CN116715597A - Production process of levothyroxine sodium - Google Patents
Production process of levothyroxine sodium Download PDFInfo
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- CN116715597A CN116715597A CN202310471105.4A CN202310471105A CN116715597A CN 116715597 A CN116715597 A CN 116715597A CN 202310471105 A CN202310471105 A CN 202310471105A CN 116715597 A CN116715597 A CN 116715597A
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- diiodo
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- thyroxine
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- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 title claims abstract description 89
- 229960003918 levothyroxine sodium Drugs 0.000 title claims abstract description 41
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 31
- 229950008325 levothyroxine Drugs 0.000 claims abstract description 92
- LCJKMEUFNHSFPB-UHFFFAOYSA-N ethyl 2-acetamido-3-[3,5-diiodo-4-(4-methoxyphenoxy)phenyl]propanoate Chemical compound IC1=CC(CC(C(=O)OCC)NC(C)=O)=CC(I)=C1OC1=CC=C(OC)C=C1 LCJKMEUFNHSFPB-UHFFFAOYSA-N 0.000 claims abstract description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 99
- 239000000243 solution Substances 0.000 claims description 98
- 238000006243 chemical reaction Methods 0.000 claims description 94
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 87
- 238000003756 stirring Methods 0.000 claims description 73
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 52
- 238000001914 filtration Methods 0.000 claims description 51
- 239000007787 solid Substances 0.000 claims description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 238000001035 drying Methods 0.000 claims description 36
- 238000002360 preparation method Methods 0.000 claims description 30
- 239000011734 sodium Substances 0.000 claims description 30
- ZOKLABLCKDZYOP-UHFFFAOYSA-N 2-chloro-4-hydroxy-5-methoxybenzaldehyde Chemical compound COC1=CC(C=O)=C(Cl)C=C1O ZOKLABLCKDZYOP-UHFFFAOYSA-N 0.000 claims description 29
- 239000007864 aqueous solution Substances 0.000 claims description 28
- 238000001816 cooling Methods 0.000 claims description 25
- 238000010438 heat treatment Methods 0.000 claims description 21
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 20
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims description 19
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 19
- AWCNZRMWUGDYFJ-UHFFFAOYSA-N bromo-bis(4-methoxyphenyl)-lambda3-iodane Chemical compound COc1ccc(cc1)[I](Br)c1ccc(OC)cc1 AWCNZRMWUGDYFJ-UHFFFAOYSA-N 0.000 claims description 19
- 239000011565 manganese chloride Substances 0.000 claims description 19
- 229940099607 manganese chloride Drugs 0.000 claims description 19
- 235000002867 manganese chloride Nutrition 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 239000003208 petroleum Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000012065 filter cake Substances 0.000 claims description 15
- 229910052708 sodium Inorganic materials 0.000 claims description 15
- 238000000967 suction filtration Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 11
- 229960000583 acetic acid Drugs 0.000 claims description 9
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 9
- 239000012362 glacial acetic acid Substances 0.000 claims description 9
- 239000005457 ice water Substances 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 9
- BEVGWNKCJKXLQC-UHFFFAOYSA-N n-methylmethanamine;hydrate Chemical compound [OH-].C[NH2+]C BEVGWNKCJKXLQC-UHFFFAOYSA-N 0.000 claims description 9
- 238000005086 pumping Methods 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 230000001105 regulatory effect Effects 0.000 claims description 9
- 238000010791 quenching Methods 0.000 claims description 8
- 230000000171 quenching effect Effects 0.000 claims description 8
- JBJWASZNUJCEKT-UHFFFAOYSA-M sodium;hydroxide;hydrate Chemical compound O.[OH-].[Na+] JBJWASZNUJCEKT-UHFFFAOYSA-M 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 230000035484 reaction time Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- YDTFRJLNMPSCFM-YDALLXLXSA-M levothyroxine sodium anhydrous Chemical compound [Na+].IC1=CC(C[C@H](N)C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 YDTFRJLNMPSCFM-YDALLXLXSA-M 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- HXNJCVUANVPHHP-INIZCTEOSA-N ethyl (2s)-2-acetamido-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoate Chemical compound IC1=CC(C[C@@H](C(=O)OCC)NC(C)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 HXNJCVUANVPHHP-INIZCTEOSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229940036555 thyroid hormone Drugs 0.000 description 2
- 239000005495 thyroid hormone Substances 0.000 description 2
- 229960004441 tyrosine Drugs 0.000 description 2
- NYPYHUZRZVSYKL-ZETCQYMHSA-N 3,5-diiodo-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC(I)=C(O)C(I)=C1 NYPYHUZRZVSYKL-ZETCQYMHSA-N 0.000 description 1
- -1 4-methoxyphenoxy Chemical group 0.000 description 1
- 206010018498 Goitre Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 201000003872 goiter Diseases 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—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 involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- 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
- C07C227/12—Formation of amino and carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a production process of levothyroxine sodium, which comprises the following steps of preparing 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester, preparing 3, 5-diiodo-L-thyroxine, preparing levothyroxine sodium and the like, and can increase the yield of products and improve the purity of the products. The invention aims to provide a production process of levothyroxine sodium, which is simple and convenient to produce, shortens the reaction time, improves the yield and has higher safety, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a production process of levothyroxine sodium.
