DESC:FIELD OF THE INVENTION
The invention relates to a process for the synthesis of a desired stereoisomer of the key intermediate (I), by utilizing selective reaction conditions, solvent and thereby suppressing the isolation of the undesired isomer.
The present invention relates to a convenient, industrially applicable process for producing the intermediate (I).

Intermediate (I)

BACKGROUND OF THE INVENTION
The compounds represented by the general formula (III), wherein A, B, C and D represent each condensed ring of the skeleton and Q1, Q2, Q3, Q4 and Q5 respectively represent one or more substituents on the rings and the terminal carbon atom C21, are synthesized using intermediate (I). The compounds (III) are active pharmaceutical ingredients exhibiting different therapeutic activities. Each of Q1, Q2, Q3, Q4 and Q5 in Compound (III) includes one or more substituents selected from groups such as alkyl, hydroxyl, ketone, ethers and unsaturation such as double bond.

Compound (III)

The compounds of general formula (III) include for example, molecules such as dydrogesterone (IIIa), cortisone (IIIb), hydrocortisone (IIIc) represented by the structures given below.

Dydrogesterone (IIIa) Cortisone (IIIb)

Hydrocortisone (IIIc)

The protection of carbonyl group(s) is an important step during development of the synthetic strategy for compounds such as (III), possessing multiple functional groups and chiral centers. During the multi-step synthesis, the carbonyl group needs to be protected against an attack by various reagents such as nucleophiles, oxidants, catalytic agents etc.
Further, it is well-known that the steroid molecules such as (IIIa), (IIIb) possess characteristic stereochemistry at different carbon atoms in the skeleton. Their therapeutic activity largely depends on the stereochemical configurations at various centers in the molecule. Hence, it is necessary that the original configuration of the starting material is retained during the protection of carbonyl group.

Cyclic acetals and ketals are the most well-established and frequently used protective functionalities for the carbonyl groups. Acetals or ketals like 1,3-dioxolanes are obtained by treating carbonyl compounds with polyhydric alcohols. The carbonyl protected intermediates are then further treated with various compatible reagents, wherein the said acetal/ketal protection is conveniently removed at an appropriate synthetic stage to provide the desired molecules.

The instant invention relates to a highly selective process for synthesis of the carbonyl protected intermediate (Ia-p) comprising treatment of the starting material progesterone (IIa) with a polyhydric alcohol using a combination of catalyst/s, promoter/s, appropriate solvent/s and reagent/s for removal of water to provide the desired enantiomer.

Compound (Ia-p)

CN 110818760 discloses a process for synthesis of dydrogesterone comprising reaction of progesterone with ethylene glycol, acetyl chloride and trimethyl orthoformate in an organic solvent selected from tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether, glyme etc.

CN 110790808 discloses a process comprising reaction of 6-dehydroprogesterone, using excess of ethylene glycol in presence of pyridine hydrobromide and triethyl orthoacetate at 72-78 0C to give the protected intermediate, 5, 7-pregnadiene-3, 20-dione-diethylketal.

US20130203718 discloses a process for preparation of the carbonyl protected intermediate (Ia-p) wherein progesterone is treated with an excess of ethylene glycol (10.4 molar equivalents) in presence of p-toluenesulfonic acid using toluene as a solvent. The reaction mixture is boiled for 16 hours followed by dilution with ether, treatment with bicarbonate to obtain an amorphous solid. Further purification by flash chromatography provides the desired intermediate.

Various prior art references such as US 3,907,842, US 3,280,155, FR 1339249 disclose similar processes for synthesis of the carbonyl protected intermediate (I a-p) comprising use of p-toluenesulfonic acid, large excess of ethylene glycol, and hazardous solvents like benzene. These methods involve tedious procedures like chromatographic purification for obtaining the desired intermediate, wherein the yields range from moderate to poor.

However, none of these references discloses a process wherein the desired enantiomer of the carbonyl protected intermediate is obtained using a polyhydric alcohol along with a combination of catalyst, promoter, water scavenger and suitable solvents without resorting to elaborate, time consuming chromatographic purification methods.

The present inventors have developed an economical and convenient process for synthesis of desired intermediate (Ia-p) in good yield, overcoming the problems faced in prior art.

OBJECT OF THE INVENTION
An objective of the present invention is to provide a convenient, robust process for synthesis of desired stereoisomer of intermediate (Ia-p) using 1 to 4 volumes of the reaction solvent.

Another object of the invention relates to conversion of progesterone (IIa) to the carbonyl-protected intermediate (Ia-p) using polyhydric alcohol in presence of catalyst(s)/ promoters, chemical agents for removal of water and solvent(s) to provide the desired compound having good enantiomeric purity in high yield.

Yet another objective of the instant invention relates to utilization of specific reaction conditions in synthesis of intermediate (I), wherein the desired enantiomer / diastereomer of carbonyl-protected intermediate is selectively obtained in the reaction of carbonyl-protection.

SUMMARY OF THE INVENTION

An aspect of the invention relates to the synthetic process for preparation of intermediate (Ia).

