DESC:FIELD OF THE INVENTION
The present invention relates to a continuous flow process for the synthesis of a key intermediate of dydrogesterone. The invention particularly relates to the photochemical synthesis of 9ß,10a-pregna-5-7-diene derivatives (I-3) such as 9ß,10a-3,20-bis(ethylenedioxy)-5,7-pregnadiene (I-3a). The synthesis is characterized in that compound I-3 is synthesized by photochemical conversion of the corresponding 9a,10ß-3,20-pregna-5-7-diene derivatives (I-1) and / or the seco-steroid intermediates (I-2), in a continuous flow reactor.

BACKGROUND OF THE INVENTION
Dydrogesterone (9ß,10a pregna-4,6-diene-3,20-dione) is an orally active steroid hormone used to treat deficiencies of progesterone in the body. It is a synthetic progesterone, marketed since 1961, under the brand names such as Duphaston®, Dydroboon® and indicated in a wide variety of gynecological conditions like threatened or recurrent miscarriage during pregnancy, dysfunctional bleeding etc. Structurally, dydrogesterone has 9ß-H, 10a-Me, and an additional double bond at 6,7 position that differs from progesterone in the steroidal skeleton. The current manufacturing process of dydrogesterone is complex with progesterone as the starting material, employing two consecutive photochemical reactions with low photochemical yields.

The use of photo-induced chemical transformations for the synthesis of steroid intermediates and active pharmaceutical ingredients like Dydrogesterone is widely reported in literature.
Rappoldt et al. in Recueil Trav. Chim. 80,43 (1961), and ibid. 90, 27-35 (1971) discloses the preparation of 9ß,10a-5,7-diene steroids especially dydrogesterone utilizing photochemical yields with limited capability.
The synthesis of Dydrogesterone involves important intermediates such as lumisterol, 3-(ethylenedioxy)-9ß,10a-pregna-5,7-diene-20-one and 3,20-bis(ethylenedioxy)-9ß,10a-pregna-5,7-diene. These intermediates can be prepared by irradiating the corresponding 9a,10ß-isomers, namely ergosterol, 3-(ethylenedioxy)-9ß,10a-pregna-5,7-diene-20-one and 3,20-bis(ethylenedioxy)-9a,10ß-pregna-5,7-diene, respectively with ultraviolet light. A considerable part of the expensive starting material is lost in this photochemical isomerization due to the formation of undesired side products. Since each step of the photochemical reaction is an uncontrollable, reversible process, the product 9ß,10a-dehydroprogesterone ketal can still be converted into other by-products under intense light conditions.
The photochemical reaction has certain disadvantages as many by-products are likely to be generated due to bond breaking in a photoisomerization reactions involving short wavelength of the incident light, having high energy. As a result, it is difficult to control the product distribution in a photochemical reaction. Further, the physical and chemical properties of the target product and its various isomers are very similar. Hence, obtaining a pure product either at the intermediate stage or in the final stage is relatively difficult. Therefore, reaction conditions either for batch or continuous flow reactor need to be modified suitably and sequentially either for reducing the impurity or for having only selected impurities which could be removed finally in the drug product, dydrogesterone.

EP0152138 discloses the synthesis of I-3a by photochemical isomerization of the corresponding 9a,10ß compound in tetrahydrofuran (THF) or methyl acetate as solvent by irradiating with an antimony lamp and/or high pressure mercury lamp, with cooling and under nitrogen atmosphere. It is also pertinent to note that none of the examples make even a remote mention about the purity of the product / impurities obtained as there are several side products which are likely to be formed in a photochemical reaction and difficult to remove.

EP0558119 discloses a reaction for the synthesis of I-3a wherein the 9a,10ß derivative is dissolved in methyl acetate as solvent, irradiated first with a medium pressure mercury lamp (260 nm filter), followed by irradiation with an indium lamp (300 nm filter). There is no mention about the purity of I-3a obtained from the photochemical reaction as several impurities are likely to be formed in an uncontrollable reaction. A brief mention is also made about continuous flow (annular flow reactors), however, there is neither any description nor any enabling disclosure about continuous flow reactors, for deriving any benefit.

