12 November 2009 ( ) WO 2009/ Al

Transcription

1 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 12 November 2009 ( ) WO 2009/ Al (51) International Patent Classification: (74) Common Representative: KHAMAR, Bakulesh Mafat C07C 227/16 ( ) C07C 229/08 ( ) lal; Cadila Pharmaceuticals LTD., "Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad 382 (21) International Application Number: 210, Gujarat (IN). PCT/IB2009/ (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: 4 May 2009 ( ) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (25) Filing Language: English CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, (26) Publication Language: English EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (30) Priority Data: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 991/MUM/ May 2008 ( ) IN MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, (71) Applicant (for all designated States except US): CADI- SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, LA PHARMACEUTICALS LTD. [IN/IN]; "Cadila UG, US, UZ, VC, VN, ZA, ZM, ZW. Corporate Campus", Sarkhej-Dholka Road, Bhat, Ahmedabad , Gujarat (IN). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors; and GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (75) Inventors/Applicants (for US only): KHAMAR, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Bakulesh Mafatlal [IN/IN]; Cadila Pharmaceuticals TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, LTD., "Cadila Corporate Campus", Sarkhej-Dholka Road, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Bhat, Ahmedabad Gujarat (IN). GURUSAMY, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), Renugadevi [IN/IN]; Cadila Pharmaceuticals LTD., OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, "Cadila Corporate Campus", Sarkhej-Dholka Road, Bhat, MR, NE, SN, TD, TG). Ahmedabad Gujarat (IN). RAVI, Maruti, Naik [IN/IN]; Cadila Pharmaceuticals LTD., "Cadila Corporate Declarations under Rule 4.17: Campus", Sarkhej-Dholka Road, Bhat, Ahmedabad 382 as to applicant's entitlement to apply for and be granted 210 Gujarat (IN). REDDY, Vedururi, Madhava [IN/IN]; a patent (Rule 4.1 1(H)) Cadila Pharmaceuticals LTD., "Cadila Corporate Cam pus", Sarkhej-Dholka Road, Bhat, Ahmedabad of inventorship (Rule 4.1 1(iv)) Gujarat (IN). EDDE, Balasubrahmanyam [IN/IN]; Cadi Published: la Pharmaceuticals LTD., "Cadila Corporate Campus", Sarkhej-Dholka Road, Bhat, Ahmedabad Gujarat with international search report (Art. 21(3)) (IN). PONNAIAH, Ravi [IN/IN]; Cadila Pharmaceuti before the expiration of the time limit for amending the cals LTD., "Cadila Corporate Campus", Sarkhej-Dholka claims and to be republished in the event of receipt of Road, Bhat, Ahmedabad Gujarat (IN). MODI, amendments (Rule 48.2(h)) Indravadan, Ambalal [IN/IN]; Cadila Pharmaceuticals LTD., "Cadila Corporate Campus", Sarkhej-Dholka Road, Bhat, Ahmedabad Gujarat (IN). (54) Title: AN IMPROVED PROCESS FOR THE PREPARATION OF LEVOTHYROXINE SODIUM WITH REDUCED LEV ELS OF IMPURITIES (57) Abstract: The invention relates to an improved process for the preparation of Levothyroxine sodium with reduced levels of impurities. The invention also provides Levothyroxine sodium pentahydrate free from 3,5-Diiodothyronine or d-enantiomer of thyroxine. The invention also provides Levothyroxine sodium pentahydrate having liothyronine below 0.5% wt / wt.