A further aspect of the invention relates to the conversion of progesterone (IIa) to the carbonyl-protected intermediate (Ia-p), possessing the desired stereochemical configuration, in good yield.

The objectives of the present invention will become apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION
The present inventors, while carrying out extensive experimentation for synthesis of compounds of general formula (III), aimed at designing a robust, yet convenient strategy for protection of the carbonyl groups. During the process, the inventors serendipitously found that the desired enantiomer of the carbonyl protected compound was predominantly obtained using polyhydric alcohols along with specific reaction conditions such as combination of solvent/s, catalyst/promoter/s and water scavengers. The instant process thus provides an industrially applicable synthetic strategy for carbonyl protection.

It was a surprising finding for the inventors that in case of substrates possessing an asymmetric carbon center adjacent to the carbonyl, the method selectively provided the desired enantiomer of the carbonyl-protected acetal or ketal intermediate. Thus, the instant method provided diastereoselective acetalization or ketalization for the chiral substrates wherein the carbonyl functionality was attached to a chiral carbon.

Scheme-1: Scheme for the synthesis of intermediate (Ia-p)

In an embodiment, progesterone (IIa) was treated with a polyhydric alcohol in presence of a catalyst, water scavenger and solvent.

The catalyst was selected from inorganic acids, organic acids, reagents such as tetrabutylammonium tribromide, aluminium trichloride and halogens like bromine, chlorine, fluorine.

The polyhydric alcohol was selected from the group comprising ethylene glycol, propylene glycol, neopentyl glycol etc.
The water scavenger was selected from triethylorthofomate, trimethylorthofomate, as well as any acetal, ester which is capable of removing water generated during the reaction.

The solvent, not belonging to class of alcoholic solvents, was selected from either an aromatic or aliphatic hydrocarbon from the group comprising of toluene, xylene, hexanes, cyclohexane or halogenated hydrocarbons such as ethylene chloride, methylene chloride, chloroform, esters like ethyl acetate, butyl acetate etc. and combinations thereof.

The reaction was carried out in the temperature range of 20 to 400C.

After completion of the reaction, as monitored by TLC, HPLC, the reaction mixture was quenched using weak base such as triethyl amine, collidine and the like. Concentration of the reaction mass, followed by addition of methanol to the residue, stirring and filtration provided the desired compound.

In a further embodiment, the reaction of progesterone (IIa) with ethylene glycol in presence of tetrabutylammonium tribromide, triethyl orthoformate and a non-alcoholic solvent selected from toluene, cyclohexane, ethyl acetate, dichloromethane and combinations thereof, provided an enantiomeric mixture of the carbonyl-protected intermediates (Ia-p) and (Ia-q).

Scheme-2: Scheme for the synthesis of intermediates (Ia-p), (Ia-q)
In another embodiment, reaction of progesterone with ethylene glycol (4 to 10 equivalents) in presence of tetrabutylammonium tribromide (0.01 to 0.05 equivalents), triethyl orthoformate (2 to 5 equivalents) using solvent selected from toluene, cyclohexane, ethyl acetate, dichloromethane and combinations thereof (1 to 4 equivalents, W/V with respect to progesterone) predominantly provided the desired isomer of the carbonyl-protected intermediate (Ia-p).

In another embodiment, progesterone was treated with ethylene glycol (6 to 9 equivalents) in presence of tetrabutylammonium tribromide (0.015 to 0.035 equivalents), triethyl orthoformate (2 to 3 equivalents) using toluene as a solvent (1 to 3 volumes, W/V with respect to progesterone). After completion of the reaction, as monitored by TLC, HPLC, the reaction mixture was quenched using triethyl amine or collidine and concentrated. Addition of methanol to the residue with stirring, followed by filtration predominantly provided the desired isomer of the carbonyl-protected intermediate (Ia-p).

Scheme-3: Scheme for the diastereoselective synthesis of intermediate (Ia-p)
Compound (Ia-p) was converted to dydrogesterone following processes known in the art such as those disclosed in IN 201811020593, CN 110818760, J. Org. Chem. vol.17, (1952), P.1369-1374.

In yet another embodiment, compounds such as pregnanolone (eltanolone), epipregnanolone, pregnenolone, epipregnenolone were subjected to the above-mentioned reaction to give the respective carbonyl-protected intermediates (I).

The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.

