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WO 2017/162668 Al 28 September 2017 (28.09.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/162668 Al 28 September 2017 (28.09.2017) P O P C T (51) International Patent Classification: (74) Agent: SIEBER, Frank; K 703, c/o Sanofi-Aventis C07D 307/77 (2006.01) A61K 31/343 (2006.01) Deutschland GmbH, Global Intellectual Property Depart ment, Industriepark Hochst, Geb. K 703, 65926 Frankfurt (21) Number: International Application am Main (DE). PCT/EP2017/056690 (81) Designated States (unless otherwise indicated, for every (22) Date: International Filing kind of national protection available): AE, AG, AL, AM, 2 1 March 2017 (21 .03.2017) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (25) Filing Language: English BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (26) Publication Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, (30) Priority Data: KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, P160021 1 23 March 2016 (23.03.2016) HU MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, (71) Applicant: CHINOIN GYOGYSZER ES VEGYESZ- RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, ETI TERMEKEK GYARA ZRT. [HU/HU]; 1045 Bud TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, apest To u. 1-5. (HU). ZA, ZM, ZW. (72) Inventors: HORTOBAGYI, Iren; c/o CHINOIN PHAR (84) Designated States (unless otherwise indicated, for every MACEUTICAL AND CHEMICAL WORKS PRIVATE kind of regional protection available): ARIPO (BW, GH, COMPANY LTD., 1045 Budapest To u. 1-5. (HU). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, LASZLOFI, Istvan; c/o CHINOIN PHARMACEUTICAL TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, AND CHEMICAL WORKS PRIVATE COMPANY LTD., TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 1045 Budapest To u. 1-5. (HU). KARDOS, Zsuzsanna; DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, c/o CHINOIN PHARMACEUTICAL AND CHEMICAL LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, WORKS PRIVATE COMPANY LTD., 1045 Budapest To SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, u. 1-5. (HU). MOLNAR, Jozsef; c/o CHINOIN PHAR GW, KM, ML, MR, NE, SN, TD, TG). MACEUTICAL AND CHEMICAL WORKS PRIVATE COMPANY LTD., 1045 Budapest To u. 1-5. (HU). Declarations under Rule 4.17 : TAKACS, Laszlo; c/o CHINOIN PHARMACEUTICAL — of inventorship (Rule 4.17(iv)) AND CHEMICAL WORKS PRIVATE COMPANY LTD., Published: 1045 Budapest To u. 1-5. (HU). TORMASI, Robertne; c/o CHINOIN PHARMACEUTICAL AND CHEMICAL — with international search report (Art. 21(3)) WORKS PRIVATE COMPANY LTD., 1045 Budapest To u. 1-5. (HU). (54) Title: PROCESS FOR THE PREPARATION OF EPOPROSTENOL SODIUM OF ENHANCED STABILITY (57) Abstract: The invention provides a stable epoprostenol sodium and a process for the preparation this pharmaceutically active ingredient. Process for the preparation of epoprostenol sodium of enhanced stability The subject of our invention is stable epoprostenol sodium which can be stored in deep freezer (-20±5 °C) for at least 3 years, and process for its preparation. Epoprostenol sodium of formula I is the synthetically produced sodium salt of the natural prostacyclin of formula IV. The names prostacyclin Na and epoprostenol Na are equal. The main therapeutic field of epoprostenol Na is treatment of pulmonary hypertension (PAH) (European Heart J., 2004, 25, 2243-2278). Epoprostenol Na or Prostacyclin Prostacyclin Na Since its isolation in 1976 (Nature, 1976, 263, 663-665) it is known that prostacyclin is the metabolite of arachidonic acid and it possesses strong vasodilatory and platelet aggregation inhibitory effect. It also became clear very soon that the molecule is chemically highly instable, in neutral or acidic aqueous solutions it transforms into the biologically inactive 6-oxo-PGFi aip a of formula V (Schema 1.) Schema 1. The reason for its extremely fast degradation (its half-life in aqueous solution at physiological pH is 3-4 minutes) is that beside the enol-ether structure, the chain-end carboxylic group accelerates the decomposition both in its protonated and ionized forms (J. C.S. Chem. Comm., 1979, 129-130). The first, and also structure-proving synthesis was performed by Corey and his group starting from THP2- PGF2 a ipha (J. A. Chem. Soc, 1977, 99, 2006-2008). The process is shown in Schema 2. Schema 2. aipha In the process THP2-PGF2 of formula VI was reacted with N-bromosuccinimide to obtain the bromo ether diastereomers of formulae VII and VIII. After removal of the THP-group (tetrahydropyranyl group) the diastereomers of formulae IX and X were separated by chromatography. The isomer of formula IX, which contains the bromo substituent in the sterically less hindered (exo) position, on treatment with potassium tertiary-butylate in