FORM 2
THE PATENTS ACT 1970(39 of 1970) AND The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13) 1. TITLE OF THE INVENTION: "Novel process for the Synthesis of Clobetasol propionate"
2. APPLICANTS:
(a) NAME: SANJEEV RAJARAM PATIL
(b) NATIONALITY: INDIAN
(c) ADDRESS: RH-85, B/412, Shri Rohideshwar Darshan, MIDC Phase II, Dombivli (East),
Dist.Thane. Mumbai- 421203, India (a) NAME: DEVANAND BABURAOSHINDE
(b) NATIONALITY: INDIAN
(c) ADDRESS: Vice Chancellor, Shivaji University, Vidyanagar, Kolhapur-416004, India
(a) NAME: MADHAV VASANT DHAMDHERE
(b) NATIONALITY: INDIAN
(c) ADDRESS: Flat No.203, Building No.l5A, Pushpnarayan Complex Devad.
New Panvel.PIN-410221, India
(a) NAME: ANIL SHRIDHARRAOBOBADE
(b) NATIONALITY: INDIAN
(c) ADDRESS: Haffkine Institute for Training, Research and Testing, Parel, Mumbai-400012, India
(a) NAME: ASHISH L.ARSONDKAR
(b) NATIONALITY: INDIAN
(c) ADDRESS: Haffkine Institute for Training, Research and Testing, Parel, Mumbai-400012, India
(a) NAME: JAIPRAKASH N.SANGSHETTI
(b) NATIONALITY: INDIAN
(c) ADDRESS: Y.B.Chavan College of Pharmacy, Aurangabad, 431004, India (a) NAME: VRUSHALI N.PATIL
(b) NATIONALITY: INDIAN
(c) ADDRESS: Haffkine Institute for Training, Research and Testing, Parel, Mumbai-400012, India

The following specification describes the invention. Field of Invention:
The present invention relates to an improved process for the preparation of Clobetasol propionate having very low levels of the ene impurity and high yield. The process is three step synthesis that begin with betamethasone. Compared with the traditional process, methane sulfonyl chloride is replaced by p-Toluenesulfonyl chloride, pyridine is replaced by Dimethylamino Pyridine which reduces toxic materials and the economic cost can be saved. In addition, the invention greatly reduces the pressure for protecting the environment and can effectively reduce the hazard on human body and pollution on the environment. Also described the detailed process and characterization data of ene impurity. Background of the invention:
Clobetasol propionate (C25H32CIFO5); CAS Registry No.[25112-46-7]; IUPAC name: 17-(2'-ChIoroacetyI)-9-fluoro-11-hydroxy-10, 13, 16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydr-
ocyclopenta[α]phenanthren-17-yl] propionate is a potent halogen adrenal corticosteroid of the gluco-corticoid class used to treat various skin disorders including eczema and psoriasis. It is also highly effective for contact dermatitis caused by exposure to poison ivy/oak.In the US 3721687Apatentshow use of methanesulfonyl chloride and Pyridine as base to protect alcohol and at the time of LiCl reaction results with 10-15%ene impurity and less yield.In the methanesulfonyl chloride step used with pyridine as base which is a hazardous.Mesyl compound converted to Clobetasol propionate by using LiCI in Dimethylformamide reaction at 100-110°C forms 10-15% with ene impurity.
Scheme-1: Clobetasol propionate synthesis from 17-propionate
The synthesis of Clobetasol propionate results in small quantities of the eneimpurity. Clobetasol propionate desired compound to be with impurities which must be minimized. Ene impurity can be reduced to very low levels by reaction itself. However, if used recrystallization reduce ene impurity it is time consuming and very expensive. Further, because recrystallizations have high losses, unacceptably low yields.