CN 102558272 B discloses a method for photoisomerization of dehydroprogesterone diketal in solvent such as tetrahydrofuran, dioxane, ethyl acetate and ethyl formate and in presence of reagents like 2,6-di-t-butyl-p-methyl phenol, 2,6-di-t-butyl-p-methoxy phenol and in presence of bases like trimethylpyridine, pyridine and triethylamine with initial photochemical exposure at a wavelength less than 300nm followed by a high-pressure mercury lamp to give a reported yield of 36% after recrystallization at low temperature. The example mentioned herein discloses very low yield (41%) based on the starting material consumed.

CN103848880 discloses the synthesis of 9ß,10a-dehydroprogesterone ketal utilizing dual wavelength microflow technology, wherein the reaction comprises of irradiating the 9a,10ß derivative in solvent such as tetrahydrofuran, dioxane, ethyl acetate and methyl THF in presence of reagents like 2,6-di-t-butyl-p-methyl phenol, 2,6-di-t-butyl-p-methoxy phenol and in presence of bases like trimethylpyridine and triethylamine with a 500W or 1000W mercury lamp in the photochemical reactor, having two systems I and II, respectively made up of silica glass and borosilicate glass. In general, the reaction leads to a mixture of products, the starting material (~36.5%), seco intermediate (~26.6%), the 9ß,10a compound (~35.8%) and other impurities (~1.1%). However, there is no mention about the impurity level of this sensitive photochemical reaction. Further, there is use of high volume of solvent about 100 times which will lengthen the time of passing of reaction mixture through reactor, work up and isolation of product from reaction mixture.

CN112275231 discloses a method utilizing microflow technology but with three photochemical illuminations (irradiations). There is use of high volume of solvent about 100 times which will lengthen the time of passing of reaction mixture through reactor, work up and isolation of product from reaction mixture.

Journal of Nutritional Science and Vitaminology, 26, 545-556, (1980) discloses the use of aqueous copper sulfate solution as filter in the photochemical conversion of cholesta-5,7-diene-1a,3ß-diol to 1a-hydroxyvitamin D3 via 1a-hydroxy pre-vitamin D3.

After a detailed study of the prior art references for photochemical conversions of steroid intermediates in batch reactors, the present inventors found the following disadvantages:
1. Long reaction times leading to increased occupancy of reactors.
2. Lack of uniformity in the exposure of the reaction mass to light prolongs the reaction time which in turn leads to associated side products and low yields, which are not suitable commercially.
3. Reproducibility of yields especially for photochemical reaction is difficult on industrial scale,
4. There is no mention about the purity of the products obtained and whether the generated associate impurities could be removed during subsequent steps or with simple purification.

Therefore, the inventors embarked on developing an improved photochemical process in continuous flow reactor wherein,
a) the impurity formation was lowered, and the associated impurities could be removed either in subsequent steps or during purification,
b) considerably shorter reaction time leading to less degradation and lower impurity level,
c) provide reasonable control on batch variations in process, and
d) Enhanced operational convenience and reaction safety for lowering environmental risks.

Use of continuous flow technology for highly sensitive reactions like photochemical isomerization provides an empowering tool to the chemists, which can be used in the synthesis of active pharmaceutical ingredients such as dydrogesterone and its intermediates. After extensive experimentation on the photochemical conversions of the dydrogesterone intermediates, the present inventors developed a photochemical process in continuous flow reactor, which was found to be superior to the prior art methods in terms of reaction time duration, reactor occupancy and the quantity of product output in much shorter duration of time as compared to batch reactors.

The instant invention relates to the advantageous use of continuous flow photo isomerization reactions for preparation of dydrogesterone intermediates, and for overcoming the short comings associated with prior art methods disclosed for batch reactors. The key intermediate of dydrogesterone (compound I-3; R1, R2 is carbonyl group protected in its ketal form) was synthesized from the compounds such as 9a,10ß intermediate (I-1) and /or the seco-intermediate (I-2) which was photochemically converted to the 9ß,10a-pregna-5-7-diene derivatives (I-3).