Background
Levothyroxine sodium, also known as L-thyroxine sodium, is a thyroid hormone drug, mainly used for the treatment of hypothyroidism and simple thyromegaly due to various causes. The L-thyroxine is used as a substitute for the deficiency of thyroid hormone in human body, has large clinical usage amount and has wide market prospect.
The extraction method of L-thyroxine mainly comprises a biological extraction method and a chemical synthesis method, wherein the biological extraction method has low extraction purity and limited quantity, so that the development of the biological extraction method is limited, the chemical synthesis method is mainly adopted at present, the final synthesis of L-thyroxine by taking tyrosine as a raw material is adopted, the types of synthesis intermediates are various, the steps are complex, the reaction yield is low, and the time is long. The prior literature describes that L-thyroxine is finally synthesized by taking L-tyrosine as a raw material and sequentially preparing intermediates such as 3, 5-diiodo-L-tyrosine, N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester, N-acetyl-L-thyroxine ethyl ester and the like, and then alkalizing by alkali liquor containing sodium, heating and filtering to obtain the L-thyroxine sodium. The synthesis scheme of N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester is mature nowadays, research direction is mainly focused on coupling reaction of N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester, the coupling agent and catalyst are mostly selected in the prior art to react under the condition of heating and sufficient oxygen to generate N-acetyl-L-thyroxine ethyl ester, but the heating and oxygen production in organic reaction have high requirements on factory safety and equipment, filtration is difficult to realize in a heated state in the subsequent preparation of L-thyroxine sodium, and the purity of the obtained product can be improved by recrystallization, but the product yield is inevitably reduced.
Based on the above-mentioned current situation, a production process with simple production, shortened reaction time, improved yield and higher safety is needed in the market.
Disclosure of Invention
The invention aims to provide a production process of levothyroxine sodium, which is simple and convenient to produce, shortens the reaction time, improves the yield and has higher safety, and is suitable for industrial production.
The technical aim of the invention is realized by the following technical scheme: a production process of levothyroxine sodium comprises the following steps:
step S1, preparation of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester:
sequentially adding N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester, di (4-methoxyphenyl) -iodine bromide, triethylamine, manganese chloride and other mixtures into a reaction kettle 1, adding solvent methanol, stirring uniformly, removing methanol under reduced pressure, adding ethyl acetate, stirring uniformly, filtering to remove solids, removing ethyl acetate under reduced pressure, adding ethanol and petroleum ether/water mixed solution into the reaction kettle, filtering, and drying the obtained solids to obtain 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester;
step S2, preparation of 3, 5-diiodo-L-thyroxine:
sequentially adding 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester and NaI.2H into a reaction kettle 2 2 Heating O, glacial acetic acid and HBr solution to reflux, maintaining the temperature, stirring for a period of time, cooling to room temperature, removing acetyl by reaction, and adding Na into the reaction solution 2 SO 3 Quenching the reaction, stirring uniformly, filtering, and drying the obtained solid to obtain 3, 5-diiodo-L-thyroxine;
step S3, preparation of L-thyroxine:
adding 3, 5-diiodo-L-thyroxine into a reaction kettle 3, adding dimethylamine water solution to provide alkaline environment, and then dripping I 2 /NaI·2H 2 O methanol solution is stirred evenly at normal temperature after being added dropwise, and Na is added 2 SO 3 Stirring, filtering, pumping the filtrate back to the reaction kettle 3, regulating the pH of the solution to be weak acid, filtering, and drying the obtained solid to obtain the L-thyroxine;
step S4, preparing levothyroxine sodium:
adding L-thyroxine into a reaction kettle 4, adding a sufficient amount of ethanol water solution, heating, adding NaOH water solution, keeping the temperature, stirring, cooling to room temperature, and carrying out suction filtration. Adding the filter cake into a reaction kettle 4, adding NaOH aqueous solution until the filter cake is completely dissolved, adjusting the pH value of the solution to be 8-10, stirring the solution uniformly, filtering the solution, and drying the obtained solid to obtain the levothyroxine sodium.