Summary of the invention:
The present invention describes the preparation of Clobetasol propionate from commercially
available betamethasone having low levels of ene impurity. In first step, betamethasone is O-
acylated at 17-position using trimethyl orthopropionate/tributyl orthopropionateindimethyl-
sulphoxide/dimethylformamide solventto betamethasone 17-propionate. Isolated by
quenching in ice water and acidified with conc.H2SO4. In the next step p-
toluenesulfonylchloride used with Dimethylamino pyridine as base in Dimethylformamide to
give tosylate compound.Tosylate compoundconverted to Clobetasol propionate by using
LiClin insitu reaction mass of Dimethylformamidewith ene impurity content less than
2.0%.After isolation ene impurity shows below 0.1%.Each step of the process of the
invention gives high yields and the isolated intermediates have high purity. In another aspect,
the present invention discloses the intermediates obtained during the synthesis of Clobetasol
propionate.
Description of the invention
Present invention describes total synthesis of Clobetasol propionate such that, by virtue of
the processes of this invention, Clobetasol propionate obtained is substantially free from the
ene impurity. Thus, the present invention provides a process which comprises of the
following steps:
Stage-1: Betamethasone to betamethasone 17-propionate
Stage-II: Betamethasone 17-propionate tobetamethasone21 -tosylate
Stage-III:Betamethasone 21-tosylateto Clobetasol propionate
The preparation of the compounds of present invention exemplified with Scheme-2 that
illustrates the preparation of Clobetasol propionate. According to the above scheme, the
process of the invention begins with the use of commercially available Betamethasone.
Accordingly, betamethasone 17-propionate (Stage-I) is prepared using dimethylformamide
solvent. The solvent is selected from the group consisting of a mixture of
dimethylsulphoxide and water, a mixture of dimethylformamide and water, a mixture of
dimethylformamide and p-toluenesulfonic acid (PTSA) as an acid catalyst, to yield an
intermediate betamethasone 17-propionate (Stage-I).
Betamethasone 17-propionate(Stage-I) is then protected with suitable reagent and
specifically using p-toluenesulfonyl chloride to yield Clobetasol 21-tosylate(Stage-II).
Preferably the reagent used in the process is p-toluenesulfonyl chloride in presence catalyst
Dimethylaminopyridine (DMAP) and solvent such as, Dimethylformamide (DMF),
Dimethylsulphoxide (DMSO) etc. to yield unknown intermediate1, Clobetasol 21-tosylate

(Stage-II). Clobetasol 21-tosylate is then converted to its pharmaceutically acceptable Clobetasol propionate by using LiClprocesses in Dimethylformamide having ene impurity content less than 1.0 %. In another embodiment, the present invention contains novel intermediate obtained during the total synthesis of Clobetasol propionate. Accordingly, the present invention discloses the intermediate Clobetasol tosylate (stage-2) of formula (scheme-2).
The invention is further explained in the following examples without limiting the scope of the invention.

Scheme 2. Synthesis of Clobetasol propionate from Betamethasone
Example 1: Betamethasone to betamethasone 17- propionate
To a 100 ml 4-neck round bottom flask (RBF) equipped with halfmoon stirrer, thermowelland addition funnel, mounted in a tub bath, was charged betamethasone (5.0g, 0.0127mole), Dimethylformamide (20ml). Cooled the reaction mass to 10-15°C. Slowly added trimethyl ortho propionate (3.42g, 0.0255mole) and p-toluenesulfonic acid (PTSA)(0.30g, 0.00174 mole) to the reaction mass at 10-15°C. Stirred the contents 10-15°C for 4 hr. The reaction was monitored for completion by TLC. Further continued stirring at the same temperature for lhr till reaction complies by TLC. After reaction completion, added H2SO4UP to pH=l.0-2.0 in to reaction mass.Reaction mass was quenched in Purified water (25ml) at 25-30°C. Cooled reaction mass temperature to 0-5°C. Stirred for 1 hr and filtered and washed with Purified water (10mlX2). Suck dried under vacuum completely to get cream coloured solid. Dried in tray drier at 50-55°C.Dry weight-5.40g(94.50%); HPLC: 98.5%;mp-215-218°C. IR (KBr, cm-1):3454.90, 3370.99 (-OH); 1719.86, 1659.10 (C=O);C25H33FO6;

