Field of the Invention:

The present invention provides a novel process for the preparation of (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 represented by structural formula-1 and also its pharmaceutically acceptable salts, preferably sodium salt represented by structural formula-la.

Formula-1 Formula-la

(lR,2R,3aS,9aS)-[[2,3,3a,4,9,9a-Hexahydro-2-hydroxy-l-[(3S)-3-hydroxyoctyl]-lH-benz[fj inden-5-yl]oxy] 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 the 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 US43 06075. 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 still a 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 "trityl group" is used for protecting the hydroxy group which is present on phenyl ring of 2-allyl-3-hydroxy-benzaldehyde which is required to synthesize Treprostinil. The trityl protecting group is removed simply by utilizing acid such as hydrochloric acid. Further, the process avoids the column chromatographic purification in many of the stages of synthesis.

Brief description of the invention:

The first aspect of the present invention is to provide a novel process for the preparation of Treprostinil and its pharmaceutically acceptable salt.

The second aspect of the present invention is to provide novel compounds which are useful intermediates in the synthesis of prostacyclins such as Treprostinil and its pharmaceutically acceptable salts, preferably its sodium salt.

Brief description of the drawings:

Figure-1: Illustrates the PXRD pattern of crystalline form of Treprostinil sodium.

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, pet.ether, 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 the like or mixtures thereof.

The term "pharmaceutically acceptable salts" in the present invention refers to "alkali metal salts" such as potassium, sodium, lithium salts and the like, "alkaline earth metal salts" such as magnesium, calcium salts and the like; "other salts" like zinc salts; "amine salts" like primary amine salts such as methyl amine, ethyl amine salts and the like; secondary amine salts such as dimethyl amine, dibutyl amine, dicyclohexyl amine, N-methyl hexyl amine salts and the like; and tertiary amine salts such as trimethyl amine, triethyl amine salts and the like; and "quaternary ammonium salts" such as tetramethyl ammonium, tetraethyl ammonium, benzyl triethyl ammonium salts and the like.

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 alkoxy, alkyl, aryl,chloro, fluoro and nitro. The substotution may be one or more.

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 R\ represents CM alkyl or aryl or arylalkyl such as methoxy carbonyl, ethoxy carbonyl, benzyloxy carbonyl, 9-(fiuorenylmethyloxy)carbonyl, tertiary butyloxy carbonyl and the like;

The term "substituted" herein the present invention wherever necessary, refers to the compound substituted by the substituents like alkyl, alkoxy, aryl, chloro, fluoro and nitro. The substitution may be one or more.

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 etc; "base" such as alkali metal carbonate and alkali metal hydroxides, sodium in liquid ammonia, organic base etc; metal catalysts in presence of hydrogen source; and reducing agents.

The main objective of the present invention is to provide a novel process for the preparation of Treprostinil and its pharmaceutically acceptable salts.

The first aspect of the present invention provides a novel process for the preparation of Treprostinil compound of formula-1 or its pharmaceutically acceptable salt, comprising of: a) Reacting 2-allyl-3-(trityloxy)benzaldehyde compound of formula-2 Wherein, Pi is hydroxy protecting group, in presence of alkyl magnesium halide in a suitable solvent to provide benzyl alkynol compound of general formula-4,

Formula-4

Wherein, 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,

Formula-5 Wherein, Pi is hydroxy protecting group, :) 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,

Formula-6 Wherein, Pi is hydroxy protecting group, d) protecting the hydroxy group of general formula-6 with a suitable protecting group to provide its corresponding O-protected compound of general formula-7,

Wherein, 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, OP2 OC(Ph)3H

Formula-8
Wherein, Pi and P2 both are same or different, each independently selected from hydroxyl protecting groups,

f) hydrogenating the compound of general formula-8 with a suitable metal catalyst in presence of an aqueous base in a suitable solvent to provide tricyclic ketone compound of general formula-9 OC(Ph)3H Formula-9 Wherein, G is hydrogen (or) Pi, g) 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,

Formula-10

h) reacting the compound of formula-10 with alkyl a-halo acetate represented by the structural formula O X-A)R 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 genera formula-11, Formula-11

Wherein, R is same as defined above, i) hydrolyzing the compound of general formula-11 in presence of an aqueous base in a suitable

solvent to provide Treprostinil compound of formula-1, j) optionally, converting the compound of formula-1 into its pharmaceutically acceptable salt.

