the various terms used , separately and in combinations , in the processes herein described are defined below . the expression “ comprising ” means “ including but not limited to .” thus , other non - mentioned substances , additives , carriers , or steps may be present . unless otherwise specified , “ a ” or “ an ” means one or more . c 1 - 3 - alkyl is a straight or branched alkyl group containing 1 - 3 carbon atoms . exemplary alkyl groups include methyl , ethyl , n - propyl , and isopropyl . c 1 - 3 - alkoxy is a straight or branched alkoxy group containing 1 - 3 carbon atoms . exemplary alkoxy groups include methoxy , ethoxy , propoxy , and isopropoxy . c 4 - 7 - cycloalkyl is an optionally substituted monocyclic , bicyclic or tricyclic alkyl group containing between 4 - 7 carbon atoms . exemplary cycloalkyl groups include but not limited to cyclobutyl , cyclopentyl , cyclohexyl , and cycloheptyl . combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds . the term “ stable ”, as used herein , refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein . as used herein , the term “ prodrug ” means a derivative of a compound that can hydrolyze , oxidize , or otherwise react under biological conditions ( in vitro or in vivo ) to provide an active compound . examples of prodrugs include , but are not limited to , derivatives of a compound that include biohydrolyzable groups such as biohydrolyzable amides , biohydrolyzable esters , biohydrolyzable carbamates , biohydrolyzable carbonates , biohydrolyzable ureides , and biohydrolyzable phosphate analogues ( e . g ., monophosphate , diphosphate or triphosphate ). as used herein , “ hydrate ” is a form of a compound wherein water molecules are combined in a certain ratio as an integral part of the structure complex of the compound . as used herein , “ solvate ” is a form of a compound where solvent molecules are combined in a certain ratio as an integral part of the structure complex of the compound . “ pharmaceutically acceptable ” means in the present description being useful in preparing a pharmaceutical composition that is generally safe , non - toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use . “ pharmaceutically acceptable salts ” mean salts which are pharmaceutically acceptable , as defined above , and which possess the desired pharmacological activity . such salts include acid addition salts formed with organic and inorganic acids , such as hydrogen chloride , hydrogen bromide , hydrogen iodide , sulfuric acid , phosphoric acid , acetic acid , glycolic acid , maleic acid , malonic acid , oxalic acid , methanesulfonic acid , trifluoroacetic acid , fumaric acid , succinic acid , tartaric acid , citric acid , benzoic acid , ascorbic acid and the like . base addition salts may be formed with organic and inorganic bases , such as sodium , ammonia , potassium , calcium , ethanolamine , diethanolamine , n - methylglucamine , choline and the like . included in the invention are pharmaceutically acceptable salts or compounds of any of the formulae herein . depending on its structure , the phrase “ pharmaceutically acceptable salt ,” as used herein , refers to a pharmaceutically acceptable organic or inorganic acid or base salt of a compound . representative pharmaceutically acceptable salts include , e . g ., alkali metal salts , alkali earth salts , ammonium salts , water - soluble and water - insoluble salts , such as the acetate , amsonate ( 4 , 4 - diaminostilbene - 2 , 2 - disulfonate ), benzenesulfonate , benzonate , bicarbonate , bisulfate , bitartrate , borate , bromide , butyrate , calcium , calcium edetate , camsylate , carbonate , chloride , citrate , clavulariate , dihydrochloride , edetate , edisylate , estolate , esylate , fumarate , gluceptate , gluconate , glutamate , glycollylarsanilate , hexafluorophosphate , hexylresorcinate , hydrabamine , hydrobromide , hydrochloride , hydroxynaphthoate , iodide , isothionate , lactate , lactobionate , laurate , malate , maleate , mandelate , mesylate , methylbromide , methylnitrate , methylsulfate , mucate , napsylate , nitrate , n - methylglucamine ammonium salt , 3 - hydroxy - 2 - naphthoate , oleate , oxalate , palmitate , pamoate ( 1 , 1 - methene - bis - 2 - hydroxy - 3 - naphthoate , einbonate ), pantothenate , phosphate / diphosphate , picrate , polygalacturonate , propionate , p - toluenesulfonate , salicylate , stearate , subacetate , succinate , sulfate , sulfosalicylate , suramate , tannate , tartrate , teoclate , tosylate , triethiodide , and valerate salts . the present invention