A production process of levothyroxine sodium

Abstract

The present invention relates to a production process of levothyroxine sodium, comprising the following steps of preparation of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, preparation of 3,5-diiodo-L-thyroxine, preparation of L-thyroxine, preparation of levothyroxine sodium, etc., which can increase the product yield and improve the purity of the product. The present invention aims to provide a production process of levothyroxine sodium, which is not only simple to produce and shorten the reaction time, but also improves the yield and has higher safety, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical synthesis, and in particular to a production process of levothyroxine sodium. Background Art

[0002] Levothyroxine sodium, also known as L-thyroxine sodium, is a thyroid hormone drug, mainly used to treat hypothyroidism and simple goiter caused by various reasons. L-thyroxine is a substitute for human thyroid hormone deficiency and has a large clinical use volume and a broad market prospect.

[0003] The extraction methods of L-thyroxine mainly include biological extraction method and chemical synthesis method. Among them, the development of biological extraction method is limited by its low extraction purity and limited quantity. At present, the chemical synthesis method is mainly used, which uses tyrosine as a raw material to finally synthesize L-thyroxine. There are many kinds of synthetic intermediates, complicated steps, low reaction yield and long time. Existing literature records that L-tyrosine is used as a raw material to prepare 3,5-diiodo-L-tyrosine, N-acetyl-3,5-diiodo-L-tyrosine, N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, N-acetyl-L-thyroxine ethyl ester and other intermediates in sequence, and finally synthesize L-thyroxine, and then alkalize it with sodium alkali solution, heat and filter to obtain L-thyroxine sodium. At present, the synthesis scheme of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester is relatively mature, and the research direction is also mainly focused on the coupling reaction of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester. The existing technology mostly uses a coupling agent plus a catalyst to react under heating and sufficient oxygen conditions to generate N-acetyl-L-thyroxine ethyl ester, but the heating and oxygen production in organic reactions have too high requirements on factory safety and equipment. It is also difficult to achieve filtration under heating in the subsequent preparation of L-thyroxine sodium, and although the purity of the obtained product can be improved by recrystallization, it will inevitably lead to a decrease in the product yield.

[0004] Based on the above situation, the market is in urgent need of a production process that is simple to produce, can shorten the reaction time, increase the yield and is safer. Summary of the invention

[0005] The present invention aims to provide a production process of levothyroxine sodium, which is not only simple in production and shortens the reaction time, but also improves the yield and has higher safety, and is suitable for industrial production.

[0006] The above technical objectives of the present invention are achieved through the following technical solutions: A production process of levothyroxine sodium, comprising the following steps:

[0007] Step S1, preparation of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester:

[0008] Sequentially add N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)-iodine bromide, triethylamine, and a mixture of manganese chloride to the reaction kettle 1, then add the solvent methanol and stir evenly, remove the methanol under reduced pressure, add ethyl acetate and stir evenly, then filter and remove the solid, remove the ethyl acetate under reduced pressure, add ethanol and a petroleum ether / water mixture to the reaction kettle, filter, and dry the obtained solid to obtain 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester;

[0009] Step S2, preparation of 3,5-diiodo-L-thyroxine:

[0010] 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, glacial acetic acid and HBr solution were added to the reaction kettle 2 in sequence, the temperature was raised to reflux, the mixture was kept warm and stirred for a period of time, and then cooled to room temperature. After the acetyl group was removed by reaction, Na2SO3 was added to the reaction solution to quench the reaction, and then the mixture was stirred and filtered. The obtained solid was dried to obtain 3,5-diiodo-L-thyroxine;

[0011] Step S3, preparation of L-thyroxine:

[0012] Add 3,5-diiodo-L-thyroxine to the reaction kettle 3, add dimethylamine aqueous solution to provide an alkaline environment, then drop I2 / NaI·2H2O methanol solution, stir evenly at room temperature after the dropwise addition, then add Na2SO3 and stir, filter, and draw the filtrate back to the reaction kettle 3, adjust the solution pH to weak acidity, filter, and dry the obtained solid to obtain L-thyroxine;

[0013] Step S4, preparation of levothyroxine sodium:

[0014] Add L-thyroxine to the reaction kettle 4, add a sufficient amount of ethanol aqueous solution, heat up, add NaOH aqueous solution, keep warm and stir, cool to room temperature, and filter. Put the filter cake into the reaction kettle 4 and add NaOH aqueous solution until it is completely dissolved, adjust the solution pH to 8-10, stir evenly, filter the solution, and dry the obtained solid to obtain sodium levothyroxine.