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, CrOs/pyridine/dichloromethane, 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, and Dess-Martin periodinane etc;

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 (i?)-2-butyl-CBS-oxazaborolidine; 9-BBN in combination with a-pinene; diisopinocamphenylborane; and B-chlorodiisopinocamphenylborane (herein after referred as DIP chloride);

In step-f) 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(triphenylphosphine)rhodium(I);

In step-g) 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-h) the "suitable base" is selected from inorganic and organic base;

In step-i) the "suitable base" is inorganic base;

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

a) Reacting 2-allyl-3-(trityloxy)benzaldehyde compound of formula-2 with 2-((S)-dec-l-yn-5-yloxy)tetrahydro-2H-pyran compound of formula-3a in presence of ethyl magnesium bromide in tetrahydrofuran provides compound of formula-4a,

b) oxidizing the compound of formula-4a with manganese dioxide in toluene provides compound of formula-5a,

c) reducing the keto group of formula-5a with Borane-DMS in presence of catalyst such as (R)-2-Methyl-CBS-oxazaborolidine in tetrahydrofuran provides compound of formula-6a,

d) protecting the hydroxy group of formula-6a with tert-butyldimethyl silyl chloride in presence of imidazole in dichloromethane provides 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,

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

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

h) 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-1 la,

i) hydrolyzing the compound of formula-lla in presence of an aqueous sodium hydroxide in methanol provides Treprostinil compound of formula-1.
ii)
The "Treprostinil" obtained by the present invention is converted into its pharmaceutically acceptable salts, by treating the Treporstinil with 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 source selected from sodium carbonate, sodium hydroxide, and sodium bicarbonate in a water-miscible solvent.

The reported processes described in the prior art, like US6700025, US6765117, US6809223, WO2012009816 and Journal of organic chemistry, 2004, 69, 1890-1902 involves the chromatographic purification in each stage of synthesis, which is tedious process and may decrease yield of the final compound. The present invention avoids the chromatographic purification at 4 stages, i.e. for compounds of formulae-5a, 8a, 9a and 11a and even though produces Treprostinil sodium with ICH purity of 99.9% by HPLC. Henceforth the present invention is more advantageous.

The chiral benzyl alkynol compound of general formula-6 is prepared directly by the reaction of compound of formula-2 and compound of general formula-3 in presence of chiral inducing agent like (+)-N-methylephederin, zinc reagents like zinc triflate and a base like organic and inorganic base in a suitable solvent. This process avoids the additional reaction steps such as oxidation followed by chiral reduction.

The "Treprostinil sodium" obtained by the present invention is characterized by its powder X-ray diffraction pattern having peaks at 5.0, 13.3, 15.1, 18.2, 20.3, 22.2 and 23.9 ± 0.2 degrees of 20 and is further characterized by its PXRD pattern as shown in figure-1.

The second aspect of the present invention provides novel compounds, which are useful intermediates in the synthesis of prostacyclins such as Treprostinil and its pharmaceutically acceptable salts.

These novel compounds are represented by the following structural formulae:

and isomers thereof, Wherein Pi and P2 both are same or different, each independently selected from hydroxy protecting groups; and G is hydrogen or Pi.

The present invention provides novel compounds, preferably selected from the above compounds in which Pi represents THP, P2 represents TBDMS and G represents THP.