provides for a process for producing treprostinil and other prostacyclin derivatives and novel intermediate compounds useful in the process . the process according to the present invention provides advantages on large - scale synthesis over the existing method . for example , the purification by column chromatography is eliminated , thus the required amount of flammable solvents and waste generated are greatly reduced . furthermore , the salt formation is a much easier operation than column chromatography . moreover , it was found that the product of the process according to the present invention has higher purity . therefore the present invention provides for a process that is more economical , safer , faster , greener , easier to operate , and provides higher purity . one embodiment of the present invention is a process for the preparation of a compound of formula i , or a hydrate , solvate , prodrug , or pharmaceutically acceptable salt thereof ( a ) alkylating a compound of formula ii with an alkylating agent to produce a compound of formula iii , w = 1 , 2 , or 3 ; y 1 is trans - ch ═ ch —, cis - ch ═ ch —, — ch 2 ( ch 2 ) m —, or — c ≡ c —; m is 1 , 2 , or 3 ; r 7 is ( 1 ) — c p h 2p — ch 3 , wherein p is an integer from 1 to 5 , inclusive , ( 2 ) phenoxy optionally substituted by one , two or three chloro , fluoro , trifluoromethyl , ( c 1 - c 3 ) alkyl , or ( c 1 - c 3 ) alkoxy , with the proviso that not more than two substituents are other than alkyl , with the proviso that r 7 is phenoxy or substituted phenoxy , only when r 3 and r 4 are hydrogen or methyl , being the same or different , ( 3 ) phenyl , benzyl , phenylethyl , or phenylpropyl optionally substituted on the aromatic ring by one , two or three chloro , fluoro , trifluoromethyl , ( c 1 - c 3 ) alkyl , or ( c 1 - c 3 ) alkoxy , with the proviso that not more than two substituents are other than alkyl , ( 4 ) cis - ch ═ ch — ch 2 — ch 3 , ( 5 ) —( ch 2 ) 2 — ch ( oh )— ch 3 , or ( 6 ) —( ch 2 ) 3 — ch ═ c ( ch 3 ) 2 ; wherein — c ( l 1 )- r 7 taken together is ( 1 ) ( c 4 - c 7 ) cycloalkyl optionally substituted by 1 to 3 ( c 1 - c 5 ) alkyl ; ( 2 ) 2 -( 2 - furyl ) ethyl , ( 3 ) 2 -( 3 - thienyl ) ethoxy , or ( 4 ) 3 - thienyloxymethyl ; m 1 is α - oh : β - r 5 or α - r 5 : β - oh or α - or 2 : β - r 5 or α - r 5 : β - or 2 , wherein r 5 is hydrogen or methyl , r 2 is an alcohol protecting group , and l 1 is α - r 3 : β - r 4 , α - r 4 : β - r 3 , or a mixture of α - r 3 : β - r 4 and α - r 4 : β - r 3 , wherein r 3 and r 4 are hydrogen , methyl , or fluoro , being the same or different , with the proviso that one of r 3 and r 4 is fluoro only when the other is hydrogen or fluoro . ( c ) contacting the product of step ( b ) with a base b to for a salt of formula i s ( d ) reacting the salt from step ( c ) with an acid to form the compound of formula i . in one embodiment , the compound of formula i is at least 90 . 0 %, 95 . 0 %, 99 . 0 %. the compound of formula ii can be prepared from a compound of formula xi , which is a cyclization product of a compound of formula x as described in u . s . pat . no . 6 , 441 , 245 . the compound of formula ii can be prepared alternatively from a compound of formula xiii , which is a cyclization product of a compound of formula xii as described in u . s . pat . no . 6 , 700 , 025 . one embodiment of the present invention is a process for the preparation of a compound having formula iv , or a hydrate , solvate , or pharmaceutically acceptable salt thereof . ( a ) alkylating a compound of structure v with an alkylating agent such as clch 2 cn to produce a compound of formula vi , ( b ) hydrolyzing the product of step ( a ) with a base such as koh , ( c ) contacting the product of step ( b ) with a base b such as diethanolamine to for a salt of the following structure , and ( d ) reacting the salt from step ( b ) with an acid such as hcl to form the compound of formula iv . in one embodiment , the purity of compound of formula iv is at least 90 . 0 %, 95 . 0 %, 99 . 0 %, 99 . 