[0015] As a further configuration of the present invention, in step S1, the molar ratio of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)-iodine bromide, triethylamine and manganese chloride is 1:1.8-2.0:1-1.2:0.07-0.09.

[0016] As a further configuration of the present invention, the methanol solvent is added in step S1 and then stirred at room temperature for 48 hours, and the volume ratio of ethanol, petroleum ether and water is 1:5:5.

[0017] As a further configuration of the present invention, in step S2, the molar ratio of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, and Na2SO3 is 1:0.3-0.35:0.23-0.25, and the heat preservation and stirring time is 3.5 hours.

[0018] As a further configuration of the present invention, the molar ratio of 3,5-diiodo-L-thyroxine, I2, NaI·2H2O, and Na2SO3 in step S3 is 1:2.0-2.2:3.0-3.2:0.35-0.45, and the concentration of the dimethylamine aqueous solution is 30-35%.

[0019] As a further configuration of the present invention, the methanol solution of I2 / NaI·2H2O is added dropwise for 2.5 to 3.0 hours in step S3, and stirred at room temperature for 1.0 hour after the addition.

[0020] As a further configuration of the present invention, in step S3, the filtrate is pumped back into the reaction kettle 3 and then cooled to 0-10° C. with ice water and stirred for 10 minutes, and the pH value of the solution is adjusted to 6 with hydrochloric acid.

[0021] As a further configuration of the present invention, in step S4, the molar ratio of L-thyroxine to NaOH is 1:4, the concentration of the ethanol aqueous solution is 85-90%, and NaOH is configured into a 30% solution and added twice, and the molar ratio of the two additions is 16-17:1 respectively.

[0022] As a further configuration of the present invention, in step S4, the temperature is raised to 80° C., a NaOH aqueous solution is added, the mixture is stirred for 10 to 15 minutes and cooled to room temperature, and the pH value of the solution is adjusted to 8 to 10 with hydrochloric acid.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] 1. The present invention provides a production process of levothyroxine sodium. The technical solution is novel and can be completed without oxygen in the production process. Methanol is used as a solvent, manganese chloride is used as a catalyst, and triethylamine provides an alkaline environment, so that the coupling reaction of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester and di(4-methoxyphenyl)-iodine bromide can be carried out at room temperature, which greatly shortens the reaction time, makes the reaction safe and stable, and improves the product yield and purity.

[0025] 2. The present invention provides a production process for levothyroxine sodium, which has a reasonable process design. In the preparation of L-thyroxine, an alkaline environment provided by a dimethylamine aqueous solution is utilized, and a methanol solution of I2 / NaI·2H2O is added dropwise. The reaction process does not require heating and reflux and only needs to react at room temperature, which not only saves energy but also improves the safety and controllability of the reaction, improves the yield and purity of the product, and facilitates the subsequent preparation of levothyroxine sodium.

[0026] 3. The present invention provides a production process for levothyroxine sodium. The method is simple to operate. The combination of the first ethanol aqueous solution and NaOH can not only improve the reaction yield but also remove some impurities. NaOH is subsequently added to adjust the pH to 8-10 and stir evenly. The generated product is more stable. No ultra-high temperature is required in the initial reaction stage, and the filtration stage is at room temperature without operations such as recrystallization. This not only simplifies the reaction steps, but also improves the yield and purity of levothyroxine sodium. DETAILED DESCRIPTION

[0027] The technical solutions in the embodiments are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0028] Example 1

[0029] Step S1, preparation of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester:

[0030] The molar ratio of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)iodine bromide, triethylamine and manganese chloride is 1:1.8:1:0.07, wherein the amount of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester is 5 mol, and the volume ratio of ethanol, petroleum ether and water is 1:5:5;

[0031] Sequentially add N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)-iodine bromide, triethylamine, and manganese chloride mixture to the reaction kettle 1, then add 50 L of methanol solvent and stir at room temperature for 48 h, remove methanol under reduced pressure, add 40 L of ethyl acetate, stir evenly, and remove solid by suction filtration, remove ethyl acetate under reduced pressure, add 7 L of ethanol and 70 L of petroleum ether / water mixture to the reaction kettle, filter, and dry the obtained solid to obtain 4.09 mol of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, with a yield of 81.80% and a purity of 98.35%;

[0032] Step S2, preparation of 3,5-diiodo-L-thyroxine:

[0033] The molar ratio of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, and Na2SO3 is 1:0.3:0.23, wherein 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester is 4 mol;

[0034] 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, 5L glacial acetic acid and 5L HBr solution were added to the reaction kettle 2 in sequence, the temperature was raised to reflux, the mixture was stirred for 3.5 hours and then cooled to room temperature. After the acetyl group was removed by reaction, Na2SO3 was added to the reaction solution to quench the reaction, and then the mixture was stirred and filtered. The obtained solid was dried to obtain 3.93 mol of 3,5-diiodo-L-thyroxine, with a yield of 98.25% and a purity of 99.14%.

