Field of the Invention:

The present invention provides a novel intermediates for the preparation of (lR,2RJ3aS,9aS)-[[2,3,3a,4,9,9a-Hexahydro-2-hydroxy-l-[(3S)-3-hydroxyoctyl]-lH-benz[fj inden-5-yl]oxy]acetic acid represented by structural formula-1 and also its pharmaceutically acceptable salts, preferably sodium salt represented by structural formula-la.

(lR,2R,3aS,9aS)-[[2,3,3a,4,9,9a-Hexahydro-2-hydroxy-l-[(3S)-3-hydroxyoctyl]-lH-benzffj inden-5-yfjoxy]acetic acid is commonly known as "Treprostinil". Treprostinil is a synthetic analog of prostacyclin (PGI2) and is marketed under the trade names Remodulin for infusion and Tyvaso for inhalation by united therapeutics corporation.

(+)-Treprostinil is an active ingredient of Remodulin, a commercial drug approved by FDA for the treatment of pulmonary arterial hypertension (PAH). Treprostinil is a stable analog of prostacyclins, which are useful pharmaceutical compounds possessing activities such as platelet aggregation inhibition, gastric secretion, lesion inhibition and bronchodilation.

Background of the Invention:

Treprostinil and its sodium salt were first described in US4306075. Several synthetic processes for treprostinil and its sodium salt were disclosed in the prior art like US6765117, US 6700025, US 6809223, WO2012009816 and Journal of organic chemistry, 2004, 69, 1890-1902. The reported processes for the preparation of Treprostinil utilize different protecting groups like methyl, benzyl, p-methoxy benzyl for protecting the hydroxy group present on phenyl ring of 2-allyl-3-hydroxy-benzaldehyde during synthesis. The different protecting groups need different reagents to deprotect them, some of them utilize costly, hazardous and difficult to handle. For example, reagents like triphenyl phosphine/n-BuLi which are utilized for deprotecting the methyl protecting group are not useful for commercial scale synthesis. The use of these reagents for deprotection makes the process expensive.

Furthermore, the prior art processes involve column chromatographic purification at each stage of the synthesis, which makes the process tedious.

Therefore, there is a still need in the art to provide an economical process for producing Treprostinil by utilizing different protecting group, which requires simple, cheaper reagents to deprotect them.

Accordingly, in the present invention "silyl group" is used for protecting the hydroxy group which is present on phenyl ring of 2-allyl-3-hydroxy-benzaldehyde, a key starting material to synthesize Treprostinil. The silyl protecting group is removed by utilizing simple reagents. Further, the process of the present invention avoid column purification in many of the stages.

Brief description of the invention:

The first aspect of the present invention is to provide a process for the preparation of tricyclic enone compound of general formula-8, which is a novel intermediate in the synthesis of Treprostinil.

The second aspect of the present invention is to provide a novel process for the preparation of Treprostinil compound of formula-1 and its pharmaceutically acceptable salts.

The third aspect of the present invention is to provide novel compounds which are useful intermediates in the synthesis of prostacyclins such as Treprostinil.

Brief description of the drawings:

Figure-1: Illustrates the DSC thermogram of Treprostinil obtained according to the process disclosed in US4668814.

Figure-2:. Illustrates the powder X-ray diffractogram of Treprostinil obtained according to the process disclosed in US4668814.

Figure-3: Illustrates the DSC thermogram of Treprostinil obtained according to the process disclosed in J. Org. Chem.2004, 69, 1890-1902.

Figure-4: Illustrates the powder X-ray diffractogram of Treprostinil obtained according to theprocess disclosed in J. Org. Chem.2004, 69, 1890-1902.

Detailed description of the Invention:

The term "suitable solvent" used in the present invention is selected from, but not limited to "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; "ether solvents" such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether and the like; "hydrocarbon solvents" such as toluene, hexane, heptane, petether, benzene, xylene, cyclohexane and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide, N-methyl-2-pyrrolidone and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like; "chloro solvents" such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like; "nitrile solvents" such as acetonitrile, butyronitrile, isobutyronitrile and the like; polar solvents such as water; and also mixtures thereof.

The term "suitable base" used in the present invention is selected from inorganic bases like"alkali metal hydroxides" such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydrides" such as sodium hydride, lithium hydride and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia; and organic bases such as triethyl amine, isopropyl amine, diisopropyl amine, diisopropylethylamine, N-methylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine; and "organolithium bases" such as methyl lithium, n-butyl lithium, lithium diisopropylamide (LDA) and the like or mixtures thereof.

In the present invention, the term "alkyl" refers to straight or branched chain hydrocarbyl groups having from 1 to about 20 carbon atoms. For instance, CM alkyl is an alkyl group having 1 to 4 carbon atoms. Exemplary alkyl includes methyl, ethyl, propyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.
In the present invention, the term "aryl" refers to substituted or unsubstituted aromatic hydrocarbon having from 6 to 20 carbon atoms. Exemplary aryl includes, phenyl and naphthalene. The aryl may be substituted with one or more substituents selected from halogen, alkoxy, alkyl, aryl and nitro.