As a further arrangement of the invention, in the step S1, the molar ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester, the di (4-methoxyphenyl) -iodine bromide, the triethylamine and the manganese chloride is 1:1.8-2.0:1-1.2:0.07-0.09.
As a further arrangement of the invention, the solvent methanol is added in the step S1 and then stirred for 48 hours at room temperature, and the volume ratio of the ethanol to the petroleum ether to the water is 1:5:5.
As a further arrangement of the present invention, in the step S2,3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester, naI.2H 2 O、Na 2 SO 3 The mol ratio of (3) is 1:0.3-0.35:0.23-0.25, and the heat preservation and stirring time is 3.5h.
As a further arrangement of the invention, in step S3, 5-diiodo-L-thyroxine, I 2 、NaI·2H 2 O、Na 2 SO 3 The molar ratio of (2) to (3) 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%.
As a further arrangement of the invention, the dripping time of the methanol solution of I2/NaI.2H2O in the step S3 is 2.5-3.0H, and the mixture is stirred for 1.0H at normal temperature after the dripping is finished.
As a further arrangement of the present invention, in the step S3, the filtrate is pumped back to the reaction kettle 3, cooled to 0-10 ℃ with ice water, stirred for 10min, and the ph=6 of the solution is adjusted with hydrochloric acid.
As a further setting of the invention, in the step S4, the molar ratio of the L-thyroxine to the NaOH is 1:4, the concentration of the ethanol aqueous solution is 85-90%, the NaOH is prepared into a solution with the concentration of 30% and is added in two times, and the molar ratio of the two times is 16-17:1 in sequence.
As a further arrangement of the present invention, in the step S4, the temperature is raised to 80 ℃, naOH aqueous solution is added, the temperature is maintained and stirred for 10 to 15min, the temperature is cooled to room temperature, and the ph=8 to 10 of the solution is adjusted by hydrochloric acid.
Compared with the prior art, the invention has the beneficial effects that:
1. the production process of the levothyroxine sodium provided by the invention is novel in technical scheme, can be completed without introducing oxygen in the production process, and utilizes methanol as a solvent and manganese chloride 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 performed at room temperature, the reaction time is greatly shortened, the reaction is safe and stable, and the product yield and purity are improved.
2. The production process of the levothyroxine sodium provided by the invention has reasonable process design, and the alkaline environment provided by dimethylamine aqueous solution is utilized in the preparation of L-thyroxine, and I is added dropwise 2 /NaI·2H 2 The methanol solution of O is not required to be heated and refluxed in the reaction process, and only needs to be reacted at normal temperature, so that not only is the energy saved, but also the safety and controllability of the reaction are improved, the yield and purity of the product are improved, and the subsequent preparation of the levothyroxine sodium is facilitated.
3. The production process of the levothyroxine sodium provided by the invention is simple to operate, the combination of adding NaOH into the ethanol aqueous solution for the first time can be used for improving the reaction yield and removing part of impurities, naOH is added subsequently, the pH is adjusted to 8-10, and after the mixture is stirred uniformly, the produced product is more stable, the ultra-high temperature is not needed in the initial reaction stage, the filtration stages are all at normal temperature, no recrystallization and other operations are carried out, so that the reaction step is simplified, and the yield and purity of the levothyroxine sodium are improved.
Detailed Description
The technical solutions in the embodiments will be clearly and completely described below. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to fall within the scope of the invention.