[0035] Step S3, preparation of L-thyroxine:

[0036] The molar ratio of 3,5-diiodo-L-thyroxine, I2, NaI·2H2O, and Na2SO3 is 1:2.0:3.0:0.35, wherein 3,5-diiodo-L-thyroxine is 2 mol and the concentration of dimethylamine aqueous solution is 30%

[0037] Add 3,5-diiodo-L-thyroxine to reactor 3, add dimethylamine aqueous solution to provide an alkaline environment, then add I2 / NaI·2H2O methanol solution dropwise, stir for 1.0 h at room temperature after adding dropwise for 2.5 h, then add Na2SO3 and stir, filter, draw the filtrate back to reactor 3, cool to 0°C with ice water, stir for 10 min, adjust the solution pH to 6 with hydrochloric acid, filter, and dry the obtained solid to obtain 1.98 mol of L-thyroxine, with a yield of 99.00% and a purity of 95.10%;

[0038] Step S4, preparation of levothyroxine sodium:

[0039] The molar ratio of L-thyroxine to NaOH is 1:4, the concentration of the ethanol aqueous solution is 85%, and NaOH is prepared into a 30% solution and added twice, and the molar ratio of the two additions is 16:1, wherein the L-thyroxine is 2 mol;

[0040] L-thyroxine was added to the reaction kettle 4, and a sufficient amount of ethanol aqueous solution was added. The temperature was raised to 80°C, and then the NaOH aqueous solution was added. The mixture was stirred for 10 minutes and cooled to room temperature. The filter cake was added to the reaction kettle 4, and the remaining NaOH aqueous solution was added until it was completely dissolved. The pH of the solution was adjusted to 8 with hydrochloric acid. After stirring, the solution was filtered and the solid was dried to obtain 1.47 mol of sodium levothyroxine, with a yield of 73.50% and a purity of 99.80%.

[0041] Example 2

[0042] Step S1, preparation of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester:

[0043] The molar ratio of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)iodine bromide, triethylamine and manganese chloride is 1:2.0:1.2:0.09, wherein the amount of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester is 5 mol, and the volume ratio of ethanol, petroleum ether and water is 1:5:5;

[0044] Sequentially add N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)-iodine bromide, triethylamine, and manganese chloride mixture to the reaction kettle 1, then add 50 L of methanol solvent and stir at room temperature for 48 hours, remove methanol under reduced pressure, add 40 L of ethyl acetate, stir evenly, and then filter to remove solids, remove ethyl acetate under reduced pressure, add 7 L of ethanol and 70 L of petroleum ether / water mixture to the reaction kettle, filter, and dry the obtained solid to obtain 4.11 mol of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, with a yield of 82.2% and a purity of 98.42%;

[0045] Step S2, preparation of 3,5-diiodo-L-thyroxine:

[0046] The molar ratio of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, and Na2SO3 is 1:0.35:0.25, wherein 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester is 4 mol;

[0047] 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, 5L glacial acetic acid and 5L HBr solution were added to the reaction kettle 2 in sequence, the temperature was raised to reflux, the mixture was stirred for 3.5 hours and then cooled to room temperature, and Na2SO3 was added to the reaction solution after the acetyl group was removed to quench the reaction, and then the mixture was stirred and filtered to obtain a solid to obtain 3.95 mol of 3,5-diiodo-L-thyroxine, with a yield of 98.75% and a purity of 99.20%;

[0048] Step S3, preparation of L-thyroxine:

[0049] The molar ratio of 3,5-diiodo-L-thyroxine, I2, NaI·2H2O, and Na2SO3 is 1:2.2:3.2:0.45, wherein 3,5-diiodo-L-thyroxine is 2 mol and the concentration of dimethylamine aqueous solution is 35%