The term "hydroxy protecting group" used herein the present invention is selected from, but not limited to "substituted or unsubstituted arylcarbonyl" such as benzoyl, p-methoxy benzoyl, p-phenyl benzoyl and the like; "branched or unbranched alkyl and alkenyl" such as tertiary butyl, allyl and the like; "substituted or unsubstituted acyl" such as acetyl, chloro acetyl, dichloro acetyl, trichloro acetyl, trifluoro acetyl, pivaloyl and the like; "substituted or unsubstituted arylalkyl" such as p-methoxy benzyl, p-nitrobenzyl, benzyl, p-bromo benzyl and the like; "(alkyl)m (aryl)3.m silyl" wherein, 'm' represents 0, 1, 2 and 3, such as trimethyl silyl, triethyl silyl, triisoporpyl silyl, tributyl silyl, dimethylisopropyl silyl, diisopropyl silyl, tert-butyldimethyl silyl, tert-butyl diphenyl silyl and the like; "alkoxyalkyl" such as methoxymethyl, 2-methoxyethoxymethyl and the like; "aryloxy alkyl" such as benzyloxymethyl and the like; "substituted or unsubstituted tetrahydro-2H-pyran-2-yl"; "substituted or unsubstituted trityl" such as trityl, 4-methyltrityl and the like; "alkyl sulfonyl" such as methane sulfonyl, ethane sulfonyl and the like; "substituted or unsubstituted aryl sulfonyl" such as tosyl, nosyl and the like; protecting groups of the formula "-CO-O-Ri" wherein Ri represents CM alkyl or aryl or arylalkyl such as methoxy carbonyl, ethoxy carbonyl, benzyloxy carbonyl, 9-(fluorenylmethyloxy)carbonyl, tertiary butyloxy carbonyl and the like;

The "suitable protecting agent" is selected such that it is capable of protecting the oxygen atom with any of the above mentioned hydroxy protecting groups.

The term "substituted" herein the present invention wherever necessary, refers to the compound substituted by the one or more substituents selected from halogen, alkyl, alkoxy, aryl and nitro.

The "suitable deprotecting agent" is selected from "acids" such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, acetic acid, trifluoro acetic acid, formic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, toluene sulfonic acid, pyridinium p-toluene sulfonic acid etc; and "hydrogen fluoride (HF) sources" such as ammonium fluoride, tertabutyl ammonium fluoride, pyridine-HF, Et3N-3HF, Zn/acetic acid, DDQ; "base" such as alkali metal carbonate and alkali metal hydroxides, sodium in liquid ammonia, organic base etc; metal catalysts in presence of hydrogen source.
The first aspect of the present invention provides a process for the preparation of tricyclic enone compound of general formula-8,
wherein, Ri, R2 and R3 are same or different, each independently selected from hydrogen, straight or branched chain alkyl and substituted or unsubstituted aryl, with a proviso that Ri=R2=R3^Hydrogen; Pi and P2 both are same or different, each independently selected from hydroxy protecting groups, comprising of: a) Reacting compound of general formula-2

wherein, Ri, R2 and R3 are same as defined above, with alkyne compound of general formula-3 wherein, Pi is hydroxy protecting group,

in presence of alkyl magnesium halide in a suitable solvent or a mixture of solvents to provide benzyl alkynol compound of general formula-4,

wherein, Rj, R2 and R3 are same as defined above; and Pi is hydroxy protecting group, b) oxidizing the compound of general formula-4 with a suitable oxidizing agent in a suitable solvent to provide benzyl alkynone compound of general formula-5,

wherein, Ri, R2 and R3 are same as defined above; and Pi is hydroxy protecting group, c) reducing the keto group of general formula-5 with a chiral reducing agent in a suitable solvent to provide chiral benzyl alkynol compound of general formula-6,

wherein, Ri, R2 and R3 are same as defined above; and Pi is hydroxy protecting group, d) protecting the hydroxy group of general formula-6 with a suitable protecting agent, optionally in presence of a base in a suitable solvent to provide its corresponding O-protected compound of general formula-7,

wherein, Rl5 R2 and R3 are same as defined above; and Pj and P2 both are same or different, each independently selected from hydroxy protecting groups,

e) reacting the compound of general formula-7 with octacarbonyl dicobalt in a suitable solvent or a mixture of solvents to provide tricyclic enone compound of general formula-8. Wherein,

In step-a) "alkyl magnesium halide" is selected from methyl magnesium bromide, ethyl magnesium bromide, methyl magnesium chloride and ethyl magnesium chloride;
In step-b) the "suitable oxidizing agent" is selected from pyridinium chlorochromate, potassium dichromate/sulfuric acid, chromium trioxide/ aqueous sulfuric acid, lead tetra acetate, pyridinium dichromate, CrCVpyridine/dichloroniethane, aluminium triisopropoxide in acetone, trichloroisocyanuric acid in presence of TEMPO, Oxalyl chloride in combination with dimethylsulfoxide and a suitable base; manganese dioxide; quaternary ammonium salt/TEMPO/oxone, N-chloro succinamide in combination with dimethylsulfide and a suitable base, sodium hypochlorite, potassium hypo chlorite, Dess-Martin periodinane; per acids such as peracetic acid, perbenzoic acid and the like;

In step-c) "chiral reducing agent" is selected from Borane-DMS, Borane-THF and Borane-diethylaniline in presence of catalysts like (R)-2-Methyl-CBS-oxazaborolidine, (i?)-2-phenyl-CBS-oxazaborolidine and (J2)-2-butyl-CBS-oxazaborolidine; 9-BBN in combination with a-pinene; diisopinocamphenylborane; and B-chlorodiisopinocamphenylborane (herein after referred as DIP chloride). In step-d) "protecting agent" is same as defined above;

In step-a) to step-e) the suitable solvent is selected from ether solvents, ester solvents, chloro solvents, alcoholic solvents, nitrile solvents, ketone solvents, hydrocarbon solvents, polar aprotic solvents and also mixtures thereof.

