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(12) Patent Application Publication (10) Pub. No.: US 2016/0168076 A1 Rao Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0168076 A1 Rao Et Al US 2016O168076A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0168076 A1 Rao et al. (43) Pub. Date: Jun. 16, 2016 (54) NOVEL PROCESS FOR THE PREPARATION (30) Foreign Application Priority Data OF LEVOTHYROXINE SODIUM Jul. 24, 2013 (IN) ........................... 3309/CHFA2013 (71) Applicant: AZICO BIOPHORE INDIA PRIVATE LIMITED, Hyderabad, Andhra Pradesh Publication Classification (IN) (51) Int. Cl. (72) Inventors: Ch.A.P. Rao, Hyderabad (IN); Sreenath C07C 229/08 (2006.01) Dasari, Hyderabad (IN) (52) U.S. Cl. CPC .................................... C07C 229/08 (2013.01) (73) Assignee: AZICO BIOPHORE INDIA PRIVATE LIMITED, Hyderabad, TG (IN) (57) ABSTRACT The present invention provides a novel process for the prepa (21) Appl. No.: 14/907,048 ration of highly pure Levothyroxine Sodium, i.e., (S)-2- (22) PCT Filed: Jan. 30, 2014 nylamino-3-4-(4-hydroxy-3, R E. Sin 5-diiodophenoxy)-3,5-diiodophe salt via ps R in NAS (86). PCT No.: PCT/B14/58662 viz 3.5-Diiodo L-Tyrosine copper complex and novel Bis (p-anisyl) iodonium Iodide. The invention also provides S371 (c)(1), levothyroxine pentahydrate free from genotoxic impurities (2) Date: Jan. 22, 2016 and liothyronine levels below 0.04% wt/wt. US 2016/0168076 A1 Jun. 16, 2016 NOVEL PROCESS FOR THE PREPARATION 1-tyrosine have been protected by Suitable protecting groups, OF LEVOTHYROXINE SODIUM characterised in that the reaction is performed at a pressure of about 20 atmospheres in the presence of an organic amine FIELD OF THE INVENTION additive using a gaseous oxidant comprising oxygen and 0001. The present invention relates to a novel process for optionally an inert diluent. The process optionally further the preparation of pure Levothyroxine Sodium, i.e., (S)-2- comprises acid hydrolysis of the biphenyl ether derivative amino-3-4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophe with hydrochloric acid to form 1-thyroxine hydrochloride salt nylpropanoic acid sodium salt via two process intermediates and generation of Sodium-1-thyroxine from the 1-thyroxine viz 3.5-Diiodo L-Tyrosine copper complex and novel Bis hydrochloride salt. (p-anisyl) iodonium Iodide. 0007 PCT publication number WO2009136249 provides a process for the preparation of levothyroxine sodium and BACKGROUND OF THE INVENTION comprises the steps of iodinating 3, 5-diiodothyronine to obtain crude levothyroxine, followed by its conversion to 0002 Levothyroxine Sodium is a synthetic form of thy disodium salt and acidifying the disodium salt to give pure roid hormone Thyroxine, which is secreted from follicular levothyroxine. The purified levothyroxine is converted to cells of thyroid gland. Levothyroxine is ideally used for the levothyroxine sodium having reduced level of impurities. treatment of thyroid hormone deficiencies such as hypothy Levothyroxine sodium obtained by this invention is substan roidism. Due to its ability to lower thyroid-stimulating hor tially free from d-enantiomer of thyroxine/3, 5-Diiodothyro mone, Levothyroxine is also used in the treatment of goiter nine impurity. The process also reports the d-enantiomer of and also to prevent the recurrence of thyroid cancer. thyroxine/3, 5-Diiodothyronine levels below the limit of 0003 Levothyroxine Sodium has the following chemical detection and liothyronine impurity below 0.5% wit/wt. The Structure. end product derived from this process is also free from coloured impurities. I O 0008. Many patent and non-patent literature describe the use of an intermediate called Bis(p-anisyl)iodonium bromide HO I Na" in the preparation of Levothyroxine sodium. Hillmann (Z. O Naturforch 1956; 11b:424-425) describes a process for the NG) assembly of the biphenyl-ether system present in Levothy I O roxine, wherein a key coupling reaction is initiated between N-Acetyl 3,5-diiodo-L-tyrosine ethyl ester, derived from the stepwise protective conversion of amine as amide and acid as (3) indicates text missing or illegible when filed ester of 3.5 dido-L-tyrosine, and Bis(p-anisyl)iodonium bro mide in the presence of copper metal or powder as a catalyst to afford (S) N-acetyl-3,5-diiodo-4-p-methoxyphenox 0004 For the preparation of Levothyroxine Sodium sev yphenylalanine ethyl ester, with 87% yield. All the three eral methods have been known. U.S. Pat. No. 2,889,363 dem protective groups in (S)-N-acetyl-3,5-diiodo-4-p-methox onstrates the use of animal natural sources as starting material yphenoxyphenylalanine ethyl ester, viz. acetamide, methyl for the preparation of thyroxine while U.S. Pat. No. 2,889,364 ether, ethyl ester were cleaved using a mixture of Hydroiodic discloses an enzymatic or bio-mimetic method of synthesis acid and Hydrobromic acid to give 3,5-Diiodothyronine. 3.5- for levothyroxine. Diiodothyronine on Subsequent iodination with iodine gave 0005. The invention disclosed in U.S. Pat. No. 2,889,363 L-thyroxine of an yield that corresponds to 92%. provides a process for the production of esters of N-acylthy roxine with a substantial reduction in the time period and 0009. The use of Bis (p-anisyl)iodonium bromide in the involves digestive coupling reactions in which alkyl esters of synthesis of thyroxine leads to the formation of an impurities N-acyldilidotyrosine yield alkyl esters of N-acylthyroxine in a called monobromo triiodo tyrosine and dibromo triiodo greatly reduced time in the presence of optimal catalyst con tyrosine which may be categorized as “Genotoxic impurities’ centration, pH range and alcohol concentration. This prior art based on the structure alerts. The levothyroxine compositions further involves a process for production of thyroxine by thus prepared are not generally preferred due to their geno incubating alkyl esters of N-acyldilidotyrosine derived from toxic impurity content associated with purified LevothyroX lower alkanols and lower alkanoic acids in aqueous solution 1C. of ethanol (70%) of pH of 9.5-10.5 and in the presence of 0010. The aforesaid prior art processes cannot be consid between 1.5 and 5% by weight of a manganese containing ered for industrial scale preparation in view of their short catalyst while passing Substantially pure oxygen through the comings such as less yield of the product, high expenses Solution and while maintaining the temperature in the range involved, pressure reactions which are less feasible for com of 25°C. to 78°C., and hydrolytically removing acyl and ester mercialization of the product, more number of reaction steps, substituents from the ester of N-acylthyroxine obtained from cycle time and concerns about the purity of the endproduct. the incubation step. Hence there is a long-felt need for the development of an 0006 PCT publication No. WO 199601 1904 discloses improved process that circumvents the above disadvantages further improvements to a six stage process for production of and provides an industrially feasible, cost effective process sodium 1-thyroxine from 1-tyrosine as described in U.S. Pat. involving the use of commercially available, simple raw No. 2,889,363 and U.S. Pat. No. 2,889,364. These improve materials in the process. At the same time it is also required ments comprise the oxidative coupling of a diiodo-1-tyrosine that the process or technology developed should be easily to form a biphenyl ether derivative, catalysed by a manganese adaptable for multikilo manufacturing plants for scaling-up salt in which the amine and acid functionality of the diiodo the most demanding API product, Levothyroxine Sodium at a US 2016/0168076 A1 Jun. 16, 2016 very cheap cost, compared to the current import costs of the 0024. The process for the preparation of Levothyroxine material and contemporary technologies in Vogue. Sodium comprises the steps of 0.025 a. Reacting 3,5-Diiodotyrosine dihydrate with OBJECTS OF THE INVENTION aqueous copper Sulphate Solution to give 3, 5-diiodo L-Tyrosine copper complex 0011. It is an object of the present invention to provide an 0026 b. Initiating coupling reaction between 3, 5-di improved and industrially realisable process for preparing iodo L-Tyrosine copper complex and Bis (p-anisyl)io Levothyroxine Sodium. donium iodide to give 2-Amino-3-(3,5-diiodo-4-(4- 0012 Another object of the present invention is to provide methoxy phenoxy)phenyl)propanoic acid in the an improved process for preparing Levothyroxine Sodium, presence of Diisopropylamine in n-Butanol. which is simple, convenient and economical with commercial 0027 c. Demethylation of 2-Amino-3-(3,5-diiodo-4- feasibility. (4-methoxyphenoxy)phenyl)propanoic acid using a 0013 Yet another object of the present invention is to mixture of Acetic acid and Hydroiodic acid to give 3.5- provide an improved process for preparing Levothyroxine diiodothyronine, an intermediate of L-Thyroxine and Sodium by involving two new process intermediates namely 0028 d. Iodinizing 3,5-diiodothyronine with methan 3,5-Diiodo L-Tyrosine copper complex and novel Bis (p-ani olic monomethylamine and Iodine to obtain Levothy syl)iodonium Iodide. roxine 0014. A further object of the present invention is to pro 0029 e. Converting Levothyroxine to its sodium salt by vide an improved process for preparing Levothyroxine using sodium hydroxide solution and n-butanol fol Sodium by using unprotected L-Thyrosine in the reaction. lowed by filtering and drying to give pure Levothyroxine 00.15 Yet another object of the invention is to provide a Sodium. process for preparing pure Levothyroxine Sodium that is 0030. It will be apparent to the skilled person that certain devoid of any genotoxic impurities generated in the process. changes and modifications may be practiced within the scope 0016. Another object of the invention is to provide a pro of the invention. Following examples illustratively demon cess for preparing pure Levothyroxine Sodium obtained with strate the process of the present invention, without posing any liothyronine impurities <0.04%.
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