DESC:FIELD OF INVENTION

The present invention relates to a process for the preparation of Levothyroxine Sodium (I).

Formula I

BACKGROUND OF THE INVENTION

Levothyroxine Sodium (I) is chemically known as (S)-2-amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,4-diiodophenyl] propanoic acid sodium salt. Levothyroxine Sodium (I) is a synthetic form of thyroid hormone Thyroxine, which is secreted from follicular cells of thyroid gland. Levothyroxine is ideally used for the treatment of thyroid hormone deficiencies such as hypothyroidism. Due to its ability to lower thyroid-stimulating hormone, Levothyroxine is also used in the treatment of goiter and also to prevent the recurrence of thyroid cancer.

Hillmann (Z.Naturforch 1956;llb:424-425) discloses a process for the preparation of Levothyroxine, 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 ester of 3,5 diido-L-tyrosine) and bis (p-anisyl)iodonium bromide in the presence of copper metal or powder as a catalyst to afford (S)-N-acetyl-3,5-diiodo-4-p-methoxyphenoxyphenylalanine ethyl ester, with 87% yield. Two protective groups in (S)-N-acetyl-3,5-diiodo-4-p-methoxyphenoxyphenylalanine ethyl ester ,viz. acetamide, ethyl ester were cleaved using a mixture of hydroiodic acid and hydrobromic acid to give 3,5-Diiodothyronine. 3,5-Diiodothyronine on subsequent iodination with iodine gave L-thyroxine of an yield that corresponds to 92%.

Levothyroxine sodium prepared as per above process, has the following drawbacks:
a) Use of bis (p-anisyl)iodonium bromide in the synthesis of thyroxine leads to the formation of an impurities called monobromo triiodo tyrosine and dibromo triiodo tyrosine which may be categorized as "Genotoxic impurities" based on the structure alerts.
b) Protection and de-protection of intermediates increases the reaction steps, which results in the low product yield and high expenses.

CN 109810009 A discloses a process for the preparation of Levothyroxine sodium (I), by reacting 3,5-diiodo-L-tyrosine (II) with copper sulfate in presence of water/NaOH to produce 3,5-diiodo-L-tyrosine copper complex (III), which undergoes coupling reaction with bis (p-anisyl)iodonium bromide in presence of n-butanol/diisopropylamine to produce 2-amino-3-(3,5-diiodo-4-(4-methoxy phenoxy)phenyl)propanoic acid (IV) followed by demethylation using acetic acid/ hydroiodic acid to produce 3,5-diiodo-L-thyronine (V). Iodination of 3,5-diiodo-L-thyronine (V) using iodine/KI in presence of methanolic methylamine to produce Levothyroxine (VI) followed by treating with aq.Na2CO3 to produce Levothyroxine sodium (I).

The process is as shown in scheme-I below:

Levothyroxine sodium prepared as per scheme-I, has the following drawbacks:
a) Use of bis (p-anisyl)iodonium bromide leads to the formation of an impurities called monobromo triiodo tyrosine and dibromo triiodo tyrosine which may be categorized as "Genotoxic impurities" based on the structure alerts.
b) Use of expensive base and expensive solvent viz. diisopropylamine, methanolic methylamine and n-butanol. Which results in an increase of the production cost of API and hence, not viable on industrial scale.
c) Use alcoholic methylamine, which is difficult to produce on commercial scale and is easily volatile in nature and storage conditions are also difficult.
IN 329097 discloses a process for the preparation of Levothyroxine sodium (I), by reacting 3,5-diiodo-L-tyrosine dihydrate (IIa) with copper sulfate in presence of water/NaOH to produce 3,5-diiodo-L-tyrosine copper complex (III), which undergoes coupling reaction with bis (p-anisyl)iodonium iodide in presence of n-butanol/diisopropylamine to produce 2-amino-3-(3,5-diiodo-4-(4-methoxy phenoxy)phenyl)propanoic acid (IV) followed by demethylation using acetic acid/ hydroiodic acid to produce 3,5-diiodo-L-thyronine (V). Iodination of 3,5-diiodo-L-thyronine (V) using iodine in presence of methanolic methylamine to produce Levothyroxine (VI) followed by treating with aq.NaOH in presence of n-propanol to produce Levothyroxine sodium (I).
The process is as shown in scheme-II below:

