NOVEL ROUTE OF PRODUCING LACTONE INTERMEDIATE USED IN THE PREPARATION OF PROSTAGLANDINS
Field of the Invention
The present invention relates to novel processes of preparing formula I used in the preparation of prostaglandins. In particular the present invention provides novel intermediates to produce formula I.
Background of the Invention
Prostaglandins and the derivatives thereof have various biological actions, such as a vasodilating action, a prophlogistic action, an inhibitory action of blood platelet aggregation, a uterine muscle contraction action, an intestine contraction action and a lowering action of intraocular pressure, and can be used in the preparation of medicaments for treatment or prevention of myocardial infarction, angina pectoris, arteriosclerosis, hypertension, or duodenal ulcer, which are valuable for human as well as veterinary applications.
For the last few decades, many academic researchers and industrial organizations have made tremendous efforts in exploring various key intermediates as well as innovative processes for efficient and cost-saving synthesis of Prostaglandins (Collines, P. W. et. al., 1993, Chem. Rev. 93,1533 ).
Specifically, lactones of Formula I are very important late-stage intermediates for synthesis of Prostaglandin 2 compounds.

o
SA^VR2-R3
0X1 ox2
Formula I Where
1-1 = = being a double bond
Xt and X2 being protecting group
1_2 = r= being a double bond
X! and X2 being OH
__ being a double bond
X! and X2 being protecting group or OH
For example, Lactones of Formula 1-1 or 1-2, wherein R2 is methylene and R3 is n-butyl, are key intermediates for the synthesis of nature Prostaglandin F2 , E2 and 12, as reported in E. J. Corey, et al, J. Am. Chem. Soc. 1970, 92, 397 ; and J. Am. Chem. Soc. 1977,99,2006.
Lactones of Formula 1-1 or 1-2, wherein R2 is methylene and R3 is benzyl, are advanced intermediates for the synthesis of Bimatoprost, as disclosed in USP 2005/0209337.
Lactones of Formula 1-1 or 1-2, wherein R2 is -CH20- and R3 is a substituted phenyl, are intermediates for the synthesis of (+)- Cloprostenol, Travoprost and (+)-Fluprostenol, as disclosed in EP 0362686 and USP 2005/0209337.
Lactones of Formula 1-3, wherein R2 is methylene and R3 is benzyl, are intermediates for the synthesis of Latanoprost, as disclosed in USP5,359,095 .
Given the above, conventional approaches for producing Lactones of Formula I encountered problems to be solved. The objective of the invention is to provide a simpler as well as a cost-effective synthesis route for Lactones of Formula I to eliminate the problems associated with the conventional processes, either in the aspect of a number of synthetic steps or in the necessity of removing unwanted isomers.

Summary of the Invention
In one aspect, the present invention provides novel processes for the preparation of the key intermediates of Formula I, which are useful in the production of prostaglandins:
O
\A*A/R2"R3
°x1 6x2
Formula I
wherein R2 is a single bond or a Ci-4-alkylene or a group of formula -CH2O-; R3 is
a Ci.7-alkyl or an aryl or an aralkyl, each of which is unsubstituted or substituted by a CM
alkyl, a halogen and a trihalomethyl; Xi and X2 are H or hydroxy protecting group , and -
is a single or double bond.
In yet another aspect, the invention provides novel processes for the preparation of the key intermediates of Formula I via a novel intermediates (3aR,4R,5R,6aS)-5-(tert-butyldiphenylsilyloxy)-4-((E)-3-oxo-l-octenyl) hexahydro-2H-cyclopenta[b]furan-2-one of formula-Ill, 0
OTBDPS o
Formula-Ill