9a,10ß-pregna-5-7-diene
(I-1); R1, R2: =O or its ketal 6E/Z-9,10-seco-pregna-5-(10),6,8-triene (I-2)
R1, R2: =O or its ketal.

9ß,10a-pregna-5-7-diene
(I-3); R1, R2: =O or its ketal

Scheme 1: Preparation of 9ß,10a-Pregna-5-7-diene derivatives (I-3)
The advantages of using continuous flow technology as compared to the batch reactor for photochemical conversions to give the key intermediate for dydrogesterone (I-3) are listed below.
a) the reaction time is shortened, and reactions are safer,
b) lower consumption of solvents with lower amount of photochemical irradiation,
c) yields are enhanced due to control on side reactions and impurity formation,
d) the reactions are economical.

OBJECTS OF THE INVENTION
An object of the present invention is to provide an economical, industrially viable and an environment friendly process for the photochemical synthesis of 9ß,10a-pregna-5-7-diene derivatives (I-3), in shorter duration of time, with purity complying to regulatory specifications.
Yet another objective of the present invention is to provide a process for the preparation of 9ß,10a 3,20-bis(ethylenedioxy)-pregna-5,7-diene (I-3a) in a continuous flow reactor, comprising the steps of dissolving compound I-1a in an organic solvent and passing it through a continuous flow reactor having a filtered light beam wherein the compound I-1a undergoes photochemical reaction and gets converted to compound I-2a at Stage I and further gets converted to compound I-3a in Stage II, followed by concentration of the reaction mixture and isolating from suitable solvents.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a continuous flow photochemical process for preparation of dydrogesterone intermediates, selected from compound I-2 and compound I-3 wherein the substituents R1 and R2 are as defined.

In another aspect, the process comprises photochemical conversion of 9a,10ß-pregna-5-7-diene compounds (I-1) and/or the seco-steroid intermediates (I-2) (substituents R1 and R2 are as defined) to provide 9ß,10a-pregna-5-7-diene derivatives (I-3), having desired purity, and in improved yield.

In yet another aspect, the present invention relates to a process for the preparation of 9ß,10a 3,20-bis(ethylenedioxy)-pregna-5,7-diene (I-3a) in a continuous flow reactor, comprising the steps of dissolving compound I-1a in an organic solvent and passing it through a continuous flow reactor having a filtered light beam, at the rate of 5ml - 60ml per minute, wherein the compound I-1a undergoes photochemical reaction and gets converted to compound I-2a at Stage I and further gets converted to compound I-3a in Stage II, followed by concentration of the reaction mixture and isolating from a mixture of acetonitrile and methanol.

9a,10ß-3,20-bis (ethylene- dioxy)-pregna-5,7-diene
(I-1a) 3,20-bis(ethylenedioxy), 6E/Z-9,10-seco-pregna-5(10),6,8-triene (I-2a)

9ß,10a-3,20-bis (ethylene- dioxy) pregna-5,7-diene
(I-3a)

Scheme 2: Preparation of 9ß,10a-3,20-bis(ethylenedioxy)-5,7-pregnadiene (I-3a)

BRIEF DESCRIPTION OF FIGURES
Figure 1 depicts the schematic representation of continuous flow reactor (tubing in helical configuration) for stage I in preparation of compound I-3a.

Figure 2 depicts the schematic representation of continuous flow reactors for stage I and stage II for preparation of compound I-3a.

DETAILED DESCRIPTION OF THE INVENTION
The present invention will be described fully hereinafter. The invention may be embodied in different forms and should not be construed as limited to the embodiments set forth herein.

As used in the specification, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

The instant invention relates to a process for preparation of 9ß,10a-pregna-5-7-diene derivatives (I-3) wherein 9a,10ß-pregna-5-7-diene compounds (I-1) and/or the seco-steroid intermediates (I-2), (R1 and R2 are as defined), undergo photochemical reaction in a continuous flow reactor.

