i
Single impurity= 2.736%
Total impurity = 3.55%
It can be seen from Example 4 that all of the tested conditions/reagents/reactants provide the
desired product. However, it may be seen that the optimum use of THF, methanol and
Sodium meta per iodate in water at optimum temperature gives the best yield and purity of
the product obtained from step 1 of the present invention.
T VT^ I DMF=, CD1=, I 1.0 gm I 1.03 gm I 103% I Description:-Off White I
„ crystalline powder
P HPLC purity =95.20 %i
Single impurity= 0.90%
Total impurity = 4.8%
i. LowqtyofCDI( 1.0 gm 0.75 gm 75%i Description:-Off White
crystalline powder
HPLC purity =74.94 %[
Single impurity= 12.44%
Total impurity = 25.06%
ii. Low volume of 1.0 gm 0.85 gm 85%J, Description:-Off White
DMF crystalline powder
HPLC purity =76.15 %i
Single impurity= 8.62%
Total impurity = 23.85%
iii. DMAC instead of 1.0 gm 0.85 gm 85%i Description:-Off White
DMF crystalline powder
HPLC purity =46.70 %[
Single impurity= 26.50%
Total impurity = 53.33%
iv. At low temperature 1.0 gm 0.35 gm 35%J. Description:-Off White
I I I I I crystalline powder
I I I I I I I Total im~uritv= 3.50%
At high temperature 1 .O gm 0.65 gm 65%J Description:- Off White
crystalline powder
HPLC purity =93.44%1
Single impurity= 1.37%
Total impurity =6.56%
EXAMPLE 5:
The second step of the present invention is the conversion of Flumethasone acid to
Flumethasone thio acid using optimum amount of DMF, CDI at a temperature of 40°Ch30C.
The above Example 5 shows that changing the temperature, concentration of the reagent or
solvent decreases the yield of the reaction drastically; hence the present invention claims the
optimum conditions.
EXAMPLE 6
3.
I.
. .
11.
. . .
III.
iv.
v.
vi.
Description:- off White
crystalline powder
HPLC purity = 97.1 0%J
Single impurity= 1.3 15%
Total impurity = 2.90%
Description:- off White
crystalline powder
HPLC purity = 97.97%J
Single impurity= 0.423%
Total impurity = 2.03%
Description:- off White
crystalline powder
HPLC purity = 49.64%J
Single impurity= 13.262%
Total impurity = 50.36%
Description:- off white
Crystalline powder
HPLC purity = 97.3 1 %1
Single impurity=0.61%
Total impurity =2.69%
Description:- off white
Crystalline powder
HPLC purity = 98.28 %J
Single impurity=0.53%
Total impurity =I .72%
Description:- off white
Crystalline powder
HPLC purity = 98.1 1%J
Single impurity=0.55%
Total impurity =1.89%
Description:- off white
Crystalline powder
HPLC purity = 98.40%J.
Single impurity=0.42%
Total impurity = 1.60%
DMAC, TEA,
Propionyl halide,
DEA=,
BCMAcetone
Using Acetone
instead ofDMAC
Using MDC instead
off DMAC
Using Pyridine
instead of TEA
Using sodium
hydroxide
solutioninstead off
diethyl amine
solution
Purification
in(Acetone +MeoH )
mixture instead of
Acetone (
Purification
in(MDC+MeoH )
mixtureinstead of
Acetone
1.05 gm
0.65 gm
0.65 gm
0.85 gm
0.67 gm
0.85gm
0.90gm
3 rd 1 .OO
gm
1 .OO
gm
1 .OO
gm
1 .O gm
1 .O gm
1.00gm
1.00gm
105%
65%J
65%J
85%J
67%J
85%J
90%J
It can be seen from Example 6 that the best results are obtained in the third step by optimum
use of DMAC, TEA, Propionyl halide, DEA, BCM and Acetone at an optimum
Description:- off white
Crystalline powder
HPLC purity = 95.07%1
Single impurity1 .15%
Total impiirity =4.93%
Description:- off white
Crystalline powder
HPLC purity = 94.60%1
Single impurity= 1.15%
Total impurity 4.40%
Description:- off white
Crystalline powder
HPLC purity = 89.95%1
Single impurity=5.34%
Total impurity =I 0.05%
Temperature in accordance with the present invention.