MS 448.52m/z 449.2255 [M+H];'HNMR (300MHZ, CDC13δ ppm): Spectrum is recorded on Varian, and Tetra Methyl Silane (TMS) as internal standard. 1H-NMR Spectrum shows Aromatic-HK-7.17-7.22(d,lH); HJ-6.37-6.38 (d,lH);Hr6.14 (s,lH); HF-4.04-4.06(s,2H);HE-2.23-2.28 (q,2H);Hc-1.39-1.43 (d,3H); HB-1.14 (t,3H);HA-0.96-2.96 (m,20H). 13CMR (300MHz, CDCl3δppm): 8.692 (CH2-CH3); 16.693; 19.664; 21.353; 23.042; 27.568; 30.387; 36.456; 43.400; 46.547; 47.422; 71.760; 93.547; 124.307; 125.728; 127.903; 129.222; 130.443; 132.472; 145.632; 153.044; 167.424; 175.031 (0-C=0); 185.772 (Cyclic C=0); 196.732 (CH-CO-CH2-OH).
Example 2: Betamethasone 17- propionateto betamethasone 21-tosylate 100ml 4-neck RBF equipped with halfmoon stirrer, thermowell, reflux condenser mountained in water bath, was charged Stage-1 (5.0g, 0.0111mole), Dimethylformamide (20ml). Added 4-Dimethylaminopyridine as base (4.10g, 0.0335mole) and p-toluenesulfonyl chloride (4.24.0g, 0.0222mole)slowly, Stirredfor2-3 hr at 25-30°C. Stirred reaction mass at 25-30°C till reaction complies by TLC.As such reaction mass used insitue for next step. Reaction mass aliquot taken (2ml) and quenched in DM water (20ml), precipited material filtered and washed with DM water (20ml). Suck dried well. Dried in tray drier at 50-55°C to get dry white solid. Dry weight-0.598g, (89.0%); HPLC: 98.5%; mp-170-175°C (dec). IR (KBr,cm-1):3291.91, 2980.39 (-OH); 1739.15, 1661.99 (CO); C32H39FO8S; MS 602.71m/z 603.2317 [M+H]; 'HNMR (300MHZ, CDCl3δppm): Spectrum is recorded on Varian, and Tetra Methyl Silane (TMS) as internal standard. 1H-NMR Spectrum shows Aromatic-HK-7.17-7.22(d,lH); HJ-6.37-6.38 (d,lH);Hl6.14 (s,lH); HG-4.334-4.393 (m,lH);HF-3.846-4.007(d,2H);HE-2.273-2.349 (q,2H);HD-l.671-1.688 (s,lH); Hc-1.306-1.331 (d,3H); HB-1.055-1.105 (t,3H);HA-0.941-2.634 (m,18H).13CMR (300MHz, CDCl3δppm): 9.055 (CH2-CH3); 17.244; 20.002; 21.353; 23.168; 27.901; 30.622; 33.508; 34.881; 36.783; 43.642; 46.637; 47.330; 48.113; 48.417; 66.613; 70.902; 93.801; 102.732; 124.415; 129.324; 130.443; 132.472; 145.632; 153.583; 168.042; 174.853 (0-C=0); 186.208 (Cyclic C=0); 205.491(CH-CO-CH2-OAr).
Example 3:Betamethasone 21-tosylateto Clobetasol propionate
As such reaction mass used insitue for next step. Added lithium chloride (LiCl)1.04 gm (0.0245mole). Stirred the reaction mass at 60-65°C for 5-6 hr.Reaction completion checked by TLC.After reaction completion, Added DM water (200ml). Stirred the reaction mass at 10-15°C for 1hr and Filtered washed with DM water (30mlx2).Dried in oven at 50-55°C to get white crystalline powder. Dry weight-4.42gm, (85.0%); HPLC:99.70%;mp-158-161°C. IR (KBr, cm-1):3299.62, 2976.53 (-OH); 1734.32, (C=0);1662.95 (C=C);C25H32C1FO5; MS