And (3aR,4R,5R,6aS)-5-(tert-butyIdiphenylsilyloxy)-4-((E)-3-hydroxy-l-octenyl)
hexahydro-2H-cyclopenta[b]furan-2-one of formula-II, O
OTBDPS OH
Formula-II
In one aspect, provided herein is an improved, efficient, commercially viable and environment friendly process key intermediate of above Formula I, which is useful in the production prostaglandins of PGF2a series selected from Latanoprost, Bimatoprost and Travoprost. Advantageously, the process involves shorter reaction times and produces the product with higher yields.
Detailed Description of the Invention
The present invention provides novel processes for the preparation of the key intermediate of Formula I, which is useful in the production of prostaglandins:
O
\A^vR2 ■R3
6X1 6x2
Formula I
wherein R2 is a single bond or a CM-alkylene or a group of formula -CH2O-; R3 is a C1.7.
alkyl or an aryl or an aralkyl, each of which is unsubstituted or substituted by a CM alkyl,
a halogen and a trihalomethyl; Xi and X2 are protecting groups for the hydroxy group or
H, and is a single or double bond.

According to another aspect, there is provided a novel intermediates
(3aR,4R,5R,6aS)-5-(tert-butyldiphenylsilyloxy)-4-((E)-3-oxo-1 -octenyl) hexahydro-2H-
cyclopenta[b]furan-2-one (formula-III) and (3aR,4R,5R,6aS)-5-(tert-
butyldiphenylsilyloxy)-4-((E)-3-hydroxy-l-octenyl)hexahydro-2H-cyclopenta[b]furan-2-one (formula-II) useful for the production of desired compound of Formula I.
Further, the present invention provides novel processes for the preparation of the key intermediate of Formula I, which are useful in the production of prostaglandins:
0
°xi 6x2
Formula I
wherein R2 is Cl-4-alkylene; R3 is methyl, XI is TBDPS or OH and X2 is OH — — is a double bond.
The invention thus provides preparation of formula 1 as mentioned in the below Scheme 1:
OTBDPS °TBDPS ° 5TBDPS OH
Formula-IV Formula-Ill Formula-II
Step-lll
O "
<*>
WvW
OH OH
Formula-I

Step-I Preparation compound III
dv° Fos:r 9vyw
- OTBDPS o
OTBDPS
Formula-IV Formula-Ill
In the present invention, the novel keto compound of formula III is prepared by the reaction of aldehyde compound of formula IV with compound of formula V in the presence of strong base in an organic solvent at a temperature between 20[deg.]C and 40[deg.]C preferably between 25[deg.]C and 30[deg.]C.
The strong bases used in above step I are selected from LiOH, KOH, NaOH and mixtures thereof. Preferably LiOH is used as a base
Organic solvents used in above step I are selected from MTBE, ETBE, diethyl-ether and mixtures thereof. Preferably MTBE is used as an organic solvent in the step-I reaction.
The aldehyde (formula-IV) is prepared according to the process disclosed in the prior-art. This aldehyde shows a good stability and can easily be stored for at least 4-5 months at a temperature between -30[deg.]C and 0[deg.]C. This makes the compound easy to handle and allows more flexibility in the production planning.
Compound of formula V i.e the witting reagent is prepared by the conventional methods proved in the prior-art as disclosed in the Scheme-II.
Scheme-II

Dimethyl methyl
/v^^COOMe Phosphonate 0 O
Methyl hexanoate n-BuLi,THF
VI -60 to -78 °C, 3 h, 80 %
Step-II
O O
*S -A
:—; ««- j •*
L X /^ ^ X / steP-" /V , /v /
yvVW vVvV^
OTBDPS o OTBDPS OH
Formula-Ill Formula-ll
The reduction of the novel ketone compound of formula is carried out by dissolving keto compound of formula III in an organic solvent and to this solution 60% of reducing agent is added.
The reduction of the novel ketone compound of formula is carried out by dissolving keto compound of formula IU in an organic solvent selected from dimethyl sulfoxide, N,N dimethylforrnamide, tetrahydrofuran, methyltetrahydrofuran or mixtures thereof. Preferably tetrahydrofuran.
Reducing agents used in the above step-II is selected from CBS, (-)-[beta]-chlorodiisopinocampheylborane and mixtures thereof. Preferably (-)-[beta]-chlorodiisopinocampheylborane is used.
The reaction is performed at a temperature between -20[deg.] C and 10[deg.] C, preferably at about -25[deg.] C and -30[deg.] C. The amount of reducing agent used is