Thorough review of cited prior arts for batch processes revealed that batch processes are unsuitable for commercial scale. Hence, there was an urgent need to develop a continuous flow process which would improve commercial viability.

The inventors while working on continuous flow process surprisingly observed that photo isomerization reaction of I-1 compounds can be carried out advantageously using continuous flow process in much shorter duration with considerably higher yield.

It is worth mentioning that the present invention utilizes only 10-30 volumes of solvent per gram of the starting material. The volume employed in the present invention is less than 25% of the volume of the solvent that is either used in batch reactor or flow reaction disclosed in prior art. Despite the extremely lower volume, it was found that there was no impact on the impurity formation in the flow process of the present invention.

The instant process provides significant control on side reactions and formation of impurities, causing reduction in the unit operations for isolation, purification of the intermediates which results in lowering the cost of the desired key intermediate as well as that of final compound. It is worth noting that the impurity is primarily the ring opened intermediate, 3,20-bis(ethylenedioxy), 6E/Z-9,10-seco-pregna-5(10),6,8-triene (I-2a), which is converted to 9ß,10a-3,20-bis(ethylene-dioxy)pregna-5,7-diene (I-3a) during recycling of the starting material, thereby increasing the yield by an additional 5-10%.

In an embodiment, for the preparation of intermediate (I-3a), Figure 1 depicts the schematic representation of the continuous flow reactor for stage I, wherein the reactor tubing has a helical configuration.

The continuous flow reactor, as depicted in figure 1 comprises of:
a) a tubular reactor placed around a glass vessel (A) in helical configuration, wherein the tubular reactor has an inlet tubing connected to a reservoir for the reaction mass, a flow pump, and an outlet tubing connected to a collection vessel for collecting the reaction mixture after reaction completion,
b) a glass vessel (A) equipped with, a medium pressure mercury vapor lamp as the irradiation source, vertically placed in the center of the vessel with both ends open, an outer glass vessel B enclosing/jacketing the helical tubular reactor, with tubing for circulation of water and /or a filter solution to maintain the temperature, to filter the irradiation providing desired range of wavelength for the photochemical reaction.

Yet another embodiment refers to the continuous flow reactor wherein,
a) the material of construction of the tubular reactor is glass or quartz, preferably quartz,
b) the irradiation source is a medium pressure mercury lamp (250 to 4000 Watts), vertically placed in the glass vessel (A).

In an embodiment, I-1a is subjected to photoisomerization reaction in an organic solvent using a continuous flow reactor in presence of a filter to provide the desired band of wavelength between 260nm and 350nm.

The organic solvent is selected from tetrahydrofuran, ethyl acetate and methyl tertiary butyl ether.

The amount of organic solvent employed is in the range of 10 volumes to 30 volumes per gram of the substrate compound I-1a.

The reaction temperature is in the range of 10 to 25°C.

The filter is selected from aqueous solution of copper sulfate and nickel sulfate. Aqueous copper sulfate solution (CuSO4) having concentration between (0-20%) at ambient temperature was circulated in vessel B as a coolant and to filter the light emitting from the source for obtaining the desired wavelength (260nm-350nm). Herein, the aqueous copper sulfate solution behaves as a light filter as well as a coolant.

In a related embodiment, the photoisomerization reaction is carried out in continuous flow reactor, stage I and stage II, wherein stage I is ring opening and stage II is ring closing.

The instant invention also encompasses more than one continuous flow reactor, arranged in series (Figure 2) to ensure that the reaction mixture obtained after completion of earlier stage is fed to the next reactor for further reaction, wherein the tubular reactors are placed helically, spirally, vertically, or horizontally, coaxially surrounding the vessel equipped with the source of irradiation.

The reaction was monitored by HPLC wherein conversion of starting compounds I-1a to I-2a and I-3a, and conversion of I-2a to I-3a was checked intermittently.