A preferred embodiment of the present invention provides a novel process for the preparation of (4R)-4,8-bis(tert-butyldimethylsilyloxy)-3-((3R)-3-(tetrahydro-2H-pyran-2-yloxy) octyl)-9,9a-dihydro-lH-cyclopenta[b]naphthalen-2(4H)-one compound of formula-8a, comprising of:

a) Reacting 2-allyl-3-(tert-butyldimethylsilyloxy)benzaldehyde compound of formula-2a with 2-((S)-dec-l-yn-5-yloxy)tetrahydro-2H-pyran compound of formula-3a in presence of ethyl magnesium bromide in tetrahydrofuran provides (6R)-l-(2-allyl-3-(tert-butyldimethyl silyloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-yn-1 -ol compound of formula-4a,

b) oxidizing the compound of formula-4a with manganese dioxide in toluene provides (6R)-1 -(2-allyl-3 -(tert-butyldimethylsilyloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-yn-l-one compound of formula-5a,

c) reducing the keto group compound of formula-5a with Borane-DMS in presence of catalyst such as (i?)-2-Methyl-CBS-oxazaborolidine in tetrahydrofuran provides (lS,6S)-l-(2-allyl-3-(tert-butyldimethylsilyloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-yn-l-ol compound of formula-6a,
d) protecting the hydroxy group of formula-6a with tert-butyldimethyl silyl chloride in presence of imidazole in dichloromethane provides (2-allyl-3-((lS,6S)-l-(tert-butyldimethyl silyloxy)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-ynyl)phenoxy)(tert-butyl) dimethylsilane compound of formula-7a,

e) reacting the compound of formula-7a with octacarbonyl dicobalt in a mixture of

acetonitrile and dichloromethane to provide compound of formula-8a. The process of the present invention can be represented schematically as follows: Scheme-I:

The second aspect of the present invention provides a novel process for the preparation of Treprostinil compound of formula-1, or its pharmaceutically acceptable salts comprising of:

a) Hydrogenating the tricyclic enone compound of general formula-8 with a suitable metal catalyst in presence of a base under hydrogen pressure in a suitable solvent or mixture of solvents to provide tricyclic ketone compound of general formula-9

Wherein, G is hydrogen (or) Pi; Ri, R2 and R3 are same or different, each independently selected from hydrogen, straight or branched chain alkyl and substituted or unsubstituted aryl, proviso that Ri=R2=R3^Hydrogen;

b) treating the compound of general formula-9 with a suitable base in a suitable solvent, followed by reducing the obtained compound with a suitable reducing agent, optionally treating the obtained compound with a suitable deprotecting agent(s) to provide tricyclic triol compound of formula-10,

c) reacting the compound of formula-10 with alkyl a-halo acetate represented by the structural formula Wherein, 'X' represents halogen such as chloro, bromo and iodo; 'R' represents CM alkyl;
in presence of a suitable base in a suitable solvent to provide Treprostinil alkyl ester compound of general formula-11,

d) hydrolyzing the compound of general formula-11 in presence of an aqueous base in a suitable solvent to provide Treprostinil compound of formula-1,
e) optionally, converting the compound of formula-1 into it's pharmaceutically acceptable salts.
Wherein,

In step-a) the "suitable base" is inorganic base or organic base; the suitable metal catalyst is selected from Pd, Pt, Ru, Pd/C, Pt/C, Ru/C, Rh/C, palladium hydroxide, palladium acetate, palladium chloride, palladium on oxide, palladium catalyzed with calcium carbonate, platinum oxide, nickel, Raney nickel, rhodium on alumina, chlorotris(triphenyl phosphine)rhodium(I);

In step-b) the "suitable base" is selected from inorganic bases such as alkali metal hydroxide; the "suitable reducing agent" is selected from sodium borohydride, lithium borohydride, lithium aluminium hydride, sodium aluminium hydride, sodium cyanoborohydride, potassium (trialkoxy)borohydride, sodium (trialkoxy) borohydride, diisobutyl aluminium hydride and vitride;
In step-c) the "suitable base" is selected from inorganic and organic base; and In step-d) the "suitable base" is inorganic base.

In step-a) to step-d) the suitable solvent is selected from ether solvents, ester solvents, chloro solvents, alcoholic solvents, nitrile solvents, ketone solvents, hydrocarbon solvents, polar aprotic solvents and also mixtures thereof.

A preferred embodiment of the present invention provides a novel process for the preparation of Treprostinil compound of formula-1, comprising of:

a) Hydrogenating the compound of formula-8a with Pd-C in presence of a aqueous potassium carbonate in ethanol to provide compound of formula-9a,

b) treating the compound of formula-9a with sodium hydroxide in ethanol, followed by reducing the obtained compound with sodium borohydride; further treating the obtained compound with hydrochloric acid to provide tricyclic triol compound of formula-10,

c) reacting the compound of formula-10 with a-bromo ethyl acetate in presence of potassium carbonate in acetone provides Treprostinil ethyl ester compound of formula-lla,
d) hydro lyzing the compound of formula-lla in presence of an aqueous sodium hydroxide in methanol provides Treprostinil.

