WO2009136249A1 - Procédé amélioré pour la préparation de lévothyroxine sodique présentant des taux réduits d’impuretés - Google Patents

Procédé amélioré pour la préparation de lévothyroxine sodique présentant des taux réduits d’impuretés Download PDF

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Publication number
WO2009136249A1
WO2009136249A1 PCT/IB2009/005468 IB2009005468W WO2009136249A1 WO 2009136249 A1 WO2009136249 A1 WO 2009136249A1 IB 2009005468 W IB2009005468 W IB 2009005468W WO 2009136249 A1 WO2009136249 A1 WO 2009136249A1
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WO
WIPO (PCT)
Prior art keywords
levothyroxine
sodium
pentahydrate
give
levothyroxine sodium
Prior art date
Application number
PCT/IB2009/005468
Other languages
English (en)
Inventor
Bakulesh Mafatlal Khamar
Renugadevi Gurusamy
Maruti Naik Ravi
Vedururi Madhava Reddy
Balasubrahmanyam Edde
Ravi Ponnaiah
Indravadan Ambalal Modi
Original Assignee
Cadila Pharmaceuticals Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cadila Pharmaceuticals Ltd. filed Critical Cadila Pharmaceuticals Ltd.
Publication of WO2009136249A1 publication Critical patent/WO2009136249A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton

Definitions

  • the invention relates to an improved process for the preparation of levothyroxine sodium with reduced levels of impurities.
  • 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 798.86 gm/mol (anhydrous), and structural formula is shown below:
  • 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.
  • US patent no. 5917087 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.
  • resulting hydrochloride salt of levothyroxine contains T 2 , T 3 and d-T 4 impurities.
  • US patent no. 2889363 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 biphe ⁇ yl ether moiety yields Levothyroxine, as a free base, which is converted to its sodium salt of Levothyroxine (pentahydrate).
  • Italian patent IT1302201 B1 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 penentahydrate comprising the steps of nitration of L-tyrosine with HNO 3 in
  • the present invention is providing the process which provides the Levothyroxine with high purity and reduced level of impurities.
  • 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.
  • 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- enant ⁇ mer of thyroxine / 3,5-Diiodothyronine impurity.
  • the end product is showing d- 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- di ⁇ itro-N-acetyl L-tyrosine ethyl ester, d.
  • step (c) 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-p- methoxy phenoxy-N-acetyl-L-phenyl alanine ethyl ester
  • 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 ⁇ yl alanine followed by preparing hydrochloride salt of same and isolating, drying it h. lodinating 3,5-Diiodo-4-p-hydroxy phe ⁇ oxy-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 .
  • 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 to treat an under active thyroid gland (hypothyroidism).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L’invention concerne un procédé amélioré pour la préparation de lévothyroxine sodique présentant des taux réduits d’impuretés. L’invention concerne également une lévothyroxine sodique pentahydratée ne contenant pas de 3,5-diiodothyronine ou l’énantiomère d de la thyroxine. L’invention concerne en outre une lévothyroxine sodique pentahydratée contenant moins de 0,5 % en poids/poids de liothyronine.
PCT/IB2009/005468 2008-05-09 2009-05-04 Procédé amélioré pour la préparation de lévothyroxine sodique présentant des taux réduits d’impuretés WO2009136249A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN991MU2008 2008-05-09
IN991/MUM/2008 2008-05-09

Publications (1)

Publication Number Publication Date
WO2009136249A1 true WO2009136249A1 (fr) 2009-11-12

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/005468 WO2009136249A1 (fr) 2008-05-09 2009-05-04 Procédé amélioré pour la préparation de lévothyroxine sodique présentant des taux réduits d’impuretés

Country Status (1)