5 %. in one embodiment , the process further comprises a step of isolating the salt of formula iv s . in one embodiment , the base b in step ( c ) may be ammonia , n - methylglucamine , procaine , tromethanine , magnesium , l - lysine , l - arginine , or triethanolamine . the following abbreviations are used in the description and / or appended claims , and they have the following meanings : in view of the foregoing considerations , and specific examples below , those who are skilled in the art will appreciate that how to select necessary reagents and solvents in practicing the present invention . the invention will now be described in reference to the following examples . these examples are not to be regarded as limiting the scope of the present invention , but shall only serve in an illustrative manner . a 50 - l , three - neck , round - bottom flask equipped with a mechanical stirrer and a thermocouple was charged with benzindene triol ( 1250 g ), acetone ( 19 l ) and k 2 co 3 ( powdered ) ( 1296 g ), chloroacetonitrile ( 567 g ), tetrabutylammonium bromide ( 36 g ). the reaction mixture was stirred vigorously at room temperature ( 23 ± 2 ° c .) for 16 - 72 h . the progress of the reaction was monitored by tlc . ( methanol / ch 2 cl 2 ; 1 : 9 and developed by 10 % ethanolic solution of pma ). after completion of reaction , the reaction mixture was filtered with / without celite pad . the filter cake was washed with acetone ( 10 l ). the filtrate was concentrated in vacuo at 50 - 55 ° c . to give a light - brown , viscous liquid benzindene nitrile . the crude benzindene nitrile was used as such in the next step without further purification . this weight is based on 100 % yield from the previous step . this is not isolated yield . a 50 - l , cylindrical reactor equipped with a heating / cooling system , a mechanical stirrer , a condenser , and a thermocouple was charged with a solution of benzindene nitrile in methanol ( 12 l ) and a solution of koh ( 844 g of koh dissolved in 4 . 25 l of water ). the reaction mixture was stirred and heated to reflux ( temperature 72 . 2 ° c .). the progress of the reaction was monitored by tlc ( for tlc purpose , 1 - 2 ml of reaction mixture was acidified with 3m hcl to ph 1 - 2 and extracted with ethyl acetate . the ethyl acetate extract was used for tlc ; eluent : methanol / ch 2 cl 2 ; 1 : 9 , and developed by 10 % ethanolic solution of pma ). after completion of the reaction (˜ 5 h ), the reaction mixture was cooled to − 5 to 10 ° c . and quenched with a solution of hydrochloric acid ( 3m , 3 . 1 l ) while stirring . the reaction mixture was concentrated in vacuo at 50 - 55 ° c . to obtain approximately 12 - 14 l of condensate . the condensate was discarded . the aqueous layer was diluted with water ( 7 - 8 l ) and extracted with ethyl acetate ( 2 × 6 l ) to remove impurities soluble in ethyl acetate . to aqueous layer , ethyl acetate ( 22 l ) was added and the ph of reaction mixture was adjusted to 1 - 2 by adding 3m hcl ( 1 . 7 l ) with stirring . the organic layer was separated and the aqueous layer was extracted with ethyl acetate ( 2 × 11 l ). the combined organic layers were washed with water ( 3 × 10 l ) and followed by washing with a solution of nahco 3 ( 30 g of nahco 3 dissolved in 12 l of water ). the organic layer was further washed with saturated solution of nacl ( 3372 g of nacl dissolved in water ( 12 l )) and dried over anhydrous na 2 so 4 ( 950 - 1000 g ), once filtered . the filtrate was transferred into a 72 - l reactor equipped with mechanical stirrer , a condenser , and a thermocouple . to the solution of treprostinil in reactor was added activated carbon ( 110 - 130 g ). the suspension was heated to reflux ( temperature 68 - 70 ° c .) for at least one hour . for filtration , a pad of celite ® 545 ( 300 - 600 g ) was prepared in sintered glass funnel using ethyl acetate . the hot suspension was filtered through the pad of celite ® 545 . the celite ® 545 was washed with ethyl acetate until no compound was seen on tlc of the washings . the filtrate ( pale - yellow ) was reduced to volume of 35 - 40 l by evaporation in vacuo at 50 - 55 ° c . for direct use in next step . this weight is based on 100 % yield from benzindene triol . it is not isolated yield . the treprostinil was carried from previous step in ethyl acetate solution and used as such for this step . the total volume of ethyl acetate should be in range of 35 - 36 l ( it should be 7 times the volume of ethanol used ). approximately 35 l of ethyl acetate was carried over from previous step and additional 1 . 0 l of ethyl acetate was used for rinsing the flask . a 50 - l , cylindrical reactor equipped with a heating / cooling system , a mechanical stirrer , a condenser , and a thermocouple was charged with a solution of treprostinil in ethyl acetate ( 35 - 40 l from the previous step ), anhydrous ethanol ( 5 . 1 l ) and diethanolamine ( 435 g ). while stirring , the reaction mixture was heated to 60 - 75 ° c ., for 0 . 5 - 1 . 