[0050] Add 3,5-diiodo-L-thyroxine to reactor 3, add dimethylamine aqueous solution to provide an alkaline environment, then add I2 / NaI·2H2O methanol solution dropwise, stir for 1.0h at room temperature after adding dropwise for 3.0h, then add Na2SO3 and stir, filter, draw the filtrate back to reactor 3, cool to 10°C with ice water, stir for 10min, adjust the solution pH to 6 with hydrochloric acid, filter, and dry the obtained solid to obtain 1.98mol of L-thyroxine, with a yield of 99.00% and a purity of 95.33%;

[0051] Step S4, preparation of levothyroxine sodium:

[0052] The molar ratio of L-thyroxine to NaOH is 1:4, the concentration of the ethanol aqueous solution is 90%, and NaOH is prepared into a 30% solution and added twice, and the molar ratio of the two additions is 17:1, wherein the L-thyroxine is 2 mol;

[0053] L-thyroxine was added to the reaction kettle 4, and a sufficient amount of ethanol aqueous solution was added. The temperature was raised to 80°C, and then the NaOH aqueous solution was added. The mixture was stirred for 15 minutes and cooled to room temperature. The filter cake was added to the reaction kettle 4 and the NaOH aqueous solution was added until it was completely dissolved. The pH value of the solution was adjusted to 10 with hydrochloric acid. After stirring, the solution was filtered and the solid was dried to obtain 1.48 mol of sodium levothyroxine, with a yield of 74.00% and a purity of 99.86%.

[0054] Example 3

[0055] Step S1, preparation of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester:

[0056] The molar ratio of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)iodine bromide, triethylamine and manganese chloride is 1:2.0:1.2:0.09, wherein the amount of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester is 5 mol, and the volume ratio of ethanol, petroleum ether and water is 1:5:5;

[0057] Sequentially add N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)-iodine bromide, triethylamine, and manganese chloride mixture to the reaction kettle 1, then add 50 L of methanol solvent and stir at room temperature for 48 hours, remove methanol under reduced pressure, add 40 L of ethyl acetate, stir evenly, and then filter to remove solids, remove ethyl acetate under reduced pressure, add 7 L of ethanol and 70 L of petroleum ether / water mixture to the reaction kettle, filter, and dry the obtained solid to obtain 4.11 mol of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, with a yield of 82.2% and a purity of 98.42%;

[0058] Step S2, preparation of 3,5-diiodo-L-thyroxine:

[0059] The molar ratio of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester and Na2SO3 is 1:0.35:0.25, wherein 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester is 4 mol;

[0060] 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, 5L glacial acetic acid and 5L HBr solution were added to the reaction kettle 2 in sequence, the temperature was raised to reflux, the mixture was stirred for 3.5 hours and then cooled to room temperature. After the acetyl group was removed by reaction, Na2SO3 was added to the reaction solution to quench the reaction, and then the mixture was stirred and filtered. The obtained solid was dried to obtain 3.58 mol of 3,5-diiodo-L-thyroxine, with a yield of 89.50% and a purity of 97.67%.

[0061] Step S3, preparation of L-thyroxine:

[0062] The molar ratio of 3,5-diiodo-L-thyroxine, I2, NaI·2H2O, and Na2SO3 is 1:2.2:3.2:0.45, wherein 3,5-diiodo-L-thyroxine is 2 mol and the concentration of dimethylamine aqueous solution is 35%

[0063] Add 3,5-diiodo-L-thyroxine to reactor 3, add dimethylamine aqueous solution to provide an alkaline environment, then add I2 / NaI·2H2O methanol solution dropwise, stir for 1.0h at room temperature after adding dropwise for 3.0h, then add Na2SO3 and stir, filter, draw the filtrate back to reactor 3, cool to 10°C with ice water, stir for 10min, adjust the solution pH to 6 with hydrochloric acid, filter, and dry the obtained solid to obtain 1.88mol of L-thyroxine, with a yield of 94% and a purity of 93.55%;

[0064] Step S4, preparation of levothyroxine sodium:

[0065] The molar ratio of L-thyroxine to NaOH is 1:4, the concentration of the ethanol aqueous solution is 90%, and NaOH is prepared into a 30% solution and added twice, and the molar ratio of the two additions is 17:1, wherein the L-thyroxine is 2 mol;

[0066] L-thyroxine was added to the reaction kettle 4, and a sufficient amount of ethanol aqueous solution was added. The temperature was raised to 80°C, and then the NaOH aqueous solution was added. The mixture was stirred for 15 minutes and cooled to room temperature. The filter cake was added to the reaction kettle 4 and the NaOH aqueous solution was added until it was completely dissolved. The pH value of the solution was adjusted to 10 with hydrochloric acid. After stirring, the solution was filtered and the solid was dried to obtain 1.37 mol of sodium levothyroxine, with a yield of 68.50% and a purity of 97.46%.