Further, this process is represented schematically as follows: Scheme-H:

Further, the compound of formula-10 can also be prepared by deprotecting the compound of formula-8 with a suitable deprotecting agent in a suitable solvent, followed by hydrogenation with a suitable catalyst in presence of a base in a suitable solvent or mixture of solvents and then reducing the obtained compound with a suitable reducing agent in a suitable solvent provides compound of formula-10.

The "Treprostinil" obtained by the present invention is converted into its pharmaceutically acceptable salts, by treating the Treporstinil with a base selected from inorganic bases such as hydroxides, carbonates and bicarbonates of alkali, alkaline earth metal and other metals; quaternary ammonium hydroxide; and organic base such as primary amine, secondary amine and tertiary amine in a suitable solvent.

Preferably, the "Treprostinil" obtained by the present invention is converted into its sodium salt by treating the Treprostinil with sodium hydroxide in acetone. Similarly, the Treprostinil is treated with diethanolamine in acetone provides its diethanolamine salt of Treprostinil.

The present inventors have in-toto repeated the process for the preparation of Treprostinil disclosed in US4668814 & J. Org. Chem.2004, 69, 1890-1902 and the obtained compound was characterized by PXRD & DSC which were depicted in figures 1 to 4.

The third aspect of the present invention provides novel compounds, which are useful intermediates in the synthesis of prostacyclins such as Treprostinil.

These novel compounds are represented by the following structural formulae: and isomers thereof, wherein, Rj, R.2 and R3 are same or different and independently selected from hydrogen, straight or branched chain alkyl and substituted or unsubstituted aryl, with a proviso that Ri=R2=R3 # Hydrogen; Pi and P2 both are same or different, each independently selected from hydroxy protecting groups;
The present invention provides novel compounds, preferably selected from the above compounds in which Rj represents tert-butyl; R2 and R3 represent methyl; Pi represents THP, P2 represents TBDMS and G represents THP.

The compound of formula-2a, a starting material of the present invention can be prepared by protecting the 2-allyl-3-hydroxybenzaldehyde with corresponding tert-butyldimethylsilyl chloride in presence of a base in a suitable solvent.

The PXRD analysis of the crystalline compounds of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10°C per minute.

The following abbreviations are used throughout the specification: TBDMS: tertiary butyl dimethyl silyl; THP: tetrahydropyran-2-yl; Cr03: chromium trioxide; TBAF: tertiary butyl ammonium fluoride; TEMPO: 2,2,6,6-Tetramethylpiperidinyloxy; PTSA: p-toluene sulfonic acid; TMS: trimethylsilyl; DMS: dimethyl sulfide; THF: tetrahydrofuran;

The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:

Example-1: Preparation of (6R)-l-(2-allyl-3-(tert-butyIdimethylsilyloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-yn-l-ol (Formula-4a)

A mixture of 2-allyl-3 -(tert-butyl dimethylsilyloxy)benzaIdehydecompoudn of formula-2a (6.3 gm) and tetrahydrofuran (70 ml) was heated to 60-65°C. 3M solution of ethyl magnesium bromide in diethyl ether (11.8 ml) was slowly added to the reaction mixture at 60-65°C under nitrogen atmosphere and stirred for 90 min at the same temperature. Cooled the reaction mixture to 0-5°C. A solution of 2-((S)-dec-l-yn-5-yloxy)tetrahydro-2H-pyran compound of formula-3a (7 gm) in tetrahydrofuran (14 ml was added to the reaction mixture at 0-5°C and stirred for 90 min at the same temperature. Quenched the reaction mixture with cold ammonium chloride solution and ethyl acetate was added. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and dried over sodium sulfate. Distilled off the solvent completely form the organic layer. The obtained compound was purified by column chromatography using petroleum ether and ethyl acetate as eluent. Distilled off the solvent completely from the pure fractions under reduced pressure to get the title compound. Yield: 13.5 gm. Example-2: Preparation of (6R)-l-(2-aIIyI-3-(tert-butyIdimethyIsiIyIoxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-yn-l-one (FormuIa-5a) Manganese dioxide (20.6 gm) was added to a mixture of (6R)-l-(2-allyl-3-(tert-butyldimethyl silyloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-yn-1 -ol compound of formula-4a (8.6 gm) and toluene (86 ml) at 25-30°C and stirred the reaction mixture for 10 hrs at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with toluene. Distilled off the solvent completely from the filtrate to get the title compound.Yield: 8.6 gm.

Example-3: Preparation of (lS,6S)-l-(2-allyl-3-(tert-butyldimethylsilyloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-yn-l-ol (Formula-6a)

(R)-2-Methyl-CBS-oxazaborolidine (33 ml) was added to a mixture of (6R)-l-(2-allyl-3-(tert-butyldimethylsilyloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-yn-l-one compound of formula-5a (17 gm) and tetrahydrofuran (170 ml) at 25-30°C under nitrogen atmosphere. Cooled the reaction mixture to -20°C to -25°C. Borane-dimethylsulfide (6.7 ml) was slowly added to the reaction mixture at -20°C to -25 °C and stirred for 90 min at the same temperature. Quenched the reaction mixture slowly with methanol. Aqueous ammonium chloride solution was added to the reaction mixture at 10-15°C. Extracted the reaction mixture with ethyl acetate and dried over sodium sulfate. Distilled off the solvent completely from the reaction mixture under reduced pressure. The obtained compound was purified by column chromatography using ethyl acetate and petroleum ether as eluent. Distilled off the solvent completely from the pure fractions under reduced pressure to get the title compound. Yield: 13.5 gm.