tert- butanol converted under hydrogen bromide elimination into the enol-ether of formula IV within 1.5 hours. The enol-ether was separated from the mild acidic aqueous solution by fast etheral extraction and was then transformed with diazomethane into the methyl ester of formula XI. The isomer of formula X, which contains the bromo substituent in the sterically hindered (endo) position, reacted under the above conditions only to a small extent. The methyl ester of formula XI in acidic medium is transformed into the 6-oxo-PGFi aip a methyl ester of formula XII, this transformation is, however, more slowly than the hydrolysis of prostacyclin (Schema 3.). Schema 3. The first synthesis was followed almost simultaneously by numerous other preparations. Key steps of the syntheses are halocyclisation of the PGF2aip a or its derivative followed by hydrogen halogenide elimination on the effect of base. Due to the chemical instability of the free acid, the product was always isolated and stored in the form of its salt. Tomoskozi and his co-workers were the first to prove (Tetrahedron Letters, 1977, 30, 2627- 2628) that the bromo- and the iodo-cyclisation reaction can also be realized from the unprotected PGF2aiPha and its methyl ester, both halo ether diastereomers transform into the cis-vinyl ether derivative (prostacyclin) on the effect of bases, the hydrogen halogenide elimination is faster in the case of the iodo- derivative, hydrogen iodide eliminates from the iodo-derivative even on the effect of potassium carbonate. In the halocyclisation reaction as iodine source, KIO3+KI in acetic acid - water mixture as solvent, or I2 in pyridine, or IC1 in acetonitrile were applied, as bromine source N-bromosuccinimide in dichloromethane, or dibromodimethylhydantoine in dichloromethane and acetonitrile, or N- bromocamphorimide in dichloromethane were applied. The hydrogen halogenide elimination was effected with potassium ethylate or potassium tertiary-butylate bases in the appropriate alcohol. In the case of iodo substituent the elimination took place even on the effect of potassium carbonate. Johnson and his co-workers (J. Am. Chem. Soc, 1977, 99, 4182-4184) were the first to prepare lyophilized prostacyclin sodium salt by hydrolysis of the methyl ester of formula XI with equivalent amount of sodium hydroxide in methanol:water=l:l mixture, followed by lyophilisation of the obtained reaction mixture containing the epoprostenol sodium salt. The lyophilisate, white powder, remained stable for at least two months at -30 °C. The methyl ester was prepared from the PGF2aip a methyl ester, applying as iodine source KI- I2 reagent in water or in dichloromethane solvent, in the presence of sodium carbonate. Reaction conditions of the hydrogen iodide elimination: with silver carbonate in tetrahydrofuran in the presence of traces of perchloric acid with l,5-diazabicyclo[4.3.0]non-5-ene (DBN) base, in benzene with potassium superoxide (K0 2) in dimethylformamide in the presence of 18-cown ether. Whittaker (Tetrahedron Letters, 1977, 32, 2805-2808) prepared the iodo ether diastereomers of formula XIV from PGF2aip a methyl ester. The iodine source, aqueous KI-I2 reagent, was added dropwise to the ether solution of PGF2 a iP h a methyl ester, the ether was previously saturated with aqueous sodium hydrogen carbonate solution. Better result was reached when the iodine was dissolved in ether or dichloromethane. The iodo ether diastereomers were treated in methanol with 10 equ. sodium methylate. After the hydrogen iodide elimination the ester group was hydrolyzed with IN sodium hydroxide solution. From the concentrated aqueous reaction mixture the epoprostenol sodium salt crystallized in the form of fine needles. The salt was filtered off, washed with IN sodium hydroxide and dried on the air, while the surface of the crystals in about 3.5 % became covered with sodium carbonate, which protected the enol-ether structure product. The sodium salt was stored in sealed tube. The process is demonstrated in Schema 4. XIV I Schema 4. Nicolau and his co-workers (J. C. S. Chem. Comm., 1977, 630-631) reacted the PGF2 a ip a methyl ester of formula XIII with iodine in dichloromethane, in the presence of potassium carbonate. Hydrogen iodide elimination from the diastereomers of formula XIV was effected in toluene at 110 °C with l,5-diazabicyclo[5.4.0]undec-5-ene (DBU) base or, more preferably in methanol, in the presence of sodium methylate. If the iodo ether diastereomers of formula XIV were treated with sodium methylate in methanol containing 5% of water, beside the hydrogen iodide elimination, hydrolysis of the ester group also took place (Schema 5.), and the resulting epoprostenol sodium salt remained stable in the solution.
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