0 h to obtain a clear solution . the clear solution was cooled to 55 ± 5 ° c . at this temperature , the seed of polymorph b of treprostinil diethanolamine salt (˜ 12 g ) was added to the clear solution . the suspension of polymorph b was stirred at this temperature for 1 h . the suspension was cooled to 20 ± 2 ° c . overnight ( over a period of 16 - 24 h ). the treprostinil diethanolamine salt was collected by filtration using aurora filter equipped with filter cloth , and the solid was washed with ethyl acetate ( 2 × 8 l ). the treprostinil diethanolamine salt was transferred to a hdpe / glass container for air - drying in hood , followed by drying in a vacuum oven at 50 ± 5 ° c . under high vacuum . at this stage , if melting point of the treprostinil diethanolamine salt is more than 104 ° c ., it was considered polymorph b . there is no need of recrystallization . if it is less than 104 ° c ., it is recrystallized in etoh - etoac to increase the melting point . in this batch , approximately 1200 ml of ethyl acetate solution of treprostinil before carbon treatment was removed for r & amp ; d carbon treatment experiments . a 50 - l , cylindrical reactor equipped with a heating / cooling system , a mechanical stirrer , a condenser , and a thermocouple was charged with slurry of treprostinil diethanolamine salt in heptane ( 35 - 40 l ). the suspension was heated to 70 - 80 ° c . for 16 - 24 h . the suspension was cooled to 22 ± 2 ° c . over a period of 1 - 2 h . the salt was collected by filtration using aurora filter . the cake was washed with heptane ( 15 - 30 l ) and the material was dried in aurora filter for 1 h . the salt was transferred to trays for air - drying overnight in hood until a constant weight of treprostinil diethanolamine salt was obtained . the material was dried in oven under high vacuum for 2 - 4 h at 50 - 55 ° c . a 250 - ml , round - bottom flask equipped with magnetic stirrer was charged with treprostinil diethanolamine salt ( 4 g ) and water ( 40 ml ). the mixture was stirred to obtain a clear solution . to the clear solution , ethyl acetate ( 100 ml ) was added . while stirring , 3m hcl ( 3 . 2 ml ) was added slowly until ph ˜ 1 was attained . the mixture was stirred for 10 minutes and organic layer was separated . the aqueous layer was extracted with ethyl acetate ( 2 × 100 ml ). the combined organic layers was washed with water ( 2 × 100 ml ), brine ( 1 × 50 ml ) and dried over anhydrous na 2 so 4 . the ethyl acetate solution of treprostinil was filtered and the filtrate was concentrated under vacuum at 50 ° c . to give off - white solid . the crude treprostinil was recrystallized from 50 % ethanol in water ( 70 ml ). the pure treprostinil was collected in a buchner funnel by filtration and cake was washed with cold 20 % ethanolic solution in water . the cake of treprostinil was air - dried overnight and further dried in a vacuum oven at 50 ° c . under high vacuum to afford 2 . 9 g of treprostinil ( yield 91 . 4 %, purity ( hplc , auc , 99 . 8 %). comparison of the former process and a working example of the process according to the present invention the quality of treprostinil produced according to this invention is excellent . the purification of benzindene nitrile by column chromatography is eliminated . the impurities carried over from intermediate steps ( i . e . alkylation of triol and hydrolysis of benzindene nitrile ) are removed during the carbon treatment and the salt formation step . additional advantages of this process are : ( a ) crude treprostinil salts can be stored as raw material at ambient temperature and can be converted to treprostinil by simple acidification with diluted hydrochloric acid , and ( b ) the treprostinil salts can be synthesized from the solution of treprostinil without isolation . this process provides better quality of final product as well as saves significant amount of solvents and manpower in purification of intermediates . although the foregoing refers to particular preferred embodiments , it will be understood that the present invention is not so limited . it will occur to those of ordinary skill in the art that various modifications may be made to the disclosed embodiments and that such modifications are intended to be within the scope of the present invention . all of the publications , patent applications and patents cited in this specification are incorporated herein by reference in their entirety .
this present invention relates to an improved process to prepare prostacyclin derivatives . one embodiment provides for an improved process to convert benzindene triol to treprostinil via salts of treprostinil and to purify treprostinil .