Example-4: Preparation of (2-allyl-3-((lR,6S)-l-(tert-butyldimethylsilyloxy)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-ynyl)phenoxy)(tert-butyl)dimethylsilane
(Formula-7a)

Imidazole (2.4 gm) was added to a pre-cooled mixture of (lS,6S)-l-(2-allyl-3-(tert-butyldimethylsilyloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-yn-1 -ol compound of formula-6a (12.4 gm) and dichioromethane (125 ml) at 0-5°C and stirred for 10 min at the same temperature. Tert-butyldimethylsilyl chloride (5 gm) was slowly added to the reaction mixture at 0-5°C and stirred for 5 hrs at the same temperature. Water and ethyl acetate were added to the reaction mixture and stirred for 5 min. Both the organic and aqueous layers were separated and dried the organic layer over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure. The obtained compound was purified by column chromatography using petroleum ether and ethyl acetate as eluent. Distilled off the solvent completely form the pure fractions under reduced pressure to get the title compound.Yield: 15.0 gm.

Example-5: Preparation of (4R)-4,8-bis(tert-butyldimethylsilyloxy)-3-((3R)-3-(tetrahydro-2H-pyran-2-yloxy)octyl)-9,9a-dihydro-lH-cyclopenta[b]naphthalen-2(4H)-one (FormuIa-8a) Octacarbonyl dicobalt (8.5 gm) was added to a solution of (2-allyl-3-((lR,6S)-l-(tert-butyldimethylsilyloxy)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-ynyl)phenoxy)(tert-butyl) dimethylsilane compound of formula-7a (15 gm) in dichioromethane (150 ml) at 25-30°C under nitrogen atmosphere and stirred for 90 min at the same temperature. Distilled off dichioromethane completely from the reaction mixture under reduced pressure. Acetonitrile was added to the reaction mixture. Slowly heated the reaction mixture to reflux temperature and stirred for 2 hrs at the same temperature. 80% of acetonitrile was distilled off from the reaction mixture under reduced pressure. Cooled the reaction mixture to 25-30°C and aqueous ammonium chloride solution was added. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous ammonium chloride solution. Air was bubbled into the organic layer for 3-4 hrs. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with ethyl acetate. Dried the filtrate over sodium sulfate and distilled off the solvent completely
under reduced pressure to get the title compound. Yield: 10.3 gm.

ExampIe-6: Preparation of (1R, 2R, 3aS, 9aS)-l-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-

hexahydro-lH-cydopenta[b]napthaIene-2,5-diol Aqueous potassium carbonate solution (2.5 gm) was added to a mixture of (4S,9aS)-4-(tert-butyldimethylsilyloxy)-8-hydroxy-3-((3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl)-9,9a-dihydro-lH-cyclopenta[b]naphthalene-2(4H)-one (50 gm) and ethanol (400 ml) at 25-30°C into autoclave. Palladium carbon (10 gm) was added to the reaction mixture at 25-30°C. 5-7 kg hydrogen pressure was applied to the reaction mixture at 30-35°C and stirred for 5 hrs at the same temperature. Filtered the reaction mixture through hyflo bed and washed the bed with ethanol. The filtrate was cooled to -12°C. Sodium hydroxide (36.84 gm) in water was cooled to 10°C. Sodium borohydride (10.49 gm) was added to the aqueous sodium hydroxide solution and stirred for 15 minutes at the same temperature. The above filtrate was added to the reaction mixture at -12°C and stirred for 60 minutes at the same temperature. Raised the temperature of the reaction mixture to 5°C. Further raised the reaction mixture temperature to 30-35°C. Distilled off the solvent completely from the reaction mixture under reduced pressure. Ethyl acetate was added to the reaction mixture at 30-35°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers werseparated. The aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed the organic layer with water. Distilled off the solvent completely from the organic layer under reduced pressure. Hydrochloric acid (500 ml) and water (500 ml) was added to the obtained crude compound at 25-30°C and stirred for 90 minutes at the same temperature. Ethyl acetate was added to the reaction mass at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Distilled off the solvent from organic layer completely under reduced pressure to get the title compound. Yield: 22.5 gm Example-7: Preparation of ethyl-2-((lR,2R,3aS,9aS)-2-hydroxy-l-((S)-3-hydroxyoctyl)-2,3,3a?4,9,9a,-hexahydro-lH-cyclopenta[b]naphthalen-5-yloxy)acetate Potassium carbonate (14.7 gm) was added to a mixture of (1R, 2R, 3aS, 9aS)-l-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-lH-cyclopenta[b]napthalene-2,5-diol (11.8 gm) and acetone (118 ml) at 25-30°C. Bromoethyl acetate (8.89 ml) and tetrabutyl ammonium bromide (0.57 gm) were added to the reaction mixture at 30-35°C. Heated the reaction mixture to 53-58°C and stirred for 5 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hyflo bed and washed with acetone. Distilled off the solvent from the filtrate completely under reduced pressure. Ethyl acetate and water was added to the reaction mass and stirred for 15 minutes. Both the organic and aqueous layers were separated. The aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with water followed by aqueous sodium bicarbonate solution.

