CLIAMS:1. A process for the preparation of compound [D],

wherein P is protecting group and R is residual side chain,
comprising reduction of compound [C],

with sodium borohydride in reverse micellar aggregate in the presence of organic solvent and surfactant.

2. The process according to claim 1, wherein the protecting group is selected from benzoyl, p-phenylbenzoyl (PPB), p-methoxy benzyl (PMB) or THP.

3. The process according to claim 1, wherein the residual side chain is selected from a group consisting of substituted and unsubstituted C1-¬C6 alkyl, C7-C16 aralkyl wherein the aralkyl group is optionally substituted with one to three substituents selected from the group consisting of C1-¬C6 alkyl, halo and CF3, and (CH2)nORa, wherein n is from 1-3 and Ra represents a C6-C10 aryl group which is optionally substituted with one to three substituents selected from the group consisting of C1-¬C6 alkyl, halo and CF3.

4. The process according to claim 1, wherein surfactant is selected from sodium diocty sulfosuccinate, sodium dihexyl sulfosuccinate, sodium lauryl sulfate.

5. The process according to claim 1, wherein the organic solvent is selected from hydrocarbon such as toluene, n-hexane, n-heptane, di-isopropylether, 2-methyl tetrahydrofuran.

6. A process for preparation of compound [D],

wherein P is protecting group and R is residual side chain,
comprising reduction of compound [C],

with sodium borohydride in water in oil micro emulsion.

7. The process according to claim 6, wherein the protecting group is selected from benzoyl, p-phenylbenzoyl (PPB), p-methoxy benzyl (PMB) or THP.

8. The process according to claim 6, wherein the residual side chain is selected from a group consisting of substituted and unsubstituted C1-¬C6 alkyl, C7-C16 aralkyl wherein the aralkyl group is optionally substituted with one to three substituents selected from the group consisting of C1-¬C6 alkyl, halo and CF3, and (CH2)nORa, wherein n is from 1-3 and Ra represents a C6-C10 aryl group which is optionally substituted with one to three substituents selected from the group consisting of C1-¬C6 alkyl, halo and CF3.

9. The process according to claim 6, wherein water in oil micro emulsion is a mixture of oil, water, surfactant and co-surfactant.

10. The process according to claim 9, wherein the oil is selected from hydrocarbon solvents such as toluene, n-hexane, n-heptane, di-isopropylether, 2-methyl tetrahydrofuran.

11. The process according to claim 9, wherein the surfactant is selected from sodium diocty sulfosuccinate, sodium dihexyl sulfosuccinate, sodium lauryl sulfate.

12. The process according to claim 9, wherein the co-surfactant is selected from propylene glycol, isopropyl alcohol, ethanol, n-butanol.

13. The process according to claim 1 and claim 6, wherein the compound [D] is further converted to prostaglandins.

14. The process according to claim 13, wherein prostaglandins are selected from Latanoprost, Bimatoprost, Travoprost, Fluprostenol and Cloprostenol.
,TagSPECI:
Field of the Invention:
The present invention relates to a novel, “green”, cost effective industrial process for the preparation of prostaglandin intermediate.

Background of the Invention:
A micelle is an aggregate of surfactant molecules dispersed in a liquid colloid. A typical micelle in aqueous solution forms an aggregate with the hydrophilic "head" regions in contact with surrounding solvent, sequestering the hydrophobic single-tail regions in the micelle center. This phase is caused by the packing behavior of single-tail lipids in a bilayer. The difficulty filling all the volume of the interior of a bilayer, while accommodating the area per head group forced on the molecule by the hydration of the lipid head group, leads to the formation of the micelle. This type of micelle is known as a normal-phase micelle (oil-in-water micelle). Reverse micelles have the head groups at the center with the tails extending out (water-in-oil micelle). Micelles are approximately spherical in shape.Ketone reduction in aqueous micellar aggregates has been well reported (Ind. Eng. Chem. Res. 2007, 46, 1923-1927; JOC, 2004, 69, 8224-8230; JOC, 2004, 69, 8231-8238; Organic Letters 2004, 22, 4133-4136). Although, in presence of chiral surfactants stereoselective reduction of ketone was reported, enantiomeric excess for corresponding hydroxyl compound was very poor (Organic Letters 2004, 22, 4133-4136; Langmuir 2005, 21, 10398-10404; Tetrahedron: Asymmetry: 1996, 7, 3055-3058).There were no literature reports, wherein stereo-selective reduction of carbonyl compound with sodium borohydride in achiral reverse micellar aggregates has been performed to obtain chiral allyl alcohol, having such a high degree of chiral induction and which has a synthetic utility.
Correa et al (JOC, 2004, 69, 8224-8230; JOC, 2004, 69, 8231-8238) reported that the ketone reduction in reverse micellar was occurred at the interface of micellar aggregates i.e. pseudo phase. It also mentions that, sodium borohydride was insoluble in organic solvent (hydrocarbon) and ketone substrate was very poor solubility in water. Moreover, anion BH4- has the same charge of the anionic surfactant. Considering all these aspects reaction can only occur at the interface of the aggregates i.e. in pseudo phase (Figure 1).