80%J
80%1
85%1
EXAMPLE 7:
0.80gm
0.80gm
0.85gm
1.00gm
1.00gm
1.00gm
k.
I.
. .
11.
. . . 111.
iv.
vii.
...
VIII.
ix.
Purification
in(Toluene+MeoH )
mixture instead off
Acetone
At high temperature
Using propionic
anhydride) instead
of propionyl halide
4th Sodium iodide in
polar aprotic solvent
Using Low volume
of solvent
Using low qty of
sodium iodide
Low Temperature
Using recovered
solvent
1 .OO
gm
1 .OO
g m
1 .OO
gin
1.00gm
1 .OO
gm
0.85gm
0.70gm
0.77
EY"
0.85 gm
0.85 gm
85%
70x1
77%1
85%
85%
Description:- off white
Crystalline powder
HPLC purity =99.22%
Single impurity = 0.142%
Total impurity = 0.78%
Description:- off white
Crystalline powder
HPLC purity =98.79%1
Single impurity = 0.40%
Total impurity = 1.2 1%
Description:- off white
Crystalline powder
HPLC purity =98.95%1
Single impurity = 0.26%
Total impurity = 1.05%
Description:- off white
Crystalline powder
HPLC purity =64.24%1
Single impurity = 33.62%
Total impurity = 35.76%
Description:- off white
Crystalline powder
HPLC purity =96.80%1
Single impurity = 1.50%
Total impi~rity = 3.20%
Using recovered
sodium iodide
Single impurity = 0.40%
It can be seen from Example 7 that all of the tested conditions/reagents/reactants though
provide the desired product but the desired result i.e highest purity and yield is obtained with
the optimum use of NaI and a polar aprotic solvent at an optimum temperature.
EXGMPLE 8
6th
75%
73961
63%J
60%1
60%1
I.
Description:- off White
powder
HPLC purity =93.16%1
Single impurity =2.54%
Total impurity =6.84%
Description:- off White
powder
HPLC purity =93.16%1
Single impurity =1.96%
Total impurity =6.84%
Description:- off White
powder
HPLC purity =93.34%4
Single impurity =2.07%
Total impurity =6.66%
Description:- off White
powder
HPLC purity =94.45%1
Single impurity =2.07%
Total impurity =5.55%
Description:- off White
powder
HPLC purity =93.95%1
Single impurity =I .90%
Total impurity =6.05%
1 .O gm
1 .OO
gm
1 .OO
gm
1.00gm
1.00gm
Acetonitrile =
Silver fluoride
Using Low volume
of acetonitrile
Using low qty of
silver fluoride
At low temperature
At high temperature
I.
. .
II.
. . . 111.
iv.
Purification in
Methanol
I I.
0.75 gm
0.73gm
0.63gm
0.60gm
0.60gm
5th
Purification in
1.0 gm
acetone
Purification in
toluene and MDC
1.0 gm
0.60 gm
1.0 gm
0.30 gm
60%1
0.50 gm
Description:- Dark brown
powder
HPLC purity =92.58 %L
30%1
Total impurity= 7.42%
Description:- Dark brown
50%1
powder
HPLC purity =90.22%1
Total impurity= 9.78%
Description:- Dark brown
powder
100%
50%1
50%1
...
111.
iv.
v.