Distilled off the solvent from the organic layer completely under reduced pressure to get the title compound. Yield: 13.5 gm

ExampIe-8: Preparation of 2-((lR,2R,3aS,9aS)-2-hydroxy-l-((S)-3-hydroxyoctyl)-
2,3?3a54,9,9a,-hexahydro-lH-cyclopenta[b]naphthalen-5-yloxy)acetic acid
A mixture of ethyl-2-((lR,2R,3aS,9aS)-2-hydroxy-l-((S)-3-hydroxyoctyl)-
2,3,3a,4,9,9a,-hexahydro-lH-cyclopenta[b]naphthalen-5-yloxy)acetate (30 gm) and methanol
(300 ml) was cooled to 0-5°C. Aqueous sodium hydroxide solution (6.3 gm of sodium
hydroxide in 32 ml of water) was added to the reaction mixture at 0-5°C. Raised the
temperature of the reaction mixture to 25-30°C and stirred for 2.5 hrs at same temperature.
Distilled off the solvent from the reaction mixture under reduced pressure. Water and ethyl
acetate was added to the reaction mixture and stirred at 25-30°C for 20 minutes. Both the organic and aqueous layers were separated. The aqueous layer was cooled to 5-10°C. Acidify the aqueous layer by adding dil HC1 at 5-10°C and stirred for 3 hrs at the same temperature.

The solid formed was filtered, washed with water and dried. Yield: 25 gm

Example-9: Purification of 2-((lR,2R,3aS,9aS)-2-hydroxy-l-((S)-3-hydroxyoctyl)-2,3?3a>4,9,9a,-hexahydro-lH-cyclopenta[b]naphthalen-5-yloxy)acetic acj(j 2-((lR,2R,3aS,9aS)-2-hydroxy-l-((S)-3-hydroxyoctyl)-2,3)3a,4,9)9a,-hexahydro-lH-cyclopenta[b]naphthalen-5-yloxy)acetic acid (30 gm) was dissolved in a mixture of acetonitrile (180 ml) and water (120 ml) at 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 2 hrs at the same temperature. The precipitated solid was filtered, washed with the mixture of acetonitrile and water and dried to get the title compound. Yield: 22 gm.

Example-10: Purification of 2-((lR,2R,3aS,9aS)-2-hydroxy-l-((S)-3-hydroxyoctyI)-2,3,3a,4,9,9a,-hexahydro-lH-cyclopenta[b]naphthalen-5-yIoxy)acetic acid

The above example-9 is repeated with tetrahydrofuran (150 ml) and hexane (450 ml) provides the title compound as a solid. . Yield: 23.5 gm. M.R: 122-124°C

The PXRD of the obtained compound is similar to figure-2 and its DSC thermogram is similar to figure-1.

Example-11: Preparation of (l(lR,2R,3aS,9aS)-[[2,3,3a,4,9,9a,-hexahydro-2-hydroxy-l-[(3S)-3-hydroxyoctyl]-lH-benz[f]inden-5-yl]oxy]acetic acid monosodium salt Sodium hydroxide solution (5.94 gm of sodium hydroxide dissolved in 29.7 ml of water) was added to a mixture of 2-((lR,2R,3aS,9aS)-2-hydroxy- l-((S)-3 -hydroxyoctyl)-2,3,3a,4,9,9a,-hexahydro-lH-cyclopenta[b]naphfhalen-5-yloxy)acetic acid (50 gm) and acetone (1.25 L) at 25-30°C. The reaction mixture was seeded with (l(lR,2R,3aS,9aS)-[[2,3,3a,4,9,9a,-hexahydro-2-hydroxy-l-[(3S)-3-hydroxyoctyl]-lH-benz[fJinden-5-yl]oxy] acetic acid monosodium salt (50 mg) at 25-30°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 3 hrs at the same temperature. The precipitated solid was filtered, washed with acetone and dried to get the title compound. Yield: 48 gm Example-12: Preparation of Treprostinil Diethanolamine Diethanolamine (25.12 gm) dissolved in water (25.12 ml) was added to the mixture of 2-((lR,2R,3aS,9aS)-2-hydroxy-l-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a,-hexahydro-lH-cyclopenta[b] naphthalen-5-yloxy)acetic acid (89 gm) and acetone (2.25 lit) at 25-30°C. The reaction mixture was seeded with Treprostinil Diethanolamine (100 mg) at 25-30°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 90 minutes at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 89 gm.