In the same publication it has been demonstrated that reduction of ketone compounds such as acetophenone, 4-methoxyacetophenone and 3-chloroacetophenone, which do not contain any other chiral center with sodium borohydride in reverse micellar gave the corresponding racemic hydroxyl compounds, meaning that there was no chiral induction.
Prostaglandin F2a [I] has general structure as,

Synthetic analogs of Prostaglandin F2a having therapeutic use includes Latanoprost [II], Bimatoprost [III], Travoprost [IV], Fluprostenol [V] and Cloprostenol [VI].
For synthesis of numerous prostaglandins compound [D] is used as a key intermediate having general structure as,

Compound [D] having structure [D1],

which is an intermediate for the synthesis of Latanoprost [II] and Bimatoprost [III],

Compound [D] having structure [D2],

which is an intermediate for the synthesis of Tavoprost [IV] and Fluprostenol [V],

Compound [D] having structure [D3],

which is an intermediate for the synthesis of Cloprostenol [VI],

There is large number of patents and patent applications disclosed different methods for the preparation of above mentioned prostaglandin intermediate [D]. One of the most widely acclaimed and versatile approach for the synthesis of Prostaglandins is through Corey Lactone [A].
As shown in scheme 1, compound [A] was converted to compound [C] through sequence of reaction, which was further converted to compound [D] through stereo-selective reduction. Stereo-selective reduction of compound [C] to compound [D] was achieved through a number of ways as described in prior art.

EP 0544 899 B1 disclosed the process for synthesis of compound [D] from compound [C] in the presence of CeCl3/NaBH4 or L-Selectride. But the diasteromeric selectivity towards the asymmetric reduction of carbonyl group to corresponding hydroxyl group was very poor.
US patent 6,689,901 disclosed the process for the synthesis of compound [D] from compound [C] in the presence of (-)-B- chlorodiisopinocampheylborane ((-)-DIPCl) at -780C in 90% de, which was further purified through column chromatography to obtain pure compound [D].
WO 2011/055377 disclosed the synthesis of compound [D] through reduction of compound [C] in presence of (R)-N-MeCBS and borane-N,N’-diethylaniline complex (DEANB) at -200C. Overall yield after column chromatography was around 30-35%, moreover diasteromeric excess for product was not given.
The prior art methods involving stereo selective reduction of ketone suffer from few fundamental disadvantages;
1. Use of costly reagents such as DIPCl or (R)-N-MeCBS.
2. Use of costly solvents such as anhydrous THF.
3. Reduction in the presence of CeCl3/NaBH4 or L-Selectride, stereo-selectivity was very poor
4. Lower yields.
5. The byproducts of these reagents are difficult to dispose.
6. Waste of refined intermediate when unwanted stereoisomer is formed in large quantity.
The prior art does not discloses any process which is environment friendly, cost effective and industrially feasible which can be used for the preparation of prostaglandin intermediate [D].
Objects of the invention
It is an object of present invention to overcome the drawbacks of the prior art.
It is another object of present invention to provide environment friendly, cost effective and industrially feasible which can be used for the preparation of prostaglandin intermediate

Summary of Invention:
The inventions embodied in this application are summarized below:

In case of reverse micellar reduction of compound [C] a high degree of chiral induction was observed for obtaining compound [D]. However, when compound (C) was reduced in organic solvent i.e. methanol with sodium borohydride, no chiral induction was observed, i.e. almost racemic product was obtained.
In the present investigation, compound [C] through interaction in pseudo phase adopts a conformation, where borohydride anion could predominately approach carbonyl group only from one direction, which results in predominately one diastereomer. In short transition state of resulting diastereomer has considerable lower energy because of its presence only in the pseudo phase.
Hence, reduction of compound [C] was attempted in micro emulsion and surprisingly it was observed that compound [D] was obtained in high diastereomeric excess.
The reduction of compound [C] was carried out in micro emulsion using sodium borohydride at 10 0C and it was found that diastereomeric excess for compound [D] was 90% de and the obtained crude product was subjected to column chromatography (Silica gel 100-200 mesh and mobile phase toluene: tetrahydrofuran (93:7) to give optically pure compound [D] having 99% de.
Interestingly, present inventors found that sodium borohydride reduction of compound [C] in achiral reverse micellar aggregates gave compound [D] in 60% de.