HPLC purity =9 1.70 %J
Total impurity= 8.30%
Description:- Dark brown
powder
HPLC purity =93.93 %1
Total impurity= 6.07% -
Description:- Dark brown
powder
HPLC purity =93.83 %5
Total impurity= 6.17%
Description:- Dark brown
powder
HPLC purity =87.67 %1
Total impurity= 12.33%
1.0 gm
1.0 gm
1.0 gin
mixtitre
Purification in ethyl
acetate and acetic
acid mixture
Purification in
acetone and
methanol mixture
Purification in
acetonitrile
1.0 gm
0.50 gm
0.50 gm
) We Claim:
1. An improved process for the preparation of a 17a-carboxylic thioate of Formula I of
Formula I,
wherein R1 represents a fluoro- or chloro- or bromo- methyl group or a 2'-fluoroethyl group;
R2 represents a group COR6 where R6 is a CI-3 alkyl group; R3 represents a hydrogen atom, . .
a methyl group (which may be in either the a- or P- configuration) or a methylene group; R4
represents a hydrogen, chlorine or fluorine atom and Rj represents a hydrogen or fluorine
atom.
comprising the steps of subjecting compounds of formula I1 to oxidation, esterification,
halogenation, reduction, deprotection and purification.
comprising the steps of:
1. subjecting compound I1 to oxidative cleavage to obtain corresponding acid;
. .
11. reacting the acid obtained from step I with a coupling agent in the presence of
hydrogen sulfide to obtain thio acid;
. . .
111. esterifying the thio acid obtained from step ii;
iv. converting the product obtained from step iii to the desired 17P-carboxylic thioate of
Formula I in one or more steps by deprotection /halogen exchange;
v. optionally purifying the product obtained.
. 2. The process as claimed in claim 1, wherein R1 is fluoromethyl group; R2 represents a
group COR6 where R6 is an ethyl group; R3 is methyl group ; R4 and Rs each is fluorine
atom.
3. The process as claimed in claim 1 or 2, wherein the compound 1 is S-fluoromethyl-
6a,9a-difluoro-11 P-hydroxy- l6a-methyl- 17a-propionyloxy-3-oxo-androsta-1,4-dien1e-7 0-
carbothioate.
4. The process as claimed in claim 3, wherein Fluticasone propionate, S-fluoromethyl-
6a,9a-difluoro-11 P-hydroxy- l6a-methyl- l7a-propionyloxy-3-oxo-androsta-1,4-dien1e7-P -
carbothioate is prepared by an improved process comprising the steps of:
i. subjecting 6a,9a-difluoro-11 P, 1 7a,2 1 -trihydroxy-16a-methyl-androsta-1,4-diene-3,20-
dione to oxidative cleavage to obtain 6a79a-difluoro- 1 1 P, 1 7a-dihydroxy- l6a-methylandrosta-
1,4-diene-3-one- 17P-carboxylic acid;
. .
11. converting 6a,9a-difluoro- 1 1 P, 1 7a-dihydroxy- 16a-methyl-androsta-1,4-diene-3-one-
17P-carboxylic acid to 6a,9a-difluoro-l l P, 17a-dihydroxy-16a-methyl-3-0x0-
androsta-1,4-diene-l7P-carbothioiacc id with a coupling agent and solvent in the
presence of Hydrogen sulfide;
iii. converting 6a79a-difluoro- 1 1 P, 17a-dihydroxy-16a-methyl-3-oxo-androsta-l,4-diene-
17P-carbothioic acid to S-chloromethyl-6a,9a-difluoro-l l P-hydroxy- 1 6a-methyl-17apropionyloxy-
3-0x0-androsta-l,4-dienel-7 P-carbothioate by reacting with propionyl
halide, triethylamine, diethylamine, alkyl halide in the presence of Dimethyl
Acetamide;
iv. converting S-chloromethyl-6a,9a-difluoro-l l P-hydroxy- l6a-methyl-17apropionyloxy-
3-0x0-androsta-1,4-diene1-7 P-carbothioate to S-iodomethyl-6a79adifluoro-
llP-hydroxy- l6a-methyl- 17a-propionyloxy-3-oxo-androsta-1,4-dien1e 7-P -
carbothioate by reacting with sodium Iodide in the presence of a polar solvent;
v. converting S-iodomethyl-6a,9a-difluoro-ll~-hydroxy-16u-methl7yal--p ropionyloxy-
3-0x0-androsta-1,4-diene-17P-carbothioatteo Crude S-fluoromethyl-6a79a-difluoro-
11 P-hydroxy- l6a-methyl- 1 7a-propionyloxy-3-0x0-androsta-1,4-diene1-7 Pcarbothioate
with Silver fluoride in the presence of Acetonitrile ;
vi. optionally, purifying S-fluoromethyl-6a,9a-difl~1oro-lP1- hydroxy-l6a-methyl- 17apropionyloxy-
3-0x0-androsta-1,4-diene1-7 P-carbothioate.