In a related embodiment, in stage I, the solution of compound I-1a in tetrahydrofuran (THF), was passed through the quartz reactor wherein the flow rate was in the range of 5 to 60 ml per minute. Reaction mixture residence time in the flow reactor was between 5 seconds to 140 minutes.

The source of irradiation is a medium pressure mercury lamp, ranging from 250W to 4000W and the reaction is carried out in the temperature range of 10 to 25°C, wherein water or aqueous copper sulfate solution, used as a filter to obtain desired wavelength range. When aqueous copper sulfate solution is used as a filter, the concentration of copper sulfate is in the range of 0 to 20% weight/volume.

In a further embodiment, the reactions are carried out in the wavelength range of 260nm to 350nm. Typically stage I is carried out in the wavelength range of 260nm to 300nm, while stage II is carried out in the wavelength range of 300nm to 350nm.

In one of the embodiment, compound I-3a is isolated by concentrating the reaction mixture and isolating from a mixture of acetonitrile and methanol.

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: Preparation of I-3a
Stage I
A solution of 9a,10ß-3,20-bis(ethylenedioxy)-pregna-5,7-diene (I-1a; 2.0gms in 150ml THF) was added to a quartz continuous flow reactor (100 ml) at the rate of 1 ml/minute, simultaneously irradiating the reaction mass using a 250W medium pressure mercury lamp, with the light passing through an aqueous copper sulfate solution (3% weight/volume). The reaction temperature was maintained in the range of 10-25°C and the photochemical reaction carried out for 100 to 120 minutes based on HPLC monitoring.
HPLC analysis of the reaction mixture indicated unreacted starting material, 9a,10ß,3,20-bis(ethylenedioxy)-pregna-5,7-diene (49.5%; 0.99gms), seco intermediate impurity (41.6%; 0.83gms), and the 9ß,10a, 3,20-bis(ethylenedioxy)-pregna-5,7-diene (8.9%; 0.18gms).
Stage II
The reaction mixture obtained in stage I was fed to a quartz continuous flow reactor (100 ml) at the rate of 1 ml/minute, simultaneously irradiating the reaction mass with a 250W medium pressure mercury lamp, in presence of aqueous copper sulfate solution (10% weight/volume), maintaining the temperature in the range of 10-25°C.
HPLC analysis of the reaction mixture after 100 to 120 minutes indicated a mixture of the starting material, 9a,10ß, 3,20-bis(ethylenedioxy)-pregna-5,7-diene (54.2%; 1.08gms), seco intermediate impurity (33.2%; 0.66gms), and the desired 9ß,10a 3,20-bis(ethylenedioxy)-pregna-5,7-diene (12.6%; 0.25gms).

Example 2: Preparation of I-3a
Stage I
A solution of I-1a (10.0g in THF, 200 ml) is fed to a quartz continuous flow reactor (100 ml) at the rate of 20 ml/minute, simultaneously irradiating the reaction mass using a 1000W medium pressure mercury lamp, in presence of aqueous copper sulfate solution (3% w/v). During the reaction, the temperature is maintained in the range of 10-25°C.
HPLC analysis of the product mixture obtained after the residence time of 15 to 17 minutes indicated a mixture of the starting material, 9a,10ß,3,20-bis(ethylenedioxy)pregna-5,7-diene (46.2%; 4.62gms) seco intermediate along with other impurities (38.5%; 3.85gms), and the 9ß,10a 3,20-bis(ethylenedioxy)-pregna-5,7-diene (15.3%; 1.53gms).
Stage II
The reaction mixture obtained in stage I is fed to a quartz continuous flow reactor (100 ml) at the rate of 15 ml/minute, simultaneously irradiating the reaction mass using a 1000W medium pressure mercury lamp, in presence of aqueous copper sulfate solution (10% weight/volume), maintaining the temperature in the range of 10-25°C.
HPLC analysis of the reaction mixture obtained after the residence time of 20 to 25 minutes, indicated the presence of the starting material, 9a,10ß-3,20-bis(ethylenedioxy)pregna-5,7-diene (36.0%; 3.60gms), seco intermediate with associated impurities (44.0%; 4.40gms), and the 9ß,10a-3,20-bis(ethylenedioxy)pregna-5,7-diene (20.0%; 2.0gms).
The yield of the desired product based on consumed starting material is 35.7%.