[0067] Example 4

[0068] Step S1, preparation of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester:

[0069] The molar ratio of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)iodine bromide, triethylamine and manganese chloride is 1:2.0:1.2:0.09, wherein the amount of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester is 5 mol, and the volume ratio of ethanol, petroleum ether and water is 1:5:5;

[0070] Sequentially add N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)-iodine bromide, triethylamine, and manganese chloride mixture to the reaction kettle 1, then add 50 L of methanol solvent and stir at room temperature for 48 hours, remove methanol under reduced pressure, add 40 L of ethyl acetate, stir evenly, and then filter to remove solids, remove ethyl acetate under reduced pressure, add 7 L of ethanol and 70 L of petroleum ether / water mixture to the reaction kettle, filter, and dry the obtained solid to obtain 4.11 mol of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, with a yield of 82.2% and a purity of 98.42%;

[0071] Step S2, preparation of 3,5-diiodo-L-thyroxine:

[0072] The molar ratio of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester and NaI·2H2O is 1:0.35, wherein 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester is 4 mol;

[0073] 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, 5L glacial acetic acid and 5L HBr solution were added to the reaction kettle 2 in sequence, the temperature was raised to reflux, the mixture was stirred for 3.5 hours and then cooled to room temperature, the acetyl group was removed by reaction, and the mixture was stirred and filtered. The obtained solid was dried to obtain 3.75 mol of 3,5-diiodo-L-thyroxine, with a yield of 93.75% and a purity of 98.42%;

[0074] Step S3, preparation of L-thyroxine:

[0075] The molar ratio of 3,5-diiodo-L-thyroxine, I2, and NaI·2H2O is 1:2.2:3.2, wherein 3,5-diiodo-L-thyroxine is 2 mol and the concentration of dimethylamine aqueous solution is 35%

[0076] Add 3,5-diiodo-L-thyroxine to reactor 3, add dimethylamine aqueous solution to provide an alkaline environment, then add I2 / NaI·2H2O methanol solution dropwise, stir for 1.0 h at room temperature after adding for 3.0 h, filter, and draw the filtrate back to reactor 3, cool to 10°C with ice water, stir for 10 min, adjust the solution pH to 6 with hydrochloric acid, filter, and dry the obtained solid to obtain 1.91 mol of L-thyroxine, with a yield of 95.5% and a purity of 94.10%;

[0077] Step S4, preparation of levothyroxine sodium:

[0078] The molar ratio of L-thyroxine to NaOH is 1:4, the concentration of the ethanol aqueous solution is 90%, and NaOH is prepared into a 30% solution and added twice, and the molar ratio of the two additions is 17:1, wherein the L-thyroxine is 2 mol;

[0079] L-thyroxine was added to the reaction kettle 4, and a sufficient amount of ethanol aqueous solution was added. The temperature was raised to 80°C, and then the NaOH aqueous solution was added. The mixture was stirred for 15 minutes and cooled to room temperature. The filter cake was added to the reaction kettle 4 and the NaOH aqueous solution was added until it was completely dissolved. The pH of the solution was adjusted to 10 with hydrochloric acid. After stirring, the solution was filtered and the solid was dried to obtain 1.40 mol of sodium levothyroxine, with a yield of 70.00% and a purity of 98.68%.

[0080] Example 5

[0081] Step S1, preparation of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester:

[0082] The molar ratio of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)iodine bromide, triethylamine and manganese chloride is 1:2.0:1.2:0.09, wherein the amount of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester is 5 mol, and the volume ratio of ethanol, petroleum ether and water is 1:5:5;

[0083] Sequentially add N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)-iodine bromide, triethylamine, and manganese chloride mixture to the reaction kettle 1, then add 50 L of methanol solvent and stir at room temperature for 48 hours, remove methanol under reduced pressure, add 40 L of ethyl acetate, stir evenly, and then filter to remove solids, remove ethyl acetate under reduced pressure, add 7 L of ethanol and 70 L of petroleum ether / water mixture to the reaction kettle, filter, and dry the obtained solid to obtain 4.11 mol of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, with a yield of 82.2% and a purity of 98.42%;