PXRD of the obtained compound is matches with PXRD of crystalline form-A disclosed in US7417070 B2. Example-13: Preparation of Treprostinil Diethanolamine Form-A Diethanolamine (25.12 gm) dissolved in water (25.12 ml) was added to the mixture of 2-((lR,2R,3aS,9aS)-2-hydroxy-l-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a,-hexahydro-lH- cyclopenta[b] naphthalen-5-yloxy)acetic acid (89 gm) and acetone (2.25 lit) at 25-30°C and stirred for 15 minutes. Cooled the reaction mixture to 0-5°C and stirred for 90 minutes at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 89 gm. Example-14: Preparation of Treprostinil Diethanolamine Form-B Acetone (1.78 lit) was added to Treprostinil diethanolamine (89 gm) and heated to reflux temperature. Ethanol (3 ml) was added to the reaction mixture at the same temperature and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered, washed with acetone and dried to get the title compound. Yield: 89 gm. Example-14: Preparation of (6R)-l-(2-aIIyI-3-(tert-butyIdimethyIsiIyIoxy)phenyI)-6-(tetrahydro-2H-pyran-2-y!oxy)undec-2-yn-l-oI (Formula-4a) A mixture of compound of formula-2a (120.7 gm) and tetrahydrofuran (300 ml) was cooled to 0-5°C. 1.72M solution of n-butyllithium was slowly added to the reaction mixture and stirred for 30-45 min at 0-5°C. A solution of compound of formula-3a (100 gm) in tetrahydrofuran (100 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 60 min at the same temperature. Quenched the reaction mixture with cold ammonium chloride solution. Both the organic and aqueous layers were separated and the aqueous layer was extracted with methyl tert-butyl ether. Combined the organic layers and washed with DM water. Distilled off the solvent completely form the organic layer. The obtained compound was purified by column chromatography using petroleum ether and ethyl acetate as eluent. Distilled off the solvent completely from the pure fractions under reduced pressure to get the title compound. Yield: 200 gm.

We Claim:

1. A process for preparation of tricyclic enone compound of general formula-8, wherein, Ri, R2 and R3 are same or different, each independently selected from hydrogen, straight or branched chain alkyl and substituted or unsubstituted aryl, with a proviso that Ri=R2=R3^Hydrogen;

Pi and P2 both are same or different, each independently selected from hydroxy protecting groups, comprising of: a) Reacting compound of general formula-2

wherein, Ri, R2 and R3 are same as defined above, with alkyne compound of general formula-3 wherein, Pi is hydroxy protecting group,

in presence of alkyl magnesium halide in a suitable solvent or a mixture of solvents to provide benzyl alkynol compound of general formula-4,

wherein, Ri, R2 and R3 are same as defined above; and Pi is hydroxy protecting group, b) oxidizing the compound of general formula-4 with a suitable oxidizing agent in a suitable solvent to provide benzyl alkynone compound of general formula-5,

wherein, Ri, R2 and R3 are same as defined above; and Pi is hydroxy protecting group, c) reducing the keto group of general formula-5 with a chiral reducing agent in a suitable solvent to provide chiral benzyl alkynol compound of general formula-6,

wherein, Ri, R2 and R3 are same as defined above; and Pi is hydroxy protecting group, d) protecting the hydroxy group of general formula-6 with a suitable protecting agent, optionally in presence of a base in a suitable solvent to provide its corresponding O-protected compound of general formula-7,

wherein, Rj, R2 and R3 are same as defined above; and Pi and P2 both are same or different, each independently selected from hydroxy protecting groups, e) reacting the compound of general formula-7 with octacarbonyl dicobalt in a suitable solvent or a mixture of solvents to provide tricyclic enone compound of general formula-8.

2. The process according to claim 1, wherein,

In step-a) alkyl magnesium halide is selected from methyl magnesium bromide and ethyl magnesium bromide, methyl magnesium chloride, and ethyl magnesium chloride;
In step-b) The suitable oxidizing agent is selected from pyridinium chlorochromate,
potassium dichrormate/sulfuric acid, chromium trioxide/aqueous sulfuric acid, lead tetra acetate, pyridinium dichromate, Cr03/pyridine/dichloromethane, aluminium

triisopropoxide, trichloro isocyanuric acid in presence of TEMPO, oxalyl chloride in combination with dimethylsulfoxide and a suitable base; manganese dioxide; quaternary ammonium salt/TEMPO/ oxone, N-chloro succinamide in combination with dimethylsulfide and a suitable base, and Dess-Martin periodinane;

In step-c) "chiral reducing agent" is selected from Borane-DMS, Borane-THF and Borane-diethylaniline in presence of catalysts like (R)-2-Methyl-CBS-oxazaborolidine, {R)-2-phenyl-CBS-oxazaborolidine and (i?)-2-butyl-CBS-oxazaborolidine; 9-BBN in combination with a-pinene; diisopinocamphenylborane; and B-chlorodiisopinocamphenyl borane (herein after referred as DIP chloride).

In step-d) "protecting agent" is same as defined above;

In step-a) to step-e) the suitable solvent is selected from ether solvents, ester solvents, chloro solvents, alcoholic solvents, nitrile solvents, ketone solvents, hydrocarbon solvents, polar aprotic solvents and also mixtures thereof.