Example 3: Preparation of I-3a
Stage I
A solution of I-1a (10.1g in THF, 200 ml) is fed to a quartz continuous flow reactor (100 ml) at the rate of 20 ml/minute, simultaneously irradiating the reaction mass using a 1000W medium pressure mercury lamp, in presence of aqueous copper sulfate solution, (3% weight/volume). During the reaction, the temperature is maintained in the range of 10-25°C. HPLC analysis of the product mixture obtained after the residence time of around 20 minutes exhibits presence of the starting material, 9a,10ß-3,20-bis(ethylenedioxy)-pregna-5,7-diene (49.8%; 5.03gms), seco intermediate along with other impurities (40.7%), and 9ß,10a-3,20-bis(ethylenedioxy)-pregna-5,7-diene (8.8%; 0.89gms).
Stage II
The reaction mixture obtained in stage I is diluted to 350 ml with THF and fed to a quartz continuous flow reactor (100 ml) at the rate of 15 ml/minute, simultaneously irradiating the reaction mass using a 1000W medium pressure mercury lamp, in presence of aqueous copper sulfate solution, (10% weight/volume), maintaining the temperature in the range of 10-25°C.
HPLC analysis of the product mixture obtained after completion of residence time of 20 to 25 minutes exhibits presence of the starting material, 9a,10ß,3,20-bis(ethylenedioxy)-pregna-5,7-diene (30.0%), seco intermediate along with other impurities (48.4%; 4.89gms), and the 9ß,10a 3,20-bis(ethylenedioxy)-pregna-5,7-diene (20.3%; 2.05gms).
Product yield based on consumed starting material is 29%.

Example 4: Preparation of I-3a
Stage I
A solution of I-1a (100.3 g in THF, 2200 ml) is fed to a quartz continuous flow reactor (100 ml) at the rate of 20 ml/minute, simultaneously irradiating the reaction mass using a 1000W medium pressure mercury lamp, in presence of water, which is used as a filter for the radiation.
During the reaction, the temperature is maintained in the range of 10-25°C. After completion of the reaction, HPLC analysis of the product mixture exhibits presence of the starting material, 9a,10ß,3,20-bis(ethylenedioxy)-pregna-5,7-diene (42.7%; 42.83gms), seco intermediate along with other impurities (53.5%; 53.66gms), and the 9ß,10a 3,20-bis(ethylenedioxy)pregna-5,7-diene (3.8%; 3.81gms).
Stage II
The reaction mixture obtained in stage I is diluted with THF (4800 ml), and the resulting solution is added to the continuous flow reactor and irradiated using a 3000W medium pressure mercury lamp, in presence of aqueous copper sulfate solution (10%), maintaining the temperature in the range of 10-25°C.
HPLC analysis of the product mixture obtained after completion of the reaction, exhibits presence of the starting material, 9a,10ß,3,20-bis(ethylenedioxy)-pregna-5,7-diene (60.5%; 60.68gms), seco intermediate along with other impurities (8.9%; 8.93gms), and the 9ß,10a,3,20-bis(ethylenedioxy)-pregna-5,7-diene (30.6%; 30.69gms).
The product yield based on consumed starting material is 77.5%.