Levothyroxine sodium prepared as per scheme-II, has the following drawbacks:
a) Use of methanolic methylamine, which is difficult to produce on commercial scale and is easily volatile in nature and storage conditions are also difficult.
b) Use of expensive base and solvent viz. diisopropylamine and n-butanol, which results in an increase of the production cost of API and hence, not viable on industrial scale.
c) Filtration of Levothyroxine sodium, which is obtained by treating Levothyroxine with NaOH/n-butanol takes more time.
d) Low yield of 3,5-diiodo-L-thyronine (V).

The aforesaid prior art processes cannot be considered for industrial scale preparation in view of their shortcomings such as less yield of the product, high expenses involved, more number of reaction steps, cycle time and concerns about the purity of the end product. Hence there is a long-felt need for the development of an improved process that circumvents the above disadvantages and provides an industrially feasible, cost effective process involving the use of commercially available, simple raw materials in the process. At the same time it is also required that the process or technology developed should be easily adaptable for multi kilo manufacturing plants for scaling-up the most demanding API, Levothyroxine sodium at a very cheap cost.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple, industrially feasible and cost effective process for the preparation of Levothyroxine sodium (I) with high purity and good yield on commercial scale.
SUMMARY OF THE INVENTION

The main embodiment of the present invention is to provide a process for the preparation of Levothyroxine sodium (I),

Formula I

which comprises,

i. reacting 3,5-diioso-L-tyrosine (II) or a hydrated form;

Formula II

with CuSO4 in presence of suitable base and suitable solvent to produce 3,5-diiodo-L-tyrosine copper complex (III);

Formula III

ii. reacting 3,5-diiodo-L-tyrosine copper complex (III) with bis (p-anisyl)iodonium iodide in presence of suitable base and suitable solvent to produce 2-amino-3-(3,5-diiodo-4-(4-methoxy phenoxy)phenyl)propanoic acid (IV);

Formula IV
iii. demethylation of 2-amino-3-(3,5-diiodo-4-(4-methoxy phenoxy)phenyl) propanoic acid (IV) to produce 3,5-diiodo-L-thyronine (V);

Formula V
iv. iodination of 3,5-diiodo-L-thyronine (V) using iodine in presence of suitable base and suitable solvent to produce Levothyroxine (VI);

Formula VI

v. Levothyroxine (VI) is converted to Levothyroxine sodium (I) in presence of sodium source and suitable solvent.
DETAILED DESCRIPTION OF THE INVENTION
The main advantages of the present invention are use of aqueous methylamine, which is easy to produce on commercial scale, non-volatile in nature and requires normal storage conditions. Use of less expensive base and solvent viz. triethylamine and methanol. Ease of filtration of Levothyroxine sodium, which is obtained by treating Levothyroxine with sodium carbonate and isopropylalcohol.
The present invention is related to a process for the preparation of Levothyroxine sodium (I).

The process comprises, reacting 3,5-diiodo-L-tyrosine dihydrate (IIa) with copper sulfate (CuSO4) to produce 3,5-diiodo-L-tyrosine copper complex (III).

The above reaction is carried out in presence of a base and in the presence/absence of a solvent or mixture of solvents thereof. The base comprises an organic base selected from triethylamine, pyridine, methyl amine, diisopropyl ethyl amine, DBU, DABCo and 2,6-Lutidine or an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof. The solvent comprises water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

3,5-Diiodo-L-tyrosine copper complex (III) is reacted with bis (p-anisyl)iodonium iodide to produce 2-amino-3-(3,5-diiodo-4-(4-methoxy phenoxy)phenyl)propanoic acid (IV).