2 TITLE OF THE INVENTION: A n Improved Process For The Preparation Of Levothyroxine Sodium With Reduced Levels Of Impurities. FIELD OF INVENTION: The invention relates to an improved process for the preparation of levothyroxine sodium with reduced levels of impurities. BACKGROUND OF THE INVENTlON:- Levothyroxine sodium is a synthetic thyroid hormone and used as a thyroid hormone replacement drug to treat an under active thyroid gland (hypothyroidism). Levothyroxine sodium contains synthetic crystalline L-3,3',5,5'-tetraiodothyronine sodium salt. Levothyroxine (T 4 ) sodium has an empirical formula of molecular weight of gm/mol (anhydrous), and structural formula is shown below: Levothyroxine sodium 3,5-Diiodothyronine (T 2 ), liothyronine (T 3 ) and the d-enantiomer of thyroxine (d-t 4 ) are major byproducts which produced during the synthesis of levothyroxine. These byproducts are biologically active; therefore it is desirable to produce levothyroxine substantially free of these compounds. Liothyronine - T Diiodothyronine - T 2 d-thyroxine - (d-t 4 ) CAS No CAS No CAS No US patent no describes the process for preparation of levothyroxine sodium comprising the steps of: a) iodination of 1-tyrosine to produce 3,5-diiodo-1 -tyrosine; b) protection of the amino group of 3,5-diiodo-1 -tyrosine with a suitable protecting group; c) protection of the carboxy group of amino protected 3,5-diiodo-1 -tyrosine as obtained in step b with a suitable protecting group; d) oxidative coupling of the protected 3,5-diiodo tyrosine as obtained from step c using oxygen as an oxidizing agent in the presence of a manganese salt catalyst and an organic amine additive. The oxygen was diluted in a gas mixture using inert gas as diluents. The oxygen was present in an amount ranging from 10% to 40%, by volume of the gas mixture; e) hydrolysis of the reaction product of step d with a mixture including hydrochloric acid to form the hydrochloride salt of 1-thyroxine, which is separated; f) formation of the sodium salt from the hydrochloride salt of levothyroxine produced from step e.

3 By following the process as described in US patent , resulting hydrochloride salt of levothyroxine contains T 2, T 3 and d-t 4 impurities. US patent no describes the process for preparation of levothyroxine sodium comprising the steps of : iodination of amino acid L-tyrosine to form 3,5Hdiiodo-L-tyrosine; the amino group is protected by acetylation; and then the acid group is converted into the ethyl ester oxidative coupling of the protected iodinated tyrosine product (using oxygen and a manganese salt catalyst) to form a biphenyl ether moiety; acid hydrolysis of bipheπyl ether moiety yields Levothyroxine, as a free base, which is converted to its sodium salt of Levothyroxine (pentahydrate). J Chem. Soc, (1949) describes the process for the synthesis of Levothyroxine sodium which is schematically mentioned below Italian patent IT B 1 describes a multi-step process for the preparation of thyroid hormones and their alkali metal salts and derivatives. The process for the preparation of Levothyroxine sodium (pentahydrate) comprising the steps of nitration of L-tyrosine with HNO 3 in H 2 SO followed by workup with NaOH to give the sodium salt of 3,5-dinitro derivative. N- Acetylation of sodium salt of 3,5-dinitro derivative by known methods and esterification by treatment with (EtO) SrO to give 91.6% 3,5-diπitro-N-acetyl-L-tyrosiπe Et ester. The resulting compound underwent O-tosylation and coupling with 4-MeOC 6 H 4 OH to give the corresponding ether (I). The corresponding ether underwent hydrogenation of nitro groups to amino groups, diazotization and iodination of these, which upon demethylation of the Me ether and hydrolysis, and ring iodination to give Levothyroxine (II). Levothyroxine is dissolved in EtOH at C and

4 treated with 50% aq. NaOH. Upon cooling gives a precipitates of moist Levothyroxi πe disodium salt. The disodium salt was filtered, dissolved in aq. NaOH and decolorized with carbon and Na 2 SO 3, filtered. The filtrate is acidified with aq. HCI, heated and basrfied with aq. Na 2 CO 3. The mixture is cooled gradually to give Levothyroxine sodium pentahydrate in 77% yield. The process is also resulting in the formation of 3,5,3'-triiodo-L-thyronine (III) and Hs Na salts, as well as the D isomers of Il and 111 and their Na salts. <"> ( J (III) There is a long-felt need to provide an improved process for preparation of levothyroxine substantially free of impurities. The present invention is providing the process which provides the Levothyroxine with high purity and reduced level of impurities. SUMMARY OF THE INVENTION: The object of the invention is to provide a process for preparing sodium salt of Levothyroxine having reduced levels of impurities. Yet another object of the invention is to provide Levothyroxine sodium pentahydrate free from 3,5-Diiodothyronine. Yet another object of the invention is to provide Levothyroxine sodium pentahydrate free from d-enantiomer of thyroxine. Yet another object of the invention is to provide Levothyroxine sodium pentahydrate having liothyronine below 0.5% wt / wl Yet another object of the invention is to provide disodium salt of Levothyroxin as an intermediate for the preparation of Levothyroxine sodium pentahydrate. DETAILED DESCRIPTION OF THE INVENTION: In accordance with the present invention the process for the preparation of levothyroxine sodium comprises the steps of: iodinizing 3,5-diiodothyronine to obtain crude levothyroxine, followed by converting to disodium salt and acidifying the disodium salt to give pure levothyroxine. The purified levothyroxine is converted to levothyroxine sodium having reduced level of impurities. Levothyroxine sodium pentahydrate obtained by the present invention is substantially free from d- enantϊαmer of thyroxine / 3,5-Diiodothyronine impurity. Wherein the end product is showing d-