Example 5: Preparation of I-3a
Compound I-1a (25 gm in 750 ml THF) was added to a 600 ml quartz continuous flow reactor and the mixture was irradiated with a light beam from 3500W medium pressure mercury lamp passed through a 6% CuSO4 filter solution. The compound I-1a solution was passed through the reactor at the rate of 60 mL/min at a temperature of 10-25°C and circulated the reactor for about 210 minutes. The HPLC test results show that there was 53.25% (13.31gms) conversion of the raw material 9a,10ß-dehydroprogesterone diethylene ketal to give 23.41% (5.85gms) of the desired product 9ß,10a-dehydroprogesterone diethylene ketal (I-3a) and associated seco impurities about 21.54% (5.39gms).
The product yield based on consumed starting material is 50% (HPLC)
The reaction mixture was concentrated under reduced pressure and the residue was diluted with acetonitrile (175 mL), the mixture was stirred at 50°C for 15-45 minutes, cooled between 25 and 30°C and filtered to give the starting material (I-1a). The acetonitrile filtrate was concentrated under reduced pressure and diluted with methanol (15 ml). The reaction mixture was stirred for 30 min at 10 to 15°C, filtered and the wet cake was washed with chilled methanol (5 ml) and dried to give (I-3a).
Yield: 4.14gms (Purity 80%; % Yield: 26.0%; based on converted starting material)
Recovered I-1a (Purity>99%, 9gms, 36% starting material recovered)

Example 6: Preparation of I-3a
Stage I
25 gm of Compound I-1a (25gms in 750 ml THF) was added to a 600 ml quartz continuous flow reactor and irradiated with a 3500W medium pressure mercury lamp. The light was passed through 6% CuSO4 filter solution and the mixture of compound I-1a was circulated through the reactor at a rate of 30 ml/min for 160 minutes with the temperature between 10 and 25°C. The mixture of compound (I-2a) was then passed into another reactor connected in series for obtaining compound (I-3a). The HPLC test results show that the content of the raw material 9a,10ß-dehydroprogesterone diethylene ketal is about 68% (17.0gms), and the content of the target product 9ß,10a-dehydroprogesterone diethylene ketal about 13.8% (3.45gms), the content of other impurities is about 17.3% (4.33gms).
Stage II
The reaction mixture obtained in Example 7a was passed through a 600 ml quartz continuous flow reactor at the rate of 30 ml/min and irradiated by using medium pressure mercury lamp with the light passing through a 10% CuSO4 solution. The temperature was maintained at 10-25°C and the mixture was circulated for 160 minutes.
The HPLC test results show that the content of the raw material 9a,10ß-dehydroprogesterone diethylene ketal is about 59% (14.75gms), and the product content is 9ß,10a-dehydroprogesterone diethylene ketal about 25.2% (6.3gms), the content of other impurities is about 14.2% (3.60gms).
The product yield based on consumed starting material is 61.5%.
The reaction mixture containing compound (I-3a) was concentrated under reduced pressure and diluted with acetonitrile (175 mL) and stirred at 50°C for 30 minutes. The reaction mixture was cooled to 25 to 30°C, filtered and dried to obtain compound (I-1a). The acetonitrile filtrate was concentrated under reduced pressure, diluted with methanol (15ml), and stirred for 30 min at 10 to 15°C, filtered and washed with methanol. Compound I-3a separating out was filtered and dried.
Yield of Compound I-3a: 4.5gms (Yield 29% based on converted starting material)
Recovered Compound (I-1a) (9.5 gms, 38%, >99% HPLC purity, recovered starting material).