[0084] Step S2, preparation of 3,5-diiodo-L-thyroxine:

[0085] The molar ratio of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, and Na2SO3 is 1:0.35:0.25, wherein 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester is 4 mol;

[0086] 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, 5L glacial acetic acid and 5L HBr solution were added to the reaction kettle 2 in sequence, the temperature was raised to reflux, the mixture was stirred for 3.5 hours and then cooled to room temperature, and Na2SO3 was added to the reaction solution after the acetyl group was removed to quench the reaction, and then the mixture was stirred and filtered to obtain a solid to obtain 3.95 mol of 3,5-diiodo-L-thyroxine, with a yield of 98.75% and a purity of 99.20%;

[0087] Step S3, preparation of L-thyroxine:

[0088] The molar ratio of 3,5-diiodo-L-thyroxine, I2, and NaI·2H2O is 1:2.2:3.2, wherein 3,5-diiodo-L-thyroxine is 2 mol and the concentration of dimethylamine aqueous solution is 35%

[0089] Add 3,5-diiodo-L-thyroxine to reactor 3, add dimethylamine aqueous solution to provide an alkaline environment, then add I2 / NaI·2H2O methanol solution dropwise, stir for 1.0 h at room temperature after adding for 3.0 h, filter, and draw the filtrate back to reactor 3, cool to 10°C with ice water, stir for 10 min, adjust the solution pH to 6 with hydrochloric acid, filter, and dry the obtained solid to obtain 1.94 mol of L-thyroxine, with a yield of 97.00% and a purity of 94.76%;

[0090] Step S4, preparation of levothyroxine sodium:

[0091] The molar ratio of L-thyroxine to NaOH is 1:4, the concentration of the ethanol aqueous solution is 90%, and NaOH is prepared into a 30% solution and added twice, and the molar ratio of the two additions is 17:1, wherein the L-thyroxine is 2 mol;

[0092] L-thyroxine was added to the reaction kettle 4, and a sufficient amount of ethanol aqueous solution was added. The temperature was raised to 80°C, and then the NaOH aqueous solution was added. The mixture was stirred for 15 minutes and cooled to room temperature. The filter cake was added to the reaction kettle 4 and the NaOH aqueous solution was added until it was completely dissolved. The pH value of the solution was adjusted to 10 with hydrochloric acid. After stirring, the solution was filtered and the solid was dried to obtain 1.45 mol of sodium levothyroxine, with a yield of 72.50% and a purity of 99.17%.

[0093] Example 6

[0094] Step S1, preparation of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester:

[0095] The molar ratio of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)iodine bromide, triethylamine and manganese chloride is 1:2.0:1.2:0.09, wherein the amount of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester is 5 mol, and the volume ratio of ethanol, petroleum ether and water is 1:5:5;

[0096] Sequentially add N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)-iodine bromide, triethylamine, and manganese chloride mixture to the reaction kettle 1, then add 50 L of methanol solvent and stir at room temperature for 48 hours, remove methanol under reduced pressure, add 40 L of ethyl acetate, stir evenly, and then filter to remove solids, remove ethyl acetate under reduced pressure, add 7 L of ethanol and 70 L of petroleum ether / water mixture to the reaction kettle, filter, and dry the obtained solid to obtain 4.11 mol of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, with a yield of 82.2% and a purity of 98.42%;

[0097] Step S2, preparation of 3,5-diiodo-L-thyroxine:

[0098] The molar ratio of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, and Na2SO3 is 1:0.35:0.25, wherein 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester is 4 mol;

[0099] 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, 5L glacial acetic acid and 5L HBr solution were added to the reaction kettle 2 in sequence, the temperature was raised to reflux, the mixture was stirred for 3.5 hours and then cooled to room temperature, and Na2SO3 was added to the reaction solution after the acetyl group was removed to quench the reaction, and then the mixture was stirred and filtered to obtain a solid to obtain 3.95 mol of 3,5-diiodo-L-thyroxine, with a yield of 98.75% and a purity of 99.20%;

[0100] Step S3, preparation of L-thyroxine:

[0101] The molar ratio of 3,5-diiodo-L-thyroxine, I2, NaI·2H2O, and Na2SO3 is 1:2.2:3.2:0.45, wherein 3,5-diiodo-L-thyroxine is 2 mol and the concentration of dimethylamine aqueous solution is 35%