5 enantiomer of thyroxine / 3,5-Diiodothyronine below the limit of detection and liothyronine impurity is below 0.5% wt / wt. The end product prepared via as described invention is free of coloured impurity. The process for preparation of Levothyroxine sodium comprises the steps, wherein compound obtained from steps a-g is prepared by conventional methods, a. nitrating L-tyrosine to give 3,5- dinitro-l-tyrosine, b. acetylating 3,5- dinitro-l-tyrosine to give 3,5- dinitro-n-acetyl L-tyrosine, c. esterifying the compound obtained from step (b) to give 3,5- diπitro-n-acetyl L-tyrosine ethyl ester, d. reacting the compound obtained from step (c) with p-tsci in presence of pyridine to give corresponding tosylate salt, which is further reacting with 4-methoxy phenol to give 3,5- DinKro-4-p-methoxy phenoxy-n-acetyl-l-phenyl alanine ethyl ester, e. the compound obtained from step (d) is hydrogenated to give 3,5-diamino-4-p-methoxy phenoxy-n-acetyl-l-phenyl alanine ethyl ester, f. the compound obtained from step (e) is tetrazotized and iodized to give 3,5-Diiodo-4-pmethoxy phenoxy-n-acetyl-l-phenyl alanine ethyl ester, g. the compound obtained from step (f) is O-demethylated, N-deacetylated, and deesterified using aqueous HI in acetic acid to give 3,5-Diiodo-4-p-hydroxy phenoxy-l-phe πyl alanine followed by preparing hydrochloride salt of same and isolating, drying i h. lodinating 3,5-Diiodo-4-p-hydroxy pheπoxy-l-phenyl alanine HCI salt using methyl amine, Iodine / potassium iodide (Kl) to give crude levothyroxine; i. converting crude levothyroxine to its disodium salt by using 50% NaOH in ethanol which is filtered and dissolved in water. The disodium salt is acidified with hydrochloric acid up to the ph 4 to 5. The product is obtained by filtration, washing with water and drying to give pure levothyroxine with purity >99 %; j. reacting purified levothyroxine with aqueous 2N sodium carbonate solution to give levothyroxine sodium pentahydrate, which is filtered and dried. The scope of the invention is further illustrated with following not limiting examples. Eχample-1 Preparation of Levothyroxine 20 gm of 3,5-Diiodo-4-p-hydroxy pheπoxy-l-phenyl alanine was added to 200 ml monomethyl amine in 1L 3 neck RBF and stirred. The reaction mixture was cooled to C and a solution of 38.6 gm of iodine and gm of potassium iodide in 80 ml of water were added drop wise over a period of 1 hr. Reaction mixture was stirred for 1 hour and 20 ml of 20% sodium metabisulphite solution was added. ph was adjusted to 5 using 2N HCl acid solution. The reaction mixture was stirred for 1 hour and then filtered. The product was air dried for 2 hours and then dried in oven at 5u-55 C for 4-5 hours. Weight 28 gm (Yield: 95%]

6 [Example: 2 Purification of Levothyroxine: 65 gm of crude Levothyroxjne was stirred with 260 ml hot ethanol. 50% NaOH solution was added to the hot reaction mixture until the clear solution obtained and then the reaction mixture was refluxed for about 15 minutes. The reaction mixture was filtered and cooled up to C and stirred for one hour to allow precipitation- The precipitate was filtered and 600 ml of water was added to the filtered solid to provide dear solution. ph was adjusted ~4 to 5 using of 2 N HCI solution. The reaction mass was stirred for about 1 hour at room temperature and material was fittered, washed with water and dried. Product weight: 5Og, (Yield; 78%, and HPLC Purity: 99%) Example-3 Preparation of Levothyroxine sodium 200ml of 2N sodium carbonate solution filtered through celite bed and charged into RBF. The reaction mixture was heated to reflux. 10 gm Levothyroxine was added in portion with stirring and dissolved in to the reaction mixture. The reaction mixture was cooled to room temperature and stirred for about 30 minutes. The precipitate was formed and filtered under nitrogen atmosphere. The product was dried under vacuum at 50-55'C for 3-4 hours. Product weight 1Og [Yield: 98%] Levothyroxine sodium obtained through above described invention having reduced levels of impurities which high purity. The end product is free from colour impurity. The levothyroxine sodium obtained via above process is useful t o treat an under active thyroid gland (hypothyroidism).