3. A process for preparation of (4R)-4,8-bis(tert-butyldimethylsilyloxy)-3-((3R)-3-(tetrahydro-2H-pyran-2-yloxy) octyl)-9,9a-dihydro-1 H-cyclopenta[b]naphthalen-2(4H)-one compound of formula-8a, comprising of:

a) Reacting 2-allyl-3-(tert-butyldimethylsilyloxy)benzaldehyde compound of formula-2a
with 2-((S)-dec-l-yn-5-yloxy)tetrahydro-2H-pyran compound of formula-3a

in presence of ethyl magnesium bromide in tetrahydrofuran provides (6R)-l-(2-allyl-3 -(tert-butyldimethyl silyloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-yn-1 -ol compound of formula-4a,

b) oxidizing the compound of formula-4a with manganese dioxide in toluene provides (6R)-1 -(2-allyl-3 -(tert-butyldimethylsilyloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-yn-l-one compound of formula-5a,

c) reducing the keto group compound of formula-5 a with Borane-DMS in presence of catalyst such as (i?)-2-Methyl-CBS-oxazaborolidine in tetrahydrofuran provides (1 S,6S)-1 -(2-allyl-3 -(tert-butyldimethylsilyloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-yn-1 -ol compound of formula-6a,

d) protecting the hydroxy group of formula-6a with tert-butyldimethyl silyl chloride in presence of imidazole in dichloromethane provides (2-allyl-3-((lS,6S)-l-(tert-butyldimethyl silyloxy)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-ynyl)phenoxy)(tert-butyl) dimethylsilane compound of formula-7a,

e) reacting the compound of formula-7a with octacarbonyl dicobalt in a mixture of acetonitrile and dichloromethane to provide compound of formula-8a.

4. A process for the preparation of (6R)-l-(2-allyl-3-(tert-butyldimethylsilyloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-yn-l-ol compound of formula-4a comprising of reacting 2-allyl-3-(tert-butyldimethylsilyloxy)benzaldehyde compound of formula-2a with 2-((S)-dec-l-yn-5-yloxy)tetrahydro-2H-pyran compound of formula-3a in presence of a suitable base selected from organolithium bases such as methyl lithium, n-butyl lithium, lithium diisopropylamide (LDA), preferably n-butyl lithium in a suitable ether solvent preferably tetrahydrofuran provides compound of formula-4a.

5. A novel process for the preparation of Treprostinil compound of formula-1, or its pharmaceutically acceptable salt, comprising of:

a) Hydrogenating the tricyclic enone compound of general formula-8 with a suitable metal catalyst in presence of a base under hydrogen pressure in a suitable solvent or mixture of solvents to provide tricyclic ketone compound of general formula-9

Wherein, G is hydrogen (or) Pj; Rj, R2 and R3 are same or different, each independently selected from hydrogen, straight or branched chain alkyl and substituted or unsubstituted aryl, proviso that Ri=R2=:R3^Hydrogen; b) treating the compound of general formula-9 with a suitable base in a suitable solvent, followed by reducing the obtained compound with a suitable reducing agent, optionally treating the obtained compound with a suitable deprotecting agent(s) to provide tricyclic triol compound of formula-10,

c) reacting the compound of formula-10 with alkyl a-halo acetate represented by the structural formula
Wherein, 'X' represents halogen such as chloro, bromo and iodo; 'R' represents CM
alkyl;
in presence of a suitable base in a suitable solvent to provide Treprostinil alkyl ester
compound of general formula-11,
Wherein, R is same as defined above,

d) hydrolyzing the compound of general formula-11 in presence of an aqueous base in a suitable solvent to provide Treprostinil compound of formula-1,

e) optionally, converting the Treprostinil into its pharmaceutically acceptable salt.

6. A novel process for the preparation of Treprostinil compound of formula-1, comprising of: a) Hydrogenating the compound of formula-8a
with Pd-C in presence of a aqueous potassium carbonate in ethanol to provide compound of formula-9a,

b) treating the compound of formula-9a with sodium hydroxide in ethanol, followed by reducing the obtained compound with sodium borohydride; further treating the obtained compound with hydrochloric acid to provide tricyclic triol compound of formula-10, c) reacting the compound of formula-10 with a-bromo ethyl acetate in presence of potassium carbonate in acetone provides Treprostinil ethyl ester compound of formula-11a,

d) hydrolyzing the compound of formula-lla in presence of an aqueous sodium hydroxide in methanol provides Treprostinil.

7. Compounds of having following structural formulae:

and isomers thereof, wherein, Rj, R2 and R3 are same or different and independently selected from hydrogen, straight or branched chain alkyl and substituted or unsubstituted aryl, with a proviso that Ri=R2=R3 ^ Hydrogen; Pi and P2 both are same or different, each independently selected from hydroxy protecting groups;

8. A process for the preparation of diethanolamine salt of Treprostinil, comprising of:

a) Dissolving Treprostinil compound of formula-1 in a suitable solvent,

b) adding a solution of diethanolamine in water to the above reaction mixture,

c) optionally, seeding with Treprostinil diethanol amine,

d) cooling and stirring the reaction mixture,

e) filtering the solid and drying to provide the diethanolamine salt of Treprostinil.

9. A process for the preparation of crystalline form-A of Treprostinil diethanol amine,comprisingof:

a) Dissolving Treprostinil compound of formula-1 in acetone,

b) adding a solution of diethanolamine in water to the above reaction mixture,

c) optionally, seeding with Treprostinil diethanolamine form-A,
d) cooling and stirring the reaction mixture,

e) filtering the solid and drying to provide the diethanolamine salt of Treprostinil.

10. A process for the preparation of crystalline form-B of Treprostinil diethanol amine,comprisingof:

a) Adding acetone to Treprostinil diethanolamine form-A,

b) heating the reaction mixture at a suitable temperature,

c) adding ethanol to the reaction mixture,

d) stirring the reaction mixture,

e) cooling the reaction mixture at a suitable temperature,

f) filtering the solid and drying to get the crystalline form-B of Treprostinil diethanolamine.