[0102] Add 3,5-diiodo-L-thyroxine to reactor 3, add dimethylamine aqueous solution to provide an alkaline environment, then add I2 / NaI·2H2O methanol solution dropwise, stir for 1.0h at room temperature after adding dropwise for 3.0h, then add Na2SO3 and stir, filter, draw the filtrate back to reactor 3, cool to 10°C with ice water, stir for 10min, adjust the solution pH to 6 with hydrochloric acid, filter, and dry the obtained solid to obtain 1.98mol of L-thyroxine, with a yield of 99.00% and a purity of 95.33%;

[0103] Step S4, preparation of levothyroxine sodium:

[0104] The molar ratio of L-thyroxine to NaOH is 1:4. NaOH is prepared into a 30% solution and added twice. The molar ratio of the two additions is 17:1, wherein L-thyroxine is 2 mol.

[0105] L-thyroxine was added to the reaction kettle 4, and the temperature was raised to 80°C, and then an aqueous NaOH solution was added. The mixture was stirred for 15 minutes and cooled to room temperature. The filter cake was added to the reaction kettle 4, and an aqueous NaOH solution was added until it was completely dissolved. The pH of the solution was adjusted to 10 with hydrochloric acid. After stirring, the solution was filtered and the solid was dried to obtain 1.44 mol of sodium levothyroxine, with a yield of 72.00% and a purity of 99.25%.

[0106] Example 7

[0107] Step S1, preparation of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester:

[0108] The molar ratio of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)iodine bromide, triethylamine and manganese chloride is 1:2.0:1.2:0.09, wherein the amount of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester is 5 mol, and the volume ratio of ethanol, petroleum ether and water is 1:5:5;

[0109] Sequentially add N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)-iodine bromide, triethylamine, and manganese chloride mixture to the reaction kettle 1, then add 50 L of methanol solvent and stir at room temperature for 48 hours, remove methanol under reduced pressure, add 40 L of ethyl acetate, stir evenly, and then filter to remove solids, remove ethyl acetate under reduced pressure, add 7 L of ethanol and 70 L of petroleum ether / water mixture to the reaction kettle, filter, and dry the obtained solid to obtain 4.11 mol of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, with a yield of 82.2% and a purity of 98.42%;

[0110] Step S2, preparation of 3,5-diiodo-L-thyroxine:

[0111] The molar ratio of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, and Na2SO3 is 1:0.35:0.25, wherein 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester is 4 mol;

[0112] 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, 5L glacial acetic acid and 5L HBr solution were added to the reaction kettle 2 in sequence, the temperature was raised to reflux, the mixture was stirred for 3.5 hours and then cooled to room temperature, and Na2SO3 was added to the reaction solution after the acetyl group was removed to quench the reaction, and then the mixture was stirred and filtered to obtain a solid to obtain 3.95 mol of 3,5-diiodo-L-thyroxine, with a yield of 98.75% and a purity of 99.20%;

[0113] Step S3, preparation of L-thyroxine:

[0114] The molar ratio of 3,5-diiodo-L-thyroxine, I2, NaI·2H2O, and Na2SO3 is 1:2.2:3.2:0.45, wherein 3,5-diiodo-L-thyroxine is 2 mol and the concentration of dimethylamine aqueous solution is 35%

[0115] Add 3,5-diiodo-L-thyroxine to reactor 3, add dimethylamine aqueous solution to provide an alkaline environment, then add I2 / NaI·2H2O methanol solution dropwise, stir for 1.0h at room temperature after adding dropwise for 3.0h, then add Na2SO3 and stir, filter, draw the filtrate back to reactor 3, cool to 10°C with ice water, stir for 10min, adjust the solution pH to 6 with hydrochloric acid, filter, and dry the obtained solid to obtain 1.98mol of L-thyroxine, with a yield of 99.00% and a purity of 95.33%;

[0116] Step S4, preparation of levothyroxine sodium:

[0117] The molar ratio of L-thyroxine to NaOH is 1:4, the concentration of the ethanol aqueous solution is 90%, and NaOH is prepared into a 30% solution, in which 2 mol of L-thyroxine is added;

[0118] Add L-thyroxine to reactor 4, add sufficient ethanol aqueous solution, heat to 80°C, add NaOH aqueous solution, keep stirring for 15 minutes, cool to room temperature, adjust the solution pH to 10 with hydrochloric acid, stir evenly, filter the solution, dry the obtained solid, and obtain 1.41 mol of sodium levothyroxine, with a yield of 70.50% and a purity of 96.83%.