The above reaction is carried out in presence of a base and in the presence of a solvent or mixture of solvents thereof. The base comprises an organic base selected from triethylamine, pyridine, monomethyl amine, dimethyl amine, trimethyl amine, ethyl amine, diethyl amine, diisopropyl ethyl amine, DBU, DABCo and 2,6-Lutidine or an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof. The solvent comprises water, methanol, ethanol, propanol, isopropanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

2-Amino-3-(3,5-diiodo-4-(4-methoxy phenoxy)phenyl)propanoic acid (IV) is demethylated in presence of acid and in presence/absence solvent to produce 3,5-diiodo-L-thyronine (V).

The acid used in above reaction is selected from an organic acid and/or inorganic acid. Organic acid comprises acetic acid, trifluoroacetic acid, formic acid, citric acid or mixtures thereof. Inorganic acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or mixtures thereof. The solvent comprises water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.
Iodination of 3,5-diiodo-L-thyronine (V) using iodine, sodium iodide, potassium iodide or mixtures thereof in presence of suitable base and suitable solvent to produce Levothyroxine (VI).
The base used in above reaction comprises an organic base selected from aqueous monomethyl amine, aqueous dimethyl amine, aqueous trimethyl amine, aqueous ethyl amine, aqueous diethyl amine, aqueous triethylamine, pyridine, diisopropyl ethyl amine, DBU, DABCo and 2,6-Lutidine or an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or mixtures thereof. The solvent comprises water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.
Levothyroxine (VI) is isolated as solid or as such used in next step. Optionally, Levothyroxine (VI) is subjected to purification either by column chromatography or by crystallization by dissolving in a solvent or by adding an anti-solvent.
Levothyroxine (VI) is converted to Levothyroxine sodium (I) in presence of sodium source and suitable solvent.
The sodium source comprises sodium carbonate and sodium bicarbonate. The solvent comprises water, methanol, ethanol, propanol, isopropanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

In another embodiment of the present invention, iodination of L-tyrosine using iodine source in presence of suitable base, suitable solvent and/or suitable acid to produce 3,5-diiodo-L-tyrosine dihydrate (IIa).
The process is shown in below scheme-III:

Scheme-III
The iodine source used in above reaction comprises iodine, sodium iodide, potassium iodide or mixtures thereof. The base comprises an organic base selected from aqueous monomethyl amine, alcoholic monomethyl amine, aqueous or alcoholic dimethyl amine, aqueous or alcoholic trimethyl amine, aqueous or alcoholic ethyl amine, aqueous or alcoholic diethyl amine, aqueous or alcoholic triethylamine, pyridine, diisopropyl ethyl amine, DBU, DABCo and 2,6-Lutidine or an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or mixtures thereof.
The solvent used in above reaction comprises water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof. The acid is selected from an organic acid and/or inorganic acid. Organic acid comprises acetic acid, trifluoroacetic acid, formic acid, citric acid or mixtures thereof. Inorganic acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or mixtures thereof.
In another embodiment of the present invention, para iodo anisole is reacted with anisole in presence of iodine source, solvent and acid and/or acid derivative to produce bis (p-anisyl)iodonium iodide.
The process is shown in below scheme-IV:

Scheme-IV
The iodine source used in above reaction comprises iodine, sodium iodide, potassium iodide or mixtures thereof. The solvent comprises water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof. The acid or acid derivative is selected from methane sulphonic acid, p-TSA, acetic acid, trifluoroacetic acid, formic acid, citric acid, acetic anhydride, propionic anhydride or mixtures thereof.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be constructed to limit the scope of the invention.