466.97m/z 467 [M+H];1HNMR (300MHZ, CDCl3δppm): Spectrum is recorded on Varian, and Tetra Methyl Silane (TMS) as internal standard. 1H-NMR Spectrum shows Aromatic-HK-7.094-7.128(d,lH); HJ-6.267-6.307 (d,lH); H16.066-6.076 (s,lH); HG-4.334-4.393 (m,lH); HF-3.846-4.007 (d,2H); HE-2.273-2.349 (q,2H); HD-1.671-1.688 (s,lH); Hc-1.306-1.331 (d,3H); HB-1.055-1.105 (t,3H); HA-0.941-2.634 (m,17H).13CMR (300MHz, CDCl3δppm): 8.692 (CH2-CH3); 16.693; 19.664; 21.353; 23.042; 27.568; 30.387; 36.456; 41.104; 46.547; 47.422; 71.760; 93.547; 124.307; 125.728; 127.903; 129.222; 130.443; 132.472; 145.632; 153.044; 168.312; 173.101 (0-C=0); 185.802 (Cyclic C=0); 204.602(CH-CO-CH2-C1).

Impurity Structural Formula Molecular
Formula
(Mol.wt.) Description Melting Point. Assay by HPLC
Betamethasone
(SM) C22H29FO5 392.46 Off white
powder 232 -234°C 99.80%
Betamethasone
17-propionate
(STG-1) C25H33FO6; 448.52 Cream colour
powder 215-218°C 98.58%
Impurity-B C22H26C1FO3 392.89 Off white
powder - 93.04%
Betamethasone
21-tosylate
(STG-2) C32H39FO8S
602.71 Off white powder 170-174°C 98.48%
Table-1 Clobetasol propionate impurities with structures MP with HPLC assay

Results and discussion
The control on magnitude of formation of eneimpurity as listed in table-1 & others in Clobetasol propionate, is successfully achieved by-I selecting betamethasone (II), {a as starting material}, for Clobetasol propionate synthesis (Scheme-I) The purity established by use of M.P.,TLC/HPLC & structure established by IR, MS and 1H NMR.

The relative retention time & identity of Impurity: B in Clobetasol propionate was established by co-injection of composite mixture of impurity: B, along with SM, Stage-1 and stage-2 under standard HPLC conditions. Column; CI8 for chromatography R,5µm, (0.25x4.6mmor
equivalent onlsocratic with a mobile phase consisting of mix 10 volumes of methanol R, 42.5 volumes of a 7.85 g/L solution of sodium dihydrogen phosphate monohydrate R adjusted to pH=5.5 with a 100 g/L solution of sodium hydroxide R and 47.5 volumes of acetonitrile R. with a flow rate of 1 ml/min and UV detection at 240nm was used.
A typical HPLC chromatogram of a laboratory batch of Clobetasol propionatewas recorded as described in the Experimental Section, and the target impurities under study were marked as Starting material betamethasone(SM)retention time (RT): 8.831 min, eneimpurity-B (RT): 13.676 min,Stage-l (RT):7.360 min, Stage-2(RT):7.725 min and Clobetasol propionate at (RT):14.746 min. The Mass compatible method described in the Experimental Section was used to detect these impurities, and the structures are shown. The spectroscopic data of eneimpurity-B was compared with those of Clobetasol propionate.
Synthesis of Ene Impurity:
Clobetasol propionateimpurity-B synthesis, characterization & genesis of formation:
(21 -chloro-9-fluoro-11 b-hydroxy-16-methylpregna-1,4,16-triene-3,20-dione): 100ml 4-neck RBF equipped with halfmoon stirrer, thermowell, reflux condenser mounted in water bath, was charged Stage-1 (5.0g,0.0111mole) in Dimethylsulphoxide (20ml) added pyridine as base(5.0 ml) and added slowlymethanesulfonylchloride (3.37g,0.0294mole) in to

reaction mass at 25-30°C.Stirred for 10 minutes at 25-30°C. Heated the reaction mass to 100-105°C. Maintained reaction temp.l00-105°C for 4-5 hrtill reaction complies by TLC.TLC shows two spots one is ene impurity spot and other mesyl protected compound.