Country Link
WO (1) WO2009136249A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011073409A1 (fr) * 2009-12-18 2011-06-23 Bracco Imaging Spa Préparation d'hormones thyroïdiennes et de leurs sels
WO2015011573A1 (fr) * 2013-07-24 2015-01-29 Azico Pharmaceuticals Private Limited Nouveau procédé pour la préparation de lévothyroxine sodique
WO2015151013A1 (fr) 2014-03-31 2015-10-08 Lupin Limited Procédé de préparation de lévothyroxine et de sels de celle-ci
US20190321316A1 (en) * 2016-07-05 2019-10-24 Emp Levo Us B.V. Methods for the preparation of a levothyroxine solution

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2579668A (en) * 1948-12-31 1951-12-25 Glaxo Lab Ltd Preparation of thyroxine and its derivatives
IT1302201B1 (it) * 1998-09-11 2000-07-31 Bracco Spa Processo per la produzione di ormoni tiroidei.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2579668A (en) * 1948-12-31 1951-12-25 Glaxo Lab Ltd Preparation of thyroxine and its derivatives
IT1302201B1 (it) * 1998-09-11 2000-07-31 Bracco Spa Processo per la produzione di ormoni tiroidei.

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CLAYTON ET AL: "The synthesis of thyroxine and related substances. Part VI. The preparation of some derivatives of DL-thyroxine", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 2., 1950, GBCHEMICAL SOCIETY. LETCHWORTH., pages 840 - 843, XP002545458 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MAZZA, PIERGIUSEPPE ET AL: "Process for the production of thyroid hormones and their salts and derivatives, including thyroxine and triiodothyronine and their free bases and monosodium salts, via their disodium salts", XP002545459, retrieved from STN Database accession no. 2003:270014 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102781907B (zh) * 2009-12-18 2015-11-25 伯拉考成像股份公司 甲状腺激素及其盐的制备方法
EP2338875A1 (fr) * 2009-12-18 2011-06-29 Bracco Imaging S.p.A Procédé de préparation d'hormones thyroïdiennes et dérivés correspondants
CN102781907A (zh) * 2009-12-18 2012-11-14 伯拉考成像股份公司 甲状腺激素及其盐的制备方法
JP2013514337A (ja) * 2009-12-18 2013-04-25 ブラッコ・イメージング・ソシエタ・ペル・アチオニ 甲状腺ホルモンおよびその塩の製造方法
US8759572B2 (en) 2009-12-18 2014-06-24 Bracco Imaging S.P.A. Process for the preparation of thyroid hormones and salts thereof
AU2010332798B2 (en) * 2009-12-18 2014-09-18 Bracco Imaging Spa Process for the preparation of thyroid hormones and salts thereof
WO2011073409A1 (fr) * 2009-12-18 2011-06-23 Bracco Imaging Spa Préparation d'hormones thyroïdiennes et de leurs sels
WO2015011573A1 (fr) * 2013-07-24 2015-01-29 Azico Pharmaceuticals Private Limited Nouveau procédé pour la préparation de lévothyroxine sodique
US9428444B2 (en) 2013-07-24 2016-08-30 Azico Biophore India Private Limited Process for the preparation of levothyroxine sodium
WO2015151013A1 (fr) 2014-03-31 2015-10-08 Lupin Limited Procédé de préparation de lévothyroxine et de sels de celle-ci
US9932295B2 (en) 2014-03-31 2018-04-03 Lupin Limited Process for preparation of levothyroxine and salts thereof
US20190321316A1 (en) * 2016-07-05 2019-10-24 Emp Levo Us B.V. Methods for the preparation of a levothyroxine solution
US11096915B2 (en) * 2016-07-05 2021-08-24 Emp Levo Us B.V. Methods for the preparation of a levothyroxine solution
US20210353577A1 (en) * 2016-07-05 2021-11-18 Emp Levo Us B.V. Methods for the preparation of a levothyroxine solution
US11938109B2 (en) 2016-07-05 2024-03-26 Emp Levo Us B.V. Methods for the preparation of a levothyroxine solution

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