7 We claim: 1. A process for preparing Levothyroxiπe sodium pentahydrate having HPLC purity >99 % comprising : a. reacting 3,5-Diiodo-4-p-hydroxy phenoxy-l-phenyl alanine HCI with methyl amine and an iodine source to give crude Levothyroxiπe, b. converting the crude Levothyroxine to its disodium salt using a sodium source in ethanol, c. separating the precipitate, d. dissolving the precipitate in water and acidifying up to ph 4 to 5, e. separating the precipitate formed, followed by washing with water and drying to give pure Levothyroxine, f. treating Levothyroxine with an aqueous sodium source to give Levothyroxine sodium pentahydrate. 2. The process as claimed in claim-1 wherein the iodine source is Iodine and/or potassium iodide. 3. The process as claimed in claim-1 wherein the sodium source is preferably sodium hydroxide, sodium bicarbonate, or sodium carbonate. 4. The process as claimed in claim-1 wherein Levothyroxin sodium pentahydrate is free from 3,5-Diiodothyronine or d-enantiomer of thyroxine. 5. The process as claimed in claim-1 wherein Levothyroxin sodium pentahydrate with liothyronine <0.5%. 6. Disodium salt of levothyroxine. 7. Levothyroxine sodium pentahydrate substantially free from 3,5-Diiodothyronine. 8. Levothyroxine sodium pentahydrate substantially free from d-enantiomer of thyroxine. 9. Levothyroxine sodium pentahydrate having liothyronine below 0.5% wt / wt.

8 A. CLASSIFICATION OF SUBJECT MATTER INV. C07C227/16 C07C229/08 International application No PCT/IB2009/ According to International Patent Classification (IPC) orto both naliona] classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) C07C Documentation searched other than minimum documentation to the extent that such documents are included In the fields searched Electronic data base consulted during the international search (name of data base and, where practical, search terms used) EPO-Internal, CHEM ABS Data, BEILSTEIN Data C. DOCUMENTS CONSIDERED TO BE RELEVANT Category * Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. DATABASE CA [Onl ine] 6-9 CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MAZZA, PIERGIUSEPPE ET AL: "Process for the production of thyroid hormones and their salts and derivatives, incl uding thyroxine and triiodothyronine and their free bases and monosodium salts, v i a their d i sodium salts" XP retrieved from STN Database accession no. 2003: cited i n the appl ication abstract 1-5 & IT Bl (BRACCO S.P.A., ITALY) 3 1 July ( ) Further documents are listed in the continuation of Box C. See patent family annex. * Special categories of cited documents. ' T * later document published after the international filing date 'A' or priority date and not in conflict with the application but document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention 'E' earlier document but published on or after the international 'X' document of particular relevance, the claimed invention filing date cannot be considered novel or cannot be considered to 'L' document which may throw doubts on priority claim(s) or involve an inventive step when the document is taken atone which is cited to establish the publication date of another 1 Y' document of particular relevance, the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the 'O' document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu other means ments, such combination being obvious to a person skilled 'P' document published prior to the international filing date but in the art. later than the priority date claimed '&' document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 11 September /09/2009 Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5θ1β Patentlaan 2 NL HV Rijswijk TeI. (+31-70) , Fax: (+31-70) Voyiazoglou, D Form PCT7ISA/21O (second sheet) (April 2005)

9 International application No PCT/IB2009/ C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category * Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. US A (ARTHUR HEMS BENJAMIN ET 1-5 AL) 25 December 1951 ( ) claim 1 ; example 7 CLAYTON ET AL: "The synthesis of 1-9 thyroxine and related substances. Part V I The preparation of some derivatives of DL-thyroxine" JOURNAL O F THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 2., 1950, pages , XP GBCHEMICAL SOCIETY. LETCHWORTH. page 842, line 64 - line 73 Form PCT/ISA/210 (continuation of second stiβet) (April 2005)

10 Information on patent family members International application No PCT/IB2009/ Patent document Publication Patent family Publication cited in search report date member(s) date IT Bl IT MI A l US CH A DE C FR A GB A Form PCT/ISA/210 (patent family annex) (April 200S)