Example 1
Step S1, preparation of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester:
the mol ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the bis (4-methoxyphenyl) -iodine bromide to the triethylamine to the manganese chloride is 1:1.8:1:0.07, wherein the mol ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the ethanol to the petroleum ether to the water is 1:5:5;
sequentially adding N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester, di (4-methoxyphenyl) -iodine bromide, triethylamine, manganese chloride and other mixtures into a reaction kettle 1, adding a solvent methanol 50L, stirring for 48 hours at room temperature, removing methanol under reduced pressure, adding ethyl acetate 40L, stirring uniformly, filtering to remove solids, removing ethyl acetate under reduced pressure, adding ethanol 7L and petroleum ether/water mixed solution 70L into the reaction kettle, filtering, and drying the obtained solids to obtain 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester 4.09mol, wherein the yield is 81.80% and the purity is 98.35%;
step S2, preparation of 3, 5-diiodo-L-thyroxine:
3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester, naI.2H 2 O、Na 2 SO 3 Wherein the molar ratio of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester is 4mol;
sequentially adding 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester and NaI.2H into a reaction kettle 2 2 Heating O, glacial acetic acid 5L and HBr5L solution to reflux, stirring for 3.5h at a constant temperature, cooling to room temperature, removing acetyl by reaction, and adding Na into the reaction solution 2 SO 3 Quenching the reaction, stirring uniformly, filtering, and drying the obtained solid to obtain 3, 5-diiodo-L-thyroxine 3.93mol, wherein the yield is 98.25%, and the purity is 99.14%;
step S3, preparation of L-thyroxine:
3, 5-diiodo-L-thyroxine, I 2 、NaI·2H 2 O、Na 2 SO 3 The molar ratio of (2) to (3) to (0) to (0.35) was 1:2.0:3.0, wherein 2mol of 3, 5-diiodo-L-thyroxine was contained in an aqueous dimethylamine solution having a concentration of 30%
Adding 3, 5-diiodo-L-thyroxine into a reaction kettle 3, adding dimethylamine water solution to provide alkaline environment, and then dripping I 2 /NaI·2H 2 O in methanol is added dropwise for 2.5h, stirred for 1.0h at normal temperature, and Na is added 2 SO 3 Stirring, filtering, pumping the filtrate back to the reaction kettle 3, cooling to 0 ℃ with ice water, stirring for 10min, adjusting the pH value of the solution to be=6 with hydrochloric acid, filtering, and drying the obtained solid to obtain 1.98mol of L-thyroxine, wherein the yield is 99.00% and the purity is 95.10%;
step S4, preparing levothyroxine sodium:
the molar ratio of the L-thyroxine to the NaOH is 1:4, the concentration of the ethanol aqueous solution is 85%, the NaOH is prepared into a solution with the concentration of 30% and is added in two times, the molar ratio of the two times is 16:1 in sequence, and the L-thyroxine is 2mol;
adding L-thyroxine into a reaction kettle 4, adding a sufficient amount of ethanol water solution, heating to 80 ℃, adding NaOH water solution, preserving heat, stirring for 10min, cooling to room temperature, and suction filtering. Adding the filter cake into a reaction kettle 4, adding the rest NaOH aqueous solution until the solution is completely dissolved, adjusting the pH=8 of the solution by hydrochloric acid, stirring uniformly, carrying out suction filtration on the solution, and drying the obtained solid to obtain 1.47mol of levothyroxine sodium, wherein the yield is 73.50%, and the purity is 99.80%.
Example 2
Step S1, preparation of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester:
the mol ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the bis (4-methoxyphenyl) -iodine bromide to the triethylamine to the manganese chloride is 1:2.0:1.2:0.09, wherein the volume ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the ethanol to the petroleum ether to the water is 1:5:5;
sequentially adding N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester, di (4-methoxyphenyl) -iodine bromide, triethylamine, manganese chloride and other mixtures into a reaction kettle 1, adding a solvent methanol 50L, stirring for 48 hours at room temperature, removing methanol under reduced pressure, adding ethyl acetate 40L, stirring uniformly, removing solids through suction filtration, removing ethyl acetate under reduced pressure, adding ethanol 7L and petroleum ether/water mixed solution 70L into the reaction kettle, filtering, and drying the obtained solids to obtain 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester 4.11mol, wherein the yield is 82.2%, and the purity is 98.42%;
step S2, preparation of 3, 5-diiodo-L-thyroxine:
3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester, naI.2H 2 O、Na 2 SO 3 Wherein the molar ratio of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester is 4 moles;
adding 3, 5-di-into the reaction kettle 2 in turnIodine-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester, naI.2H 2 Heating O, glacial acetic acid 5L and HBr5L solution to reflux, stirring for 3.5h at a constant temperature, cooling to room temperature, removing acetyl by reaction, and adding Na into the reaction solution 2 SO 3 Quenching the reaction, stirring uniformly, filtering, and drying the obtained solid