2-allyl-3-(trityloxy)benzaldehyde compound of formula-2, a starting material of the present invention can be prepared by the method represented by following scheme:

2-((S)-dec-l-yn-5-yloxy)tetrahydro-2H-pyran compound of formula-3a, a starting material of the present invention can be synthesized by any of the known methods or by the method represented by following scheme:

Treprostinil sodium obtained by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after drying of the product.

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;
Et: Ethyl; Ph: phenyl;
K2CO3: potassium carbonate;
C(Ph)3Cl: trityl chloride; Cul: copper iodide; and
DHP: 3,4-dihydro-2H-pyran.

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 A0 and continuous scan speed of 0.03°/min.

Treprostinil and Treporstinil sodium of the present invention were analyzed by HPLC under the following conditions:

Apparatus: A liquid chromatograph is equipped with variable wavelength U.V detector;

Column: Sunfire CI8, 150X4.6mm, 3.5 um or equivalent;

Flow rate: 0.8 ml/min;
Wavelength: 217 nm;
Column temperature: 25°C;
Injection volume: lOuL;
Run time: 40 minutes;
Diluent: Methanol: Acetonitrile: 0.1% TFA in water (35:30:35);
Elution: Isocratic; and
Sample concentration: 1.0 mg/ml.
The process of the present invention is represented schematically as follows:

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 (6S)-l-(2-allyl-3-(trityloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy) undec-2-yn-l-ol (Formula-4a)

A mixture of 2-((S)-dec-l-yn-5-yloxy)tetrahydro-2H-pyran compound of formula-3a (7.0 g) and tetrahydrofuran (70 ml) was heated to 60-65°C. Ethyl magnesium bromide (24 ml) was added to the reaction mixture and stirred for 1 lA hr at the same temperature. The reaction mixture was cooled to 25-30°C. A solution of 2-allyl-3-(trityloxy) benzaldehyde compound of formula-2 (4.33 g) and tetrahydrofuran (14 ml) was added to the reaction mixture under nitrogen atmosphere at 25-30°C and stirred for 5 hrs. After completion of the reaction, the reaction mixture was quenched with ammonium chloride solution. Ethyl acetate was added to the reaction mixture. Both the organic and aqueous layers were separated; the aqueous layer was extracted with ethyl acetate. Combined organic layers and dried with sodium sulphate and distilling off the solvent from the organic layer to get crude title compound. The crude title compound was purified by column chromatography by eluting the column using pet. ether followed ethyl acetate. The pure fractions were collected and distilled under reduced pressure to get title compound. Yield: 4.0 gms.

Example-2: Preparation of (6S)-l-(2-allyl-3-(trityloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy) undec-2-yn-l-one (Formula-5a)

To a mixture of compound of formula-4a (8.6 g) and toluene (86 ml), manganese dioxide (16.5 g) was added at 25-30°C and the reaction mixture was stirred for 10 hrs at the same temperature. After completion of the reaction, filtered the reaction mixture through hy-flow bed and washed with toluene. Distilled off the solvent completely from the filtrate to get title compound. Yield: 8.3 gms.

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

To a mixture of compound of formula-5a (17 g) and tetrahydrofuran (170 ml), (R)-2-methyl-CBS-oxazaborolidine (26.5 ml) was added at 25-30°C under nitrogen atmosphere. The reaction mixture was cooled to -20 to -25°C. Borane-DMS (5.5 ml) was added slowly to the reaction mixture at -20 to -25°C and stirred for 1 lA hr. After completion of the reaction, the reaction mixture was quenched with methanol. Aqueous ammonium chloride solution was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The organic layer was dried with sodium sulphate and then distilled off the solvent under reduced pressure to get crude title compound. The crude compound was purified by column chromatography by eluting the column using ethyl acetate followed by pet. ether. The pure fractions were collected and distilled under reduced pressure to get title compound. Yield: 8.0 gms.