Claims

1. A production process of levothyroxine sodium, characterized in that: The following steps are involved: Step S1, preparation of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester: Sequentially add N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)-iodine bromide, triethylamine, and a mixture of manganese chloride to the reaction kettle 1, then add the solvent methanol and stir evenly, remove the methanol under reduced pressure, add ethyl acetate and stir evenly, then filter and remove the solid, remove the ethyl acetate under reduced pressure, add ethanol and a petroleum ether / water mixture to the reaction kettle, filter, and dry the obtained solid to obtain 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester; Step S2, preparation of 3,5-diiodo-L-thyroxine: 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, glacial acetic acid and HBr solution were added to the reaction kettle 2 in sequence, the temperature was raised to reflux, the mixture was kept warm and stirred for a period of time, and then cooled to room temperature. After the acetyl group was removed by reaction, Na2SO3 was added to the reaction solution to quench the reaction, and then the mixture was stirred and filtered. The obtained solid was dried to obtain 3,5-diiodo-L-thyroxine; Step S3, preparation of L-thyroxine: Add 3,5-diiodo-L-thyroxine to the reaction kettle 3, add dimethylamine aqueous solution to provide an alkaline environment, then drop I2 / NaI·2H2O methanol solution, stir evenly at room temperature after the dropwise addition, then add Na2SO3 and stir, filter, and draw the filtrate back to the reaction kettle 3, adjust the solution pH to weak acidity, filter, and dry the obtained solid to obtain L-thyroxine; Step S4, preparation of levothyroxine sodium: Add L-thyroxine to the reaction kettle 4, add a sufficient amount of ethanol aqueous solution, add NaOH aqueous solution after heating, keep warm and stir, cool to room temperature, filter, put the filter cake into the reaction kettle 4 and add NaOH aqueous solution until it is completely dissolved, adjust the solution pH to 8-10, stir evenly and filter the solution, dry the obtained solid to obtain levothyroxine sodium.

2. The production process of levothyroxine sodium according to claim 1, characterized in that: In the step S1, the molar ratio of N-acetyl-3,5-diiodo-L-tyrosine ethyl ester, di(4-methoxyphenyl)-iodine bromide, triethylamine and manganese chloride is 1:1.8-2.0:1-1.2:0.07-0.

09.

3. The production process of levothyroxine sodium according to claim 1, characterized in that: In the step S1, the methanol solvent is added and stirred at room temperature for 48 hours, and the volume ratio of ethanol, petroleum ether and water is 1:5:

5.

4. The production process of levothyroxine sodium according to claim 1, characterized in that: In the step S2, the molar ratio of 3,5-diiodo-4-(4-methoxyphenoxy)-N-acetyl-L-phenylalanine ethyl ester, NaI·2H2O, and Na2SO3 is 1:0.3-0.35:0.23-0.25, and the heat preservation and stirring time is 3.5 hours.

5. The production process of levothyroxine sodium according to claim 1, characterized in that: In the step S3, the molar ratio of 3,5-diiodo-L-thyroxine, I2, NaI·2H2O, and Na2SO3 is 1:2.0-2.2:3.0-3.2:0.35-0.45, and the concentration of the dimethylamine aqueous solution is 30-35%.

6. The production process of levothyroxine sodium according to claim 1, characterized in that: In the step S3, the methanol solution of I2 / NaI·2H2O is added dropwise for 2.5 to 3.0 hours, and stirred at room temperature for 1.0 hour after the addition is completed.

7. The production process of levothyroxine sodium according to claim 1, characterized in that: In step S3, the filtrate is pumped back into the reaction kettle 3 and then cooled to 0-10° C. with ice water and stirred for 10 min. The pH value of the solution is adjusted to 6 with hydrochloric acid.

8. The production process of levothyroxine sodium according to claim 1, characterized in that: In step S4, the molar ratio of L-thyroxine to NaOH is 1:4, the concentration of the ethanol aqueous solution is 85-90%, and NaOH is prepared into a 30% solution and added twice, and the molar ratio of the two additions is 16-17:1 respectively.

9. The production process of levothyroxine sodium according to claim 1, characterized in that: In step S4, the temperature is raised to 80° C., a NaOH aqueous solution is added, the mixture is stirred for 10 to 15 minutes, cooled to room temperature, and the pH value of the solution is adjusted to 8 to 10 with hydrochloric acid.