. 5. The process as claimed in claim 1-4, wherein oxidative cleavage in step (i) is carried
out in the presence of an oxidizing agent in a suitable solvent .
6. The process as claimed in claims 4 or 5, wherein the oxidizing agent is sodium metaperiodate.
I 7. The process as claimed in claims 4 or 5, wherein the solvent is selected from the
group consisting of alcohol, ketone, hydrocarbon, chlorinated solvents or their mixtures.
8. The process as claimed in claims 1 to 7, wherein the solvent is a mixture of methanol
and tetrahydrofuran.
9. The process as claimed in claims 1 to 8, wherein ratio of methanol: tetrahydrofuran is
in the range of 1 :3 to 3:s.
10. The process as claimed in claims 1 to 9, wherein the ratio of oxidizing agent is in the
range of 1 :2.1 to 1 :3.1 and the solvent is in the range of 1 :4 to 1 : 1 1 with respect to 6u79adifluoro-
1 lP,1 7a,2 1 -trihydroxy- 16a-methyl-androsta-1,4-diene-3,20-dione.
11. The process as claimed in claims 1 to 4, wherein the coupling agent in step (ii) is
selected from the group consisting of dicyclohexane carbide and n,n carbonyl-di-imidazole.
12. The process as claimed in claims 1 to 1 1, wherein the ratio of coupling agent is in the
range of 1:2 to 1 :2.5 and the ratio of solvent is in the range of 1 :2.5 to 15.09 wrt to 6a,9adifluoro-
1 1 P, 17a-dihydroxy- 16a-methyl-androsta-l,4-diene-3-on1e7-P -carboxylic acid.
13. The process as claimed in claim 4, wherein the solvent in step (ii) is selected from the
group consisting of alcohol, ketone, hydrocarbon, chlorinated solvents or their mixtures.
14. The process as claimed in claim 4, wherein step (iii) propionyl halide is in the ratio
1 :3.1, triethylamine in the ratio of 1 :3.6, diethylamine is in the ratio 1 : 10, alkyl halide is in
the ratio of 1 :2.1 and Dimethyl Acetamide is in the ratio of 1 :5.09 and acetone is in the ratio
1 :4.0 w.r.t to Flumethasone thioacid, 6u.9~-difluoro-l l P, 17u-dihydroxy-16u-methyl-3-0x0-
androsta-1,4-diene-l7P-carbothioica cid.
& 15. The process as claimed in claim 14, wherein alkyl halide is selected from
iodochloromethane or bromochloromethane.
16. The process as claimed in claim 14, wherein the reaction is carried at a temperature of
0°C*50C.
17. The process as claimed in step (iv) of claim 4, wherein sodium Iodide is in the ratio of
1:8.61 and the polar solvent is in the ratio of 1:24 w.r.t to Cloticasone propionate, Schloromethyl-
6a,9a-difluoro-11 P-hydroxy- 16a-methy1-17a-propionyloxy-3-oxo-androsta-1,4-
diene- 17P-carbothioate.