Scheme-3: Clobetasol impurity-B synthesis from 17-propionate
Reaction mass quenched in DM water (20ml), Precipiited material filtered and washed with DM water (20ml). Suck dried well. Dissolved wet solid in MDC and dried over sodium sulphate filtered and adsorbed on silica. Purified by column chromatography (S1O2) and eluted with hexane and ethyl acetate to furnish off white powder,TLC: practically Single spot. Its structure was confirmed by 1H-NMR & Mass spectral analysis. Off white powder; HPLC Purity-93.04% C22H26CIFO3: MS392.89m/z393,395 [M+H]; 415 [M+Na];IR (KBr, cm_1):3336.27, 2943.74 (-OH); 1737.22 (C=0); 1663.92 (C=C); 1H-NMR Spectrum, of Clobetasol ene impurity, is recorded on Varian, VXR-300 MHz (1H-NMR) in DMSO-d6δppmand Tetra Methyl Silane (TMS) as internal standard. 1H-NMR Spectrum shows Aromatic-HK-7.294-7.314 (d,lH); HJ-6.209-6.232(d,lH);Hl-6.07 (s,lH); HG-4.624-4.631 (s,2H);HF-4.054-4.076 (s,lH);HE-2.635-2.680 (q,2H);HD-l.824-1.838 (s,lH); Hc-1.653-1.702 (m,lH); HB-1.517 (q,3H);HA-0.901-1.426 (m,13H).

I claim
1. An improved process for the preparation of compound of formula (1) substantially free from the ene impurity, which comprising of the steps of;

a) Betamethasone 17-propionate(stage-l),
Charging Betamethasone in Dimethylformamide and P-toluenesulfonic acid at 10-15°C under Stirring & followed by addition of trimethyl ortho propionate/tributyl ortho propionate, further continued stirring at the same temperature for 3-5 hrs,the reaction was monitored for completion by TLC,reaction mass was quenched in purified water at 10-15°C,acidified with 2N H2SO4UP to pH=1.0-2.0,Solid isolated filtered, again washed with DM water,filteredthe wet solid and suck dried completely,wet solid dried in tray drier at 50-55°C completely,

b) Betamethasone 21 -Tosylate (stage-2),
charging of Stage-1 in DMF under stirring and addition of p-Dimethylaminopyridine followed by addition of P-toluenesulfonylchloride and reaction at 60-65°C,the reaction was monitored for completion by TLC,insitu used reaction mass for next step,
c)Clobetasol propionate,
In insitu reaction mass added LiCl and continued stirring at the same temperature to remove tosylate group at 60-65°C to chloro group,monitored reaction completion by TLC, after

reaction completion, quenched the reaction mass in ice water and material precipitated out,filtered, suck dried and washed with DM water,dried in oven to obtain Clobetasol propionate.
2. The process according to claim 1,wherein the protecting agent in stage-II is selected from best leaving group, mainly p-toluenesulfonylchloride in DMF solvent medium.
3. The process according to claim l,wherein Dimethylaminopyridine (DMA)used in stage-II is in the presence of solvent selected from dimethylformamide (DMF), Dimethylsulphoxide(DMSO).

4. The process according to claim 1, wherein the said reaction of step (a) is carried out at ambient temperature, preferably at 10-20°C temperature.
5. The process according to claim 1 , wherein the said reaction of step (b) preferably carried out at a temperature range between 45°C to I00°C, more preferably 55°C to 65°C.
6. The process according to claim 1, wherein the said reaction of step (c) is carried out at ambient temperature to reflux temperature, preferably at 55°C to 65°C.