between 1 and 4 moles per mole of 6; the excess of borane is then removed by quick filtration on silica gel. Purification by column chromatography is performed in order to remove all the inorganic impurities and the by-products. Thus a novel intermediate compound of formula II is obtained.
Step-III
j—J Step-III j—i
OTBDPS OH ^H OH
Formula-ll Formula-'
The removal of the protecting group TBDPS- from novel intermediate compound of formula II is then performed by reaction of tetra-butylammonium fluoride in an organic solvent at a temperature between 20[deg.]C and 35[deg.]C, more preferably between 25[deg.]C and 30[deg.]C. The yield of the desired compound of formula 1 is about 90%.
Organic solvent used in step-Ill is selected from dimethyl sulfoxide, N,N dimethylformamide, tetrahydrofuran, methyltetrahydrofuran or a mixtures thereof, more preferably tetrahydrofuran.
Experiment 1:
(3aR,4R,5R,6aS)-5-(tert-butyldiphenylsUyloxy)-4-((E)-3-oxo-l-octenyl) hexahydro-2H-cyclopenta[b]furan-2-one (Formula III)
Dimethyl 2-oxo-4-methylbutylphosphonate (98.2 g, 0.441 mol) was added to the four necked round bottom flask; the dimethyl 2-oxo-4-methylbutylphosphonate is charged with MTBE (1639 mL) and stirred for 5 minutes, and LiOH.H20 (18.3 g, 0.437 mol) was added to the reaction mass under inert atmosphere and the mixture was stirred for 4 to 5 h

at a temperature between 25[deg.]C to 30[deg.]C. The mixture was cooled to 0-5[deg.]C for 30 minutes; White color solids was observed. Subsequently a solution of (3aR,4R,5R,6aS)-5-(tert-butyldiphenylsilyloxy)-2-oxohexahydro-2H-cyclopenta[b] furan-4-carbaldehyde (formula TV) (163.9 g, 0.401 mol) in MTBE (1639 mL) was added drop wise to reaction mass for 1 hr at 0[deg.]C to 5[deg.]C and stirred . The temperature of the reaction mass was further increased for 20 mns by continuously stirring at 25 to 30 [deg.]C and the reaction was checked by TLC analysis.
The reaction was settled for 5 mns, and after separation of the layers the aqueous one was extracted with two times using MTBE (819.5 mL) and the combined organic layers were washed with brine (410 mL). Organic layer was dried for 10 mns with sodium sulphate, later it was washed with MTBE (1639 mL). The organic layer was transferred and distilled under vacuum at below 40 [deg.]C to afford pale yellow liquid of titled compound of formula III which was used in further reaction without the need of any purification. [Yield: 97.15%]
(3aR,4R,5R,6aS)-5-(tert-butyldiphenylsilyloxy)-4-((E)-3-hydroxy-l-octenyl) hexahydro -2H -cyclopenta[b]furan-2-one (Formula II)
(3aR,4R,5R,6aS)-5-(tert-butyldiphenylsilyloxy)-4-((E)-3-oxo-l-octenyl) hexahydro-2H-cyclopenta[b]furan-2-one (Formula III) (197.0 g, 0.390 mol) was dissolved in tetrahydrofuran (1.57 L) under inert atmosphere and cooled to -25[deg.]C to -30[deg.]C. A 55% of (-)-[beta]-chlorodiisopinocampheylborane in heptane (569.0g in 900 mL, 0.975 mol) was added dropwise to reaction mass for 15-20 mns at 25[deg.]C to -30[deg.]C and stirred for 2 hrs. The temperature of the reaction mass was raised to 25[deg.]C to 30[deg.]C and stirred for further 16 hrs, and the reaction was checked by TLC analysis. THF was removed completely from reaction mass under vacuum below 40 [deg.]C once the reaction was completed; the reaction mass was cooled to 25[deg.]C to 30[deg.]C. The two layers were separated and the aqueous layer was extracted two times with ethyl acetate (2x 985 mL). The combined organic layers were washed with water (985.0 mL) and organic layer was washed with brine (985 mL). Organic layer was transferred and