Examples:

Example-1: Preparation of 3,5-Diiodo L- Tyrosine copper Complex

RBF was charged with 1600ml of water and 16gms of sodium hydroxide at 20-25°C and stirred to get clear solution. 100g of 3,5 diiodo tyrosine dihydrate was added to the above reaction mass and stirred for an hour to get clear solution .Copper sulphate solution (36.34gms dissolved in 225ml of water at 40-45°C,and maintain for 30-45min at 40-45°C) was then added in to the reaction mixture over a period of 15-30 min at 20-25°C and maintained for 2 - 2.5 hrs at 20-25°C. The resultant reaction mixture was filtered and washed with 250ml of DM water and the wet cake was proceed to next step without drying.
Example-2: Preparation of 2-amino-3-(3,5-diiodo-4-(4-methoxyphenoxy) phenyl)propanoic acid

RBF was charged with above wet cake and 2000ml of DM water to which 1600ml of methanol was added over a period of 15-20min at 15-20°C. RBF was then charged with 32gm of triethyl amine at 20°C and 200g of of Bis (P-anisyl)iodonium iodide was added into the reaction mixture at 20-25°C. The reaction mixture was maintained for 1-1hr 30 min at 20-25°C and slowly raised the reaction mass temperature to 65-70°C and maintained for 5-6hrs at 65-70°C. Cooled the reaction mass temperature to 25-30°C, and maintained for 45 min at 25-30°C followed by filtered and washed with100 ml of DM water and 100ml of Methanol (wash the wet material twice with methanol and DM water) and the wet cake was proceed to next step without drying.

The above wet cake was stirred with 1000ml of DM water and 1000ml of Toluene at 20-25°C followed by slowly added dil HCl solution for 30-45min at 25-30°C (add 150gms of HCl in 130ml of DM water), stirred the reaction mass for 2-2hrs 30 min at 25-30°C. Filtered the reaction mass and washed with 150ml of Toluene (twice), 175ml of Methyl isobutyl ketone (twice) and hydrochloric acid solution (take 58gms of HCl and 250ml of DM water). The wet cake was proceed to next step without drying.

The above wet cake was stirred with 830ml of DM water and 207gms of HCl for 2-3hrs at 25-30°C, filtered and washed with mixture of 834ml of DM water and 207gms HCl.

RBF was charged with 420g acetic acid and above wet compound, stirred the reaction mass at 25-30°C for 15- 30 min. 500g of aq. hydro iodic acid was added then raised the reaction mass temperature to 60-65°C, further raised the reaction mass temperature to 103-108°C and maintained for 6-8hrs at 103-108°C, then cooled the reaction mass to 20-25°C. The reaction mixture was quenched with aq. sodium bisulphite solution (100g of Sodium bisulphite in 2000ml DM). The pH of the reaction mixture was adjusted to 3-5 with sodium hydroxide solution (208.3gms of NaOH dissolved in 416ml of DM water at 20-25°C) and maintained for 30-45min at 20-25°C. Filtered the reaction mass and washed with 500ml of DM water (thrice) followed by 200ml of methanol (twice). The wet cake was proceed to next step without drying.

Example-3: Preparation of Levothyroxine

RBF was charged with 400ml of DM water and 335.11g of potassium iodide, stirred the contents for 10-15min at 20-25°C, 106.34g of iodine was added under stirring and continued the stirring of the contents for 20-25minutes at 20-25°C then charged 1280ml of DM water. 1000ml of aqueous mono methyl amine and 100gms of 3,5 diiodothyronine was taken in to another RBF, and stirred for 15-20min to get clear solution, cooled the reaction mass to 3-8°C. Slowly added the above iodine solution in to the reaction mass at 3-8°C over a period of 1-2 hrs and maintained for 30-45 minutes at 3-8°C followed by raised the reaction mass temperature to 20-25°C, charged 100gms of sodium bisulphate and 300gms of sodium acetate in to the reaction mixture at 20-25°C and maintained for 30-45min at 25-30°C. Filtered the reaction mass and washed with 100ml water (twice) followed by 200ml of acetonitrile (twice) and unloaded the wet compound.