Example 7: Preparation of I-3a
Stage I
25 gm of (I-1a) in THF (750ml) was circulated through a 600 ml quartz continuous flow reactor and irradiated with 3500W medium pressure mercury lamp. The light from the lamp was filtered through a 6% CuSO4 solution. The solution containing (I-1a) was circulated through the reactor at a rate of 30 ml/min and at a temperature of 10-25°C for about 160 minutes. The HPLC test results show that the content of the raw material 9a,10ß-dehydroprogesterone diethylene ketal is about 68.3% (17.03gms), and the product content is 9ß,10a-dehydroprogesterone diethylene ketal about 13.9 % (3.48gms), the content of other impurities is about 17.8% (4.45gms).
Stage II
The solution obtained from Example 8a was used as such for the photochemical ring closing reaction. The solution was passed through the 600 mL quartz continuous flow reactor at a rate of 30 ml/min and irradiated with a medium pressure mercury lamp with the light beam passing through a 10% CuSO4 solution. The temperature of the continuous flow reactor was maintained at 10-25°C and the mixture passed for about 150 minutes. The HPLC test results indicate raw material 9a,10ß-dehydroprogesterone diethylene ketal 58% (14.5gms), the target product 9ß,10a-dehydroprogesterone diethylene ketal is 23.5% (5.89gms), and seco impurity about 16.5% (4.13gms).
The product yield based on consumed starting material is 56.1%.
The reaction mixture was concentrated under reduced pressure and the residue was diluted with acetonitrile (175 mL) and stirred at 50°C for 30 minutes. The reaction mixture was cooled to 25 to 30°C and filtered, to obtain I-Ia (9.5 gms, 38% recovered starting material >99% HPLC purity). The filtrate was concentrated at reduced pressure and methanol (15 ml) was added and stirred for 30 min at 10 to 15°C, filtered and dried to give I-3a (4.3gms, 31% based on the recovered starting material, >80% HPLC purity).
Yield: 4.3 gms 27.7% based on converted starting material.

Example 8: Preparation of I-3a
Stage I
Compound I-1a (25gms in 750 ml THF) was circulated through 600 ml quartz continuous flow reactor and irradiated with a 3500W medium pressure mercury lamp with light passing through water before passing through compound (I-1a) solution proceeding at a rate of 60 ml/min through the reactor. The temperature of the continuous flow reactor was maintained at 10-25°C for about 120 minutes. The HPLC test results showed the raw material 9a,10ß-dehydroprogesterone diethylene ketal about 28.55% (7.14gms), the content of the target product 9ß,10a-dehydroprogesterone diethylene ketal about 3.09% (0.77gms), and the content of other impurities about 66.5% (16.6gms of ring opened product).
Stage II
The reaction mixture obtained in Example 9a was carried forward for the photochemical ring closing reaction. The mixture was passed through a 600 ml quartz continuous flow reactor at a rate of 60 ml/min. The solution was irradiated by a light beam generated by a medium pressure mercury lamp passed through a 10% CuSO4 solution. The temperature of the continuous flow reactor was maintained at 10-25°C and solution of Example 9a was passed through the reactor for 120 minutes. The HPLC test results show that the content of the raw material 9a,10ß-dehydroprogesterone diethylene ketal is about 41.41% (10.35gms), the product content 9ß,10a-dehydroprogesterone diethylene ketal about 12.66 % (3.17gms), and the content of other impurities is about 41.69% (10.42gms).

,CLAIMS:We claim:

1) A process for the preparation of 9ß,10a 3,20-bis(ethylenedioxy)-pregna-5,7-diene (I-3a) in a continuous flow reactor,

9a,10ß-3,20-bis (ethylene- dioxy)-pregna-5,7-diene (I-1a) 3,20-bis(ethylenedioxy), 6E/Z-9,10-seco-pregna-5(10),6,8-triene (I-2a)
9ß,10a-3,20-bis (ethylene- dioxy) pregna-5,7-diene
(I-3a)


comprising the steps of dissolving compound I-1a in an organic solvent and passing it through a continuous flow reactor having a filtered light beam, at the rate of 5ml - 60ml per minute, wherein the compound I-1a undergoes photochemical reaction and gets converted to compound I-2a at Stage I and further in stage II compound I-2a gets converted to compound I-3a followed by concentration of the reaction mixture and isolating from a mixture of acetonitrile and methanol.

2) The process as claimed in claim 1, wherein the organic solvent is selected from the group comprising of tetrahydrofuran, ethyl acetate and methyl tertiary butyl ether.

3) The process as claimed in claim 2, wherein the organic solvent is employed in the amount of 10-30 volumes per gram of the substrate compound I-1a.

4) The process as claimed in claim 1, wherein the wavelength of the filtered light beam for both stage I and stage II is in the range of 260nm -350nm.