Description of accompanying drawing
Figure 1 shows interface of the aggregates i.e. in pseudo phase

Detail Description of the Invention:

The present invention relates to novel, “green”, cost effective industrial process for the preparation of prostaglandin intermediate having formula [D] in the presence of reverse micellar aggregates as well as water in oil micro emulsions

wherein P is protecting group and R is residual side chain.

According to one embodiment, the present invention provides the synthesis of compound [D],

wherein P is protecting group and R is residual side chain, comprising stereo-selective reduction of compound [C],

by sodium borohydride in reverse micellar aggregates in the presence of organic solvent and surfactant.
The protecting group is selected from but not limited to benzoyl, p-phenylbenzoyl (PPB), p-methoxy benzyl (PMB) or THP and the like.
The residual side chain is selected from a group consisting of substituted and unsubstituted C1-¬C6 alkyl, C7-C16 aralkyl wherein the aralkyl group is optionally substituted with one to three substituents selected from the group consisting of C1-¬C6 alkyl, halo and CF3, and (CH2)nORa, wherein n is from 1-3 and Ra represents a C6-C10 aryl group which is optionally substituted with one to three substituents selected from the group consisting of C1-¬C6 alkyl, halo and CF3.
The organic solvent is selected from but not limited to hydrocarbon such as toluene, n-hexane, n-heptane, di-isopropylether, 2-methyl tetrahydrofuran and the like; most preferably toluene.
The surfactants is selected form but not limited to sodium diocty sulfosuccinate, sodium dihexyl sulfosuccinate, sodium lauryl sulfate and the like; preferably sodium lauryl sulfate.
The reaction is carried out at temperatures from 0oC to 80oC, preferably 10oC to 30oC; most preferably at 25oC.
The ratio of surfactant to compound [C] is from 20-90% w/w; preferably 40-60% w/w; most preferably 60% w/w.
The mole ratio of sodium borohydride to compound [C] is from 0.2 mole to 5 mole; preferably 0.5 mole to 3 mole; more preferably 2 mole.
According to another embodiment, the present invention provides synthesis of compound [D] comprising stereo-selective reduction of compound [C] by sodium borohydride in the presence of water in oil micro emulsion.
Micro emulsions are clear, thermodynamically stable, isotropic liquid mixtures of oil, water and surfactant, frequently in combination with a co-surfactant.
The oil i.e. organic phase is selected from but not limited to hydrocarbon solvents such as toluene, n-hexane, n-heptane, di-isopropylether, 2-methyl tetrahydrofuran and the like; most preferably toluene.
The surfactants is selected form but not limited to sodium diocty sulfosuccinate, sodium dihexyl sulfosuccinate, sodium lauryl sulfate and the like; preferably sodium lauryl sulfate.
The co-surfactant is selected from but not limited to propylene glycol, isopropyl alcohol, ethanol, n-butanol and the like; most preferably n-butanol.
The reaction is carried out at temperatures from 0oC to 80oC, preferably 5o to 30oC; most preferably at 10oC.
The mole ratio of sodium borohydride to compound [C] is from 0.2 mole to 5 mole; preferably 0.5 mole to 3 mole; more preferably 2 mole.
The present invention is further illustrated by foregoing examples, which should not be construed by way of limiting the scope of the present invention.
Example1: Preparation of (3aR,4R,5R,6aS)-4-((S,E)-3-hydroxy-5-phenylpent-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate by reduction in micellar system