Example-4: Preparation of ((lS,6S)-l-(2-allyl-3-(trityloxy)phenyl)-6-(tetrahydro-2H-pyran-2-yloxy)undec-2-ynyloxy)(tert-butyl)dimethylsilane (formula-7a)

A mixture of compound of formula-6a (12.4 g) and dichloromethane (125 ml) was cooled to 0-5°C. Imidazole (1.95 g) was added to the reaction mixture and stirred for 10 minutes at the same temperature. Tertiary butyl dimethyl silyl chloride (4.05 g) was added slowly to the reaction mixture at 0-5°C and stirred for 5 hrs. After completion of the reaction, ethyl acetate followed by water was added to the reaction mixture. The reaction mixture was stirred and separated both the organic and aqueous layers, the organic layer was dried with sodium sulphate and distilled off under the reduced pressure to get crude title compound. The crude compound was purified by column chromatography by eluting the column using pet.ether followed ethyl acetate. The pure fractions were collected and distilled off under reduced pressure to get title compound. Yield: 15 gms. Example-5: Preparation of (4R)-4-(tert-butyldimethyIsilyIoxy)-3-((3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl)-8-(trityloxy)-9,9a-dihydro-lH-cyclopenta[b]naphthalen-2(4H)-one (Formula-8a)

To a solution of the compound of formula-7a (15 g) and dichloromethane (150 ml), octacarbonyl dicobalt (7.11 g) was added at 25-30°C under nitrogen pressure and stirred for 1 lA hr. After completion of the reaction, the solvent from the reaction mixture was distilled off to get a dark brown viscous liquid. Acetonitrile (120 ml) was added to the reaction mixture; the reaction mixture was heated to reflux temperature and stirred for 2 hrs at the same temperature to complete cyclization. After completion of the reaction, the reaction mixture was cooled to below 50°C. Distilled off 80% of the solvent from the reaction mixture under reduced pressure and cooled to 25-30°C. Saturated ammonium chloride solution was added to it and stirred for 10 minutes. Both the organic and aqueous layers were separated; the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with ammonium chloride solution. Dried with sodium sulphate and then distilled off under reduced pressure to get title compound. Yield: 15 gms.

Example-6: Preparation of (3aS,9aS)-l-((3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl)-5-(trityloxy)-3a,4,9,9a-tetrahydro-lH-cyclopenta[b]naphthalen-2(3H)-one (Formula-9a)

To a mixture of compound of formula-8a (20 g) and ethanol (200 ml), a solution of potassium carbonate (1 g) and water (3 ml), followed by Pd-C (10 g) were added under nitrogen pressure. The reaction mixture was stirred for 4 hrs at 25-30°C under hydrogen pressure 4.0 to 4.5 kg/cm2. After completion of the reaction, filtered the reaction mixture through hy-flow bed, washed the bed with ethanol and distilled off the solvent from the filtrate under reduced pressure to get tile compound. Yield: 13.0 gms. Example-7: Preparation of tricyclic triol (Formula-10)

A mixture of compound of formula-9a (17 g) and ethanol (170 ml) was cooled to -10 to -5°C. Sodium hydroxide solution (sodium hydroxide (10.35 g) in water (79 ml)) was added slowly to the reaction mixture at -10 to -5°C and stirred for Vz hr. Sodium borohydride (1.96 g) was added to the reaction mixture at -10 to -5°C and stirred for 1 Vz hr. After completion of the reaction, the temperature of the reaction mixture was raised to 25-30°C, 10% hydrochloric acid (150 ml) was added to the reaction mixture at 25-30°C and stirred for 11 hrs. After completion of the reaction, the reaction mixture was concentrated and added water followed by ethyl acetate to the reaction mixture. Both the organic and aqueous layers were separated; the organic layer was washed with water, dried with sodium sulfate and distilled under reduced pressure. Dichloromethane was added to the obtained compound at 25-30°C and cooled the reaction mixture to 0-5°C and stirred for 2 hrs. Filtered the solid, and then dried to get title compound. Yield; 6.0 gms; MR: 113-120°C. Example-8: Preparation of Treprostinil ethyl ester (Formula-lla)