distilled under vacuum at below 40[deg.]C affording 690.0 g of pale yellow oil. The reaction mass was cooled at 25[deg.]C to 30[deg.]C and DCM (400 mL) was added and mixed well. Purification on silica gel was performed and DCM was removed.
A column chromatographic purification on silica gel (eluted with diisopropyl ether) was performed and checked the TLC; secondly the column is eluted with ethyl acetate and TLC was checked affording 200 g of crude material after first column purification.
The crude material from first column purification was taken and DCM (100 mL) was added and mixed well. Purification on silica gel was performed and DCM was removed.
A column chromatographic purification on silica gel (eluted with 5.0 L to 5% of ethylacetate and hexane medium, gradually increasing the % of ethylacetate and hexane medium) was performed and checked the TLC affording 110.0 g of titled compound of formula II in pale yellow syrup. [Yield: 55.62 %, Purity by HPLC: 97.26%].
(3aR,4R,5R,6aS)-4-((S,E)-3-hydroxy-l-octenyl-5-hydroxy)hexahydro-2H-cyclopenta [b] furan-2,5-dione
(3aR,4R,5R,6aS)-5-(tert-butyldiphenylsilyloxy)-4-((E)-3-hydroxy-1 -octenyl) hexahydro -2H -cyclopenta[b]furan-2-one (Formula II) (110 g, obtained above) was dissolved in tetrahydrofuran (550 ml) and stirred the solution for 5 minutes at 25-30[deg.]C under inert atmosphere, the reaction mass was cooled to 0-5[deg.]C and stirred for another 5 mns. The solution was followed by the addition of TBAF.3H2O (91.6 mL) for 3 mns at 0-5[deg.]C . The temperature of the reaction mixture was raised to 25-35[deg.]C and then stirred for 16 hours, and the reaction was checked by TLC analysis. THF was removed completely from reaction mass under vacuum below 40 [deg.]C once the reaction was completed; the reaction mass was cooled to 25[deg.]C to 30[deg.]C, 10% citric acid solution was added followed by DCM (550 mL) and stirred for 10 mns.. The two layers were separated and the aqueous layer was extracted two times with DCM (550 ml & 330 mL). The combined organic layers were washed 3 times with brine (550 mL, 2 x 330

mL). Organic layer was transferred and distilled under vacuum at below 40[deg.]C affording 130.0 g of crude compound of formula I as honey color. The reaction mass was cooled at 25[deg.]C to 30[deg.]C and DCM (200 mL) was added and mixed well. Purification on silica gel was performed and DCM was removed.
A column chromatographic purification on silica gel (eluted with 5.0 L of 10% acetone/ hexane medium, gradually increasing the % of acetone/ hexane medium) was performed and checked the TLC affording 60 g crude material of titled compound as honey color syrup after first column purification.
The crude material from first column purification was taken and DCM (100 mL) was added and mixed well. Purification on silica gel was performed and DCM was removed.
A column chromatographic purification on silica gel (eluted with 5.0 L to 5% of ethylacetate and hexane medium, gradually increasing the % of ethylacetate and hexane medium) was performed and checked the TLC affording 55.0 g of crude compound of formula I as pale yellow syrup.
The crude material from second column purification was taken and DCM (100 mL) was added and mixed well. Purification on silica gel was performed and DCM was removed.
A column chromatographic purification on silica gel ( first eluted with 5.0 L of DCM, secondly eluted 10.0 L of 1% methanol/DCM medium with gradually increasing the % of methanol/DCM medium) was performed and checked the TLC affording 50.0 g of titled compound of formula I (Corey lactone PG diol) as pale yellow color syrup. [Yield: 85.8 %, Purity by HPLC: 95.48%].