WO2009136249A1 - An improved process for the preparation of levothyroxine sodium with reduced levels of impurities - Google Patents
An improved process for the preparation of levothyroxine sodium with reduced levels of impurities Download PDFInfo
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- 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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- levothyroxine
- sodium
- pentahydrate
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- levothyroxine sodium
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- 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
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- 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
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.
Description
TITLE OF THE INVENTION:
An 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 (T4) sodium has an empirical formula of
molecular weight of 798.86 gm/mol (anhydrous), and structural formula is shown below:
Levothyroxine sodium
3,5-Diiodothyronine (T2), liothyronine (T3) and the d-enantiomer of thyroxine (d-T4) 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 - T3 3|5 Diiodothyronine - T2 d-Thyroxine - (d-T4)
CAS No. 6893-02-3 CAS No. 534-51-0 CAS No. 51-49-0
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.
By following the process as described in US patent 5917087, resulting hydrochloride salt of levothyroxine contains T2, T3 and d-T4 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 bipheπyl ether moiety yields Levothyroxine, as a free base, which is converted to its sodium salt of Levothyroxine (pentahydrate).
J Chem. Soc, (1949) 3424-33 describes the process for the synthesis of Levothyroxine sodium which is schematically mentioned below
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 (pentahydrate) comprising the steps of nitration of L-tyrosine with HNO3 in
H2SO4 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)2SrO to give 91.6% 3,5-diπitro-N-acetyl-L-tyrosiπe Et ester. The resulting compound underwent O-tosylation and coupling with 4-MeOC6H4OH 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 55-60°C and
treated with 50% aq. NaOH. Upon cooling gives a precipitates of moist Levothyroxiπe disodium salt. The disodium salt was filtered, dissolved in aq. NaOH and decolorized with carbon and Na2SO3, filtered. The filtrate is acidified with aq. HCI, heated and basrfied with aq. Na2CO3. 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-
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-p- methoxy 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-pheπyl alanine followed by preparing hydrochloride salt of same and isolating, drying it 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 0-50C and a solution of 38.6 gm of iodine and 104.9 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-55βC for 4-5 hours. Weight 28 gm (Yield: 95%]
[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 0-50C 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 2N 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 to treat an under active thyroid gland (hypothyroidism).
Claims
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.
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| IN991MU2008 | 2008-05-09 | ||
| IN991/MUM/2008 | 2008-05-09 |
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| WO2009136249A1 true WO2009136249A1 (en) | 2009-11-12 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011073409A1 (en) * | 2009-12-18 | 2011-06-23 | Bracco Imaging Spa | Process for the preparation of thyroid hormones and salts thereof |
| WO2015011573A1 (en) * | 2013-07-24 | 2015-01-29 | Azico Pharmaceuticals Private Limited | Novel process for the preparation of levothyroxine sodium |
| WO2015151013A1 (en) | 2014-03-31 | 2015-10-08 | Lupin Limited | A 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 |
Citations (2)
| 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 (en) * | 1998-09-11 | 2000-07-31 | Bracco Spa | PROCESS FOR THE PRODUCTION OF THYROID HORMONES. |
-
2009
- 2009-05-04 WO PCT/IB2009/005468 patent/WO2009136249A1/en not_active Ceased
Patent Citations (2)
| 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 (en) * | 1998-09-11 | 2000-07-31 | Bracco Spa | PROCESS FOR THE PRODUCTION OF THYROID HORMONES. |
Non-Patent Citations (2)
| 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)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102781907B (en) * | 2009-12-18 | 2015-11-25 | 伯拉考成像股份公司 | The preparation method of Triiodothyronine and salt thereof |
| EP2338875A1 (en) * | 2009-12-18 | 2011-06-29 | Bracco Imaging S.p.A | Process for the preparation of thyroid hormones and derivatives thereof |
| CN102781907A (en) * | 2009-12-18 | 2012-11-14 | 伯拉考成像股份公司 | Process for the preparation of thyroid hormones and salts thereof |
| JP2013514337A (en) * | 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 | Method for producing thyroid hormone and salts thereof |
| 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 (en) * | 2009-12-18 | 2011-06-23 | Bracco Imaging Spa | Process for the preparation of thyroid hormones and salts thereof |
| WO2015011573A1 (en) * | 2013-07-24 | 2015-01-29 | Azico Pharmaceuticals Private Limited | Novel process for the preparation of levothyroxine sodium |
| US9428444B2 (en) | 2013-07-24 | 2016-08-30 | Azico Biophore India Private Limited | Process for the preparation of levothyroxine sodium |
| WO2015151013A1 (en) | 2014-03-31 | 2015-10-08 | Lupin Limited | A process for preparation of levothyroxine and salts thereof |
| 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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