To a mixture of tricyclic triol compound of formula-10 (11.8 g) and acetone (120 ml), added potassium carbonate (14.7 g) at 25-30°C. Bromo ethyl acetate (4.7 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was heated to 60-65°C and stirred for 4 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C. Filtered the reaction mixture through hy-flow bed and washed with acetone. Distilled off the solvent from the filtrate to obtain crude compound. Dissolved the obtained crude compound in a mixture of ethyl acetate (120 ml) and water (60 ml). Both the organic and aqueous layers were separated; the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined, dried with sodium sulphate and then distilled off the solvent under reduced pressure to get title compound. Yield: 12.5 gms

Example-9: Preparation of Treprostinil (Formula-1)

To a mixture of Treprostinil ethyl ester compound of formula-1 la (11. 8 g) and methanol (120 ml), added 2M sodium hydroxide (1.7 g) solution and stirred for 2 lA hrs at 25-30°C. After completion of the reaction, distilled off the solvent completely under reduced pressure to get crude compound. This crude compound was dissolved in a mixture of water and ethyl acetate. Both the organic and aqueous layers were separated; pH of the reaction mixture was adjusted to 1.5 using 3M HC1 solution. The aqueous layer was extracted with ethyl acetate. Distilled off the solvent from the organic layer under reduced pressure to get crude compound. This crude compound was dissolved in methanol (11.8 ml). Water (35.4 ml) was added to it and stirred for 1 72 hr. Filtered the solid, washed with water and then dried to get title compound. Acetonitrile (11.8 ml) followed by water (23.6 ml) was added to the obtained compound and heated the reaction mixture to 80-85°C and stirred for 30 mins. The reaction mixture was cooled to 25-30°C and stirred for 30 mins. Filtered the precipitated solid, washed with a mixture of acetonitrile and water and then dried to get title compound. Yield: 9.0 gms; MR: 121-123°C; Purity by HPLC: 99.8%. Example-10: Preparation of Treprostinil sodium (Formula-la)

5M sodium hydroxide (1.84 g) solution was added slowly to a mixture of Treprostinil compound of formula-1 (12 g) and acetone (300 ml) at 25-30°C and stirred for 1 Vz hr at the same temperature. Filtered the obtained solid and washed with acetone. Again acetone (300 ml) was added to the obtained solid at 25-30°C and stirred for 30 mins. The reaction mixture was cooled to 25-30°C. Filtered the obtained solid, washed with acetone and then dried to get title compound. Yield: 10 gms; MR: 150-153°C; purity by HPLC: 99.9% PXRD of the obtained compound is shown in figure-1. Example-11: Preparation of 3-(allyloxy)benzaldehyde (Formula-12)

To a clean & dry RBF, 3-hydroxy benzaldehyde (200 g) and acetone (2 lit) were added. To this reaction mixture, sodium iodide (22.9 g), allyl bromide (275 g) and potassium carbonate (361.6 g) are added at 25-30°C; heated the reaction mixture to 60-65°C and stirred for 5 hrs. After completion of the reaction, Filtered the reaction mixture through hy-flow bed, washed with acetone and distilled off solvent from the filtrate under reduced pressure to get residue. The obtained crude compound was dissolved in a mixture of methyl tertiary butyl ether and water. Both the organic and aqueous layers were separated; the organic layer was dried with sodium sulphate and then distilled off the solvent under reduced pressure to get pure title compound. Yield: 239.0 gms.