EXAMPLES

Example 1: Synthesis of the intermediate (Ia)
Tetrabutylammonium tribromide (TBATB, 0.15 g) was added to the mixture of progesterone (IIa, 5.0 g), ethylene glycol (7.9 g), triethyl orthoformate (7.1 g) in toluene (15 ml). The mixture was stirred in the temperature range of 25 to 300C.
After completion of the reaction as monitored by TLC and HPLC, collidine was added to the reaction mixture, followed by concentration of the reaction mass. Addition of methanol to the residue, stirring and filtration provided compound (Ia-p) as solid.
Yield : 3.84 g (60%)
Purity: 87.5% (HPLC)

Example 2: Synthesis of intermediate (Ia-p)
Tetrabutylammonium tribromide (TBATB, 0.15 g) was added to the mixture of progesterone (IIa, 5.0 g), ethylene glycol (8.0 g), triethyl orthoformate (7.1 g) in toluene (5 ml), and stirred in the temperature range of 25 -300C.
After completion of the reaction as monitored by TLC and HPLC, triethylamine was added to the mixture, followed by concentration of the reaction mass. Addition of methanol to the residue, stirring and filtration provided intermediate (Ia-p) as solid.
Yield: 4.80 g (75.3%)
Purity: 93.4% (HPLC)

Example 3: Synthesis of the intermediate (Ia)
Progesterone (IIa, 12.5 g), was added to ethyl acetate (25 ml) under stirring at 25 to 300C. Ethylene glycol (17.5 g), triethyl orthoformate (17.8 g) and tetrabutylammonium tribromide (TBATB, 0.77g ) were then added to the mixture
After completion of the reaction as monitored by TLC and HPLC, triethyl amine was added to the reaction mixture, followed by concentration of the reaction mass. Addition of methanol to the residue, stirring and filtration provided compound (Ia) as solid.
Yield : 11.6 g (72%)
Purity: (Ia-p)81.2 % (HPLC), and (Ia-q) 11.3 % (HPLC)

Example 4: Synthesis of intermediate (Ia)
Tetrabutylammonium tribromide (TBATB, 0.15 g) was added to the mixture of progesterone (IIa, 5.0 g), ethylene glycol (8.0 g), triethyl orthoformate (11.8 g) in dichloromethane (20 ml), and stirred in the temperature range of 25 -300C.
After completion of the reaction as monitored by TLC and HPLC, S-collidine was added to the mixture, followed by concentration of the reaction mass. Addition of methanol to the residue, stirring and filtration provided intermediate (Ia) as solid.
Yield: 4.52 g (70.1%)
Purity: (Ia-p) 81.2 % (HPLC), and (Ia-q) 11.3 % (HPLC)

Example 5: Synthesis of intermediate (Ia-p)
Progesterone (IIa, 1000.0 g) was added to toluene (1500 ml) under stirring, at 25 to 300C, followed by addition of ethylene glycol (1600.0 g), triethyl orthoformate (1420.0 g) and tetrabutylammonium tribromide (TBATB, 45.0 g). The stirring was continued at 25 to 300C till completion of the reaction, as monitored by TLC, HPLC.
After completion of the reaction, S-collidine was added to the stirred mixture, followed by concentration of the reaction mass. Addition of methanol to the residue, stirring and filtration provided intermediate (Ia-p) as solid.
Yield: 1041.6 g, 81.5 %
Purity: 98.3% (HPLC)

Example 6: Synthesis of intermediate (Ia-p)
Tetrabutylammonium tribromide (TBATB, 0.15 g) was added to the mixture of progesterone (IIa, 5.0 g), ethylene glycol (8.0 g), triethyl orthoformate (7.1 g) in cyclohexane (25 ml), and stirred in the temperature range of 25 -300C.
After completion of the reaction was monitored by TLC and HPLC, collidine is added to the mixture, followed by concentration of the reaction mass. Addition of methanol to the residue, stirring and filtration provided intermediate (Ia-p) as solid.
Yield: 4.92 g (76.9%)
Purity: (Ia-p)12.7 % (HPLC), and (Ia-q) 75.9 % (HPLC)

,CLAIMS:
1. A process for the preparation of compound (Ia-p), comprising reaction of progesterone (IIa) with a polyhydric alcohol in presence of a catalyst, water scavenger, solvent (1 to 3 volumes) and isolating the compound (Ia-p).

2. The process as claimed in claim 1, wherein the polyhydric alcohol is ethylene glycol.

3. The process as claimed in claim 1, wherein the catalyst is tetrabutylammonium tribromide.

4. The process as claimed in claim 1, wherein the water scavenger is triethyl orthoformate.

5. The process as claimed in claim 1, wherein the solvent is selected from toluene, ethyl acetate, dichloromethane and cyclohexane.

6. The process as claimed in claim 1, wherein reaction of progesterone (IIa) with ethylene glycol (4 to 10 equivalents) in presence of tetrabutylammonium tribromide (0.01 to 0.05 equivalents), triethyl orthoformate (2 to 5 equivalents) and a non-alcoholic solvent (1 to 4 equivalents W/V) provided compound (Ia-p).

7. The process as claimed in claim 1, wherein after completion of reaction, compound (Ia-p) is isolated by a process comprising concentrating the reaction mass, adding methanol, followed by stirring and filtration.

8. A process comprising reaction of progesterone (IIa) with ethylene glycol (6 to 9 equivalents) in presence of tetrabutylammonium tribromide (0.015 to 0.035 equivalents), triethyl orthoformate (2 to 3 equivalents) using toluene as a solvent (1 to 3 equivalents W/V), followed by isolation using methanol provided compound (Ia-p).