In a multi neck reactor, equipped with nitrogen bubbling inlet, thermo-pocket and overhead stirrer, was charged (3aR,4R,5R,6aS)-2-oxo-4-((E)-3-oxo-5-phenylpent-1-en-1-yl)hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate (1.3 g, 2.7 mmol) at 25°-30°C. To this was added successively, toluene (150 mL), deionized water (60 mL) and sodium lauryl sulfate (0.8 g, 60% w/w) at the same temperature. The reaction mixture was cooled to 0°C and sodium borohydride (0.2 g, 5.4 mmol) was added in two successive portions and stirred at 0°C for 4-5 min. Subsequent to that, temperature of the reaction mass was allowed to rise upto ambient tempearature (25°-30°C) and it was stirred overnight at 25°-30°C. Solvent was evaporated from reaction mass and ethyl acetate (200 mL) was added. After separation of organic layer, ethyl acetate was evaporated to afford crude product (1.2 g) which was analyzed by HPLC having 60 % de. Crude material was subsequently subjected to flash chromatography (Colum: Silica gel 100-200; mobile phase toluene: THF (93:7) to obtain both isomers.
Retention time of (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-5-phenylpent-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate : 25.8 min
Retention time of (3aR,4R,5R,6aS)-4-((S,E)-3-hydroxy-5-phenylpent-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate : 26.9 min

Chromatographic System:
Instrument : HPLC equipped with Pump, UV detector and Recorder.
Column : Zorbax Rx C8 (4.6 x 250 mm), 5µm
Wavelength : UV at 210nm
Flow rate : 1.5mL/min
Injection volume : 10?L
Column oven temp : 25°C
Auto sampler temp : 10°C
Mobile phase-A:
Prepare a homogeneous mixture of 0.01% (v/v) phosphoric acid in HPLC grade water. Adjust pH of the mixture to 3.0 ± 0.05 with potassium hydroxide. Filter and sonicate to degas.

Mobile phase-B:
Use HPLC grade acetonitrile as mobile phase-B.
Diluent preparation:
Use HPLC grade methanol as a diluent.

Gradient Programme:

Time (In mins) Mobile phase-A (%) Mobile phase-B (%)
0.01 60 40
35.00 35 65
45.00 25 75
52.00 25 75
53.00 60 40
60.00 Stop

Example 2: Preparation of (3aR,4R,5R,6aS)-4-((S,E)-3-hydroxy-5-phenylpent-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate by reduction in microemulsion system

In a multineck reactor, equipped with nitrogen bubbling inlet, thermo pocket and overhead stirrer, was charged (3aR,4R,5R,6aS)-2-oxo-4-((E)-3-oxo-5-phenylpent-1-en-1-yl)hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate (5.2 g, 10.8 mmol) at 25°-30°C. To this was added successively, toluene (250 mL), deionized water (100 mL), sodium lauryl sulfate (3.2 g, 60% w/w) and n-butanol (20 mL) at the same temperature. The reaction mixture was cooled to 0°C and sodium borohydride (0.82 g, 21.6 mmol) was added in two successive portions and stirred at 0°C for 10-15 min. Subsequent to that, temperature of the reaction mass was allowed to rise up to ambient temperature (25°-30°C) and it was stirred for 3-4 h. After checking TLC, an additional equivalent of sodium borohydride (0.41 g) was added and stirred overnight at 25°-30°C. Brine (200 mL) was added and reaction mass washed thoroughly, after which organic layer was separated and washed with water (200 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product (5.3 g), which was analyzed by HPLC having 65 % de. Crude material was subsequently subjected to flash chromatography (Colum: Silica gel 100-200; mobile phase toluene: THF (93:7) to obtain desired isomers of compound [D] (4.0 g) having 99% de.

Example 3:
Preparation of (3aR,4R,5R,6aS)-4-((S,E)-3-hydroxy-5-phenylpent-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate by reduction in microemulsion system at low temperature

In a multineck reactor, equipped with nitrogen bubbling inlet, thermo pocket and overhead stirrer, was charged (3aR,4R,5R,6aS)-2-oxo-4-((E)-3-oxo-5-phenylpent-1-en-1-yl)hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate (0.5 g, 1.04 mmol) at 25°-30°C. To this was added successively, toluene (100 mL), deionized water (30 mL), sodium lauryl sulfate (0.12 g, 60% w/w) and n-butanol (5 mL) at the same temperature. The reaction mixture was cooled to 0°C and sodium borohydride (0.82 g, 21.6 mmol) was added in three successive portions and stirred at 0°C for 30-35 min. Subsequent to that, temperature of the reaction mass was allowed to rise up to 10°C and it was stirred overnight at that temperature. Brine (100 mL) was added and reaction mass washed thoroughly, after which organic layer was separated and washed with water (200 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product (0.48 g), which was analyzed by HPLC having 90 % de. Crude material was subsequently subjected to flash chromatography (Colum: Silica gel 100-200; mobile phase toluene: THF (93:7) to obtain desired isomers of compound [D] (0.4 g) having 99% de