Example-12: Preparation of 2-aIIyI-3-hydroxybenzaIdehyde (Formula-13)

A mixture of 3-(allyloxy)benzaldehyde compound of formula-12 (26 g) and decalin (52 ml) was heated to 210-215°C and stirred for 7 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C. Toluene was added to the reaction mixture at 25-30°C and stirred for 18 hrs. Further the reaction mixture was cooled to 0-5°C and stirred for 3 hrs. Filtered the solid and washed with heptane. The obtained solid was slurried in heptane. Filtered the precipitated solid, washed with heptane and then dried to get title compound. Yield: ll.Ogms. Example-13: Preparation of 2-allyl-3-(trityloxy)benzldehyde (Formula-2)

Sodium bicarbonate (26.1 g) was added to a mixture of compound of formula-13 (10 g) and acetone (100 ml) at 25-30°C. Trityl chloride (18.9 ml) was added slowly to the reaction mixture at 25-30°C and stirred for 5 hrs. After completion of the reaction, filtered the reaction mixture through celite bed and washed with acetone. Distilled off the solvent from the filtrate under reduced pressure. Ethyl acetate followed by water was added to the obtained compound and stirred for 10 minutes. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with the mixture of triethyl amine and water and then distilled under reduced pressure to get crude compound. The crude compound was purified by column chromatography by eluting the column with pet.ether followed by ethyl acetate. The pure fractions were collected and distilled under reduced pressure to get pure title compound. Yield: 7.0 gms; MR: 135-137°C. Example-14: Preparation of (S)-l-chloroheptane-2-oI (Formula-14)

A mixture of (S)-(+)-epichlorohydrin (20 g), copper iodide (4.12 g) and tetrahydrofuran (200 ml) was cooled to -55 to -50°C under nitrogen atmosphere. n-Butyl magnesium chloride (113.4 ml) was added slowly to the reaction mixture -55 to -50°C under nitrogen atmosphere. The temperature of the reaction mixture was raised to 25-30°C and stirred for 5 hrs. After completion of the reaction, the reaction mixture was quenched with ammonium chloride solution. Extracted the reaction mixture with ethyl acetate twice. Combined the organic layers, dried with sodium sulphate and then distilled off the solvent under reduced pressure to get title compound. Yield: 25 gms. Example-15: Preparation of 2-((S)-l-chloroheptan-2-yIoxy)tetrahydro-2H-pyran (Formula-15)

A mixture of (S)-l-chloroheptane-2-ol compound of formula-14 (25 g) and n-hexane (250 ml) was cooled to 0-5°C. 3,4-dihydro-2H-pyran (23.8 g), followed by p-toluene sulfonic acid (1.43 g) were added to the reaction mixture at 0-5°C and stirred for 1 hr at 0-5°C. After completion of the reaction, water followed by ethyl acetate was added to the reaction mixture and stirred the reaction mixture for 10 minutes. Both the organic and aqueous layers were separated; the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined, washed with sodium carbonate solution, dried with sodium sulphate and then distilled off the solvent under reduced pressure to get title compound. Yield: 35 gms.

Example-16: Preparation of trimethyl ((5S)-5-(tetrahydro-2H-pyran-2-yloxy)dec-l-ynyl) silane (FormuIa-16)

A mixture of l-(trimethylsilyl)-l-propyne (5.4 g) and tetrahydrofuran (50 ml) was cooled to -20 to -25°C. n-butyl lithium (29 ml) was added to the reaction mixture at -20 to -25°C and stirred for 3 hrs. A solution of 2-((S)-l-chloroheptan-2-yloxy)tetrahydro-2H-pyran compound of formula-15 (5 g) in tetrahydrofuran (20 ml) was added to the reaction mixture at -20 to -25°C and stirred for 30 mins. The temperature of the reaction mixture was raised to 25-30°C and stirred for 4 hrs. After completion of the reaction, the reaction mixture was quenched with ammonium chloride solution and extracted with ethyl acetate twice. Combined the organic layers, washed with water, dried with sodium sulfate and then distilled off the solvent completely under reduced pressure to get title compound. Yield: 7 gms. Example-17: Preparation of 2-((S)-dec-l-yn-5-yloxy)tetrahydro-2H-pyran (Formula-3)

A mixture of trimethyl ((5S)-5-(tetrahydro-2H-pyran-2-yloxy)dec-l-ynyl)silane compound of formula-16 (17 g) and tetrahydrofuran (170 ml) was cooled to 0-5°C. A solution of tertiary butyl ammonium fluoride (31.5 g) in tetrahydrofuran (150 ml) was added to the reaction mixture at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 4 hrs. After completion of the reaction, distilled off the solvent from the reaction mixture under reduced pressure. Ethyl acetate and water were added to the obtained compound. Both the organic and aqueous layers were separated; and the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined, dried with sodium sulphate and then distilled off the solvent under reduced pressure to get crude compound. The obtained crude compound was purified by column chromatography by eluting the column using pet.ether followed by ethyl acetate. The pure fractions were collected and distilled off the solvent to get pure title compound. Yield: 6.5 gms.

We Claim:

1. A process for preparation of Treprostinil or its pharmaceutically acceptable salt, comprising of:

a) Reacting 2-allyl-3-(trityloxy)benzaldehyde compound of formula-2 with alkyne compound of general formula-3 Formula-3 Wherein, Pi is hydroxy protecting group selected from aryl alkyl, aryl carbonyl, alkyl, alkenyl, acyl, alkoxy alkyl, aryloxy alkyl, tetrahydro-2H-pyran-2-yl, alkyl sulfonyl, aryl sulfonyl, protecting groups represented by formula "-CO-O-Ri" wherein Ri represents CM alkyl or aryl or arylalkyl; (alkyl)m (aryl)3.m silyl, wherein, m represents 0, 1, 2 and 3. Each alkyl aryl groups are substituted or unsubstituted;

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

Formula-4 Wherein, Pi is hydroxy protecting group as defined above,

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,

Formula-5 Wherein, Pi is hydroxy protecting group as defined above,

c) reducing the keto group of general formula-5 with chiral reducing agent in a suitable solvent to provide chiral benzyl alkynol compound of general formula-6, Formula-6

Wherein, Pi is hydroxy protecting group as defined above,

d) protecting the hydroxy group of general formula-6 with a suitable protecting group to provide its corresponding O-protected compound of general formula-7,

Formula-7 Wherein, Pi and P2 both are same or different, each independently selected from hydroxyl protecting groups as defined above,

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

Formula-8 Wherein, P2 and P2 both are same or different, each independently selected from hydroxyl protecting groups as defined above,

f) hydrogenating the compound of general formula-8 with a suitable metal catalyst in presence of an aqueous base in a suitable solvent to provide tricyclic ketone compound of general formula-9,
Formula-9 Wherein, G is hydrogen or Pi;

g) 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,

h) reacting the compound of formula-10 with alkyl cc-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, Formula-11 Wherein, R is same as defined above,

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

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

2. The process according to claim 1, which comprises of:

a) Reacting 2-allyl-3-(trityloxy)benzaldehyde compound of formula-2 with 2-((S)-dec-l-yn-5-yloxy)tetrahydro-2H-pyran compound of formula-3a Formula-3a in presence of alkyl magnesium halide in a suitable solvent to provide compound of formula-4a, Formula-4a

b) oxidizing the compound of formula-4a with a suitable oxidizing agent in a suitable solvent to provide compound of formula-5a,

c) reducing the keto group of formula-5a with a suitable chiral reducing agent in a suitable solvent to provide compound of formula-6a, Formula-6a

d) protecting the hydroxy group of formula-6a with tert-butyl dimethylsilyl chloride in presence of a suitable base in a suitable solvent to provide compound of formula-7a, Formula-7a

e) reacting the compound of formula-7a with octacarbonyl dicobalt in a suitable solvent or a mixture of solvents to provide compound of formula-8a, Formula-8 a

f) hydrogenating the compound of formula-8a with a suitable metal catalyst in presence of an aqueous base in a suitable solvent to provide compound of formula-9a,

g) treating the compound of formula-9a with a suitable base in a suitable solvent, followed by reducing the obtained compound with a suitable reducing agent; further treating the obtained compound with a suitable acid to provide tricyclic triol compound of formula-10,

h) reacting the compound of formula-10 with ethyl a-bromo acetate in presence of a suitable base in a suitable solvent to provide Treprostinil ethyl ester compound of formula-1 la, Formula-lla

i) hydrolyzing the compound of formula-lla in presence of an aqueous base in a suitable solvent to provide Treprostinil.

3. The process according to claims 1 and 2, 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) The 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-butyl-CBS-oxazaborolidine, (R)-2-phenyl-CBS-oxazabroolidine; 9-BBN in combination with a-pinene; and diisopinocamphenylborane;

In step-d) the suitable base is inorganic or organic base;

In step-f) 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, and chlorotris(triphenylphosphine) rhodium(I);

In step-g) 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 cyano borohydride, potassium (trialkoxy)borohydride, sodium (trialkoxy) borohydride, diisobutyl aluminium hydride and vitride;

In step-h) the suitable base is selected from inorganic and organic base;

In step-i) the suitable base is inorganic base;

In step-a) to step-i) 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.

4. The process according to claims 1 and 2, comprising of:

a) Reacting 2-allyl-3-(trityloxy)benzaldehyde compound of formula-2 with 2-((S)-dec-l-yn-5-yloxy)tetrahydro-2H-pyran compound of formula-3a in presence of ethyl magnesium bromide in tetrahydrofuran provides compound of formula-4a,

b) oxidizing the compound of formula-4a with manganese dioxide in toluene provides compound of formula-5a,

c) reducing the keto group of formula-5a with Borane-DMS in presence of a catalyst such as (R)-2-methyl-CBS-oxazaborolidine in tetrahydrofuran provides compound of formula-6a,

d) protecting the hydroxy group of formula-6a with tert-butyldimethyl silyl chloride in presence of imidazole in dichloromethane to provide 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,

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

g) 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,

h) 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-1 la,

i) hydrolyzing the compound of formula-1 la in presence of an aqueous sodium hydroxide in methanol provides Treprostinil.

5. The process according to claims 1, 2 and 4, further comprising the conversion of compound of formula-1 into its sodium salt by treating Treprostinil with sodium hydroxide in a suitable solvent such as ketone solvents to provide Treprostinil sodium.

6. A compound of formula, selected from

and isomers thereof, wherein, Pi and P2 both are same or different, each independently selected from hydroxy protecting groups; G is hydrogen or Pj.

7. A compound according to claim 6, wherein Pi represents tetrahydropyran-2-yl (THP), P2 represents tertiary butyl dimethyl silyl (TBDMS), and G represents tetrahydropyran-2-yl.

8. A process for the preparing a tricyclic enone compound of general formula-8 useful in preparing treprostinil, which comprises of reacting the chiral benzyl alkynol compound of general formula-7 with octacarbonyl dicobalt in a suitable solvent selected from ether solvents, ester solvents, chloro solvents, alcoholic solvents, nitrile solvents, ketone solvents, hydrocarbon solvents, polar aprotic solvents and their mixtures.

9. A process for preparing tricyclic ketone compound of formula-9, comprising of hydrogenating the tricyclic enone compound of general formula-8 with a suitable metal catalyst in a suitable solvent selected from ether solvents, ester solvents, chloro solvents, alcoholic solvents, nitrile solvents, ketone solvents, hydrocarbon solvents, polar aprotic solvents and their mixtures.

10. A process for preparing benzyl alkynol compound of general formula-4, comprising of reacting the 2-allyl-3-(trityloxy)benzaldehyde compound of formula-2 with alkyne compound of general formula-3 in presence of alkyl magnesium halide in a suitable solvent.