Charged 1000ml of DM water and above wet compound in to RBF. Adjusted the reaction mass pH to 6.5-7 with dil HCl solution (100g of Con HCl in 100ml of DM water), stirred the reaction mass for 1-2hrs at 25-30°C. Filtered the reaction mass and washed with 100ml of water (twice) followed by 200ml of acetonitrile (twice). Dried the compound at 50-55°C under vacuum for 6-8 hrs. Yield of Levothyroxine is 120 -140g.

Example-4: Preparation of Levothyroxine Sodium

RBF was charged with 636ml of methanol and Levothyroxine, cooled the reaction mass to 0-5°C and slowly charged 23g of HCl to get clear solution. The reaction mass was filtered through 0.45 micron membrane and the filtrate pH was adjusted to 7.5-8.5 at 5-10°C with aqueous ammonia. The reaction mass was then heated to 60-65°C and maintained for 1-2 hrs at 60-65°C, followed by cooling to 40-45°C and filtered at 45°C and washed with hot methanol (twice). The wet cake is then charged with soda ash solution (25g of Soda ash in 500ml of dm water and filter through 0.2µ micron filter) at 25-30°C (pH was maintained at 9.0-10.5), followed by slow addition of 160ml of isopropyl alcohol. Heated the reaction mass to 50-55°C and maintained for 60-90min at 50-55°C followed by cool the reaction mass temperature to 25-30°C and maintained for 60-90 min at 25-30°C. Filtered the reaction mass and washed the wet cake with mixture isopropyl alcohol and water followed by wash with soda ash solution and suck dried for 15-20min at 25-30°C to get 80g - 90g of pure Levothyroxine sodium with MC NMT10%. ,CLAIMS:WE CLAIM:

1. A process for the preparation of Levothyroxine sodium (I),

Formula I

which comprises,

i. reacting 3,5-diioso-L-tyrosine (II) or a hydrated form;

Formula II

with CuSO4 in presence of suitable base and suitable solvent to produce 3,5-diiodo-L-tyrosine copper complex (III);

Formula III
ii. reacting 3,5-diiodo-L-tyrosine copper complex (III) with bis (p-anisyl)iodonium iodide in presence of suitable base and suitable solvent to produce 2-amino-3-(3,5-diiodo-4-(4-methoxy phenoxy)phenyl)propanoic acid (IV);

Formula IV
iii. demethylation of 2-amino-3-(3,5-diiodo-4-(4-methoxy phenoxy)phenyl) propanoic acid (IV) to produce 3,5-diiodo-L-thyronine (V);

Formula V
iv. iodination of 3,5-diiodo-L-thyronine (V) using iodine in presence of suitable base and suitable solvent to produce Levothyroxine (VI);

Formula VI

v. Levothyroxine (VI) is converted to Levothyroxine sodium (I) in presence of sodium source and suitable solvent.

2. The process as claimed in claim 1, wherein suitable base used in step-i, step-ii and step-iv comprises an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or an organic base selected from triethylamine, pyridine, aqueous or alcoholic methyl amine, ethyl amine, diisopropyl ethyl amine, DBU, DABCo and 2,6-Lutidine or mixtures thereof.

3. The process as claimed in claim 1, wherein suitable solvent used in step-i, step-ii, step-iv and step-v comprises water, methanol, ethanol, propanol, isopropanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, methyl isobutyl ketone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

4. The process as claimed in claim 1, wherein demethylation of step-iii is carried out in presence of acetic acid, propionic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and/or mixtures thereof.

5. The process as claimed in claim 1, wherein iodination of step-iv is carried out in presence of sodium iodide, potassium iodide.

6. The process as claimed in claim 1, wherein sodium source used in step-v comprises sodium hydroxide, sodium carbonate, sodium bicarbonate.

7. The process as claimed in claim 1, wherein the product of step-i, step-ii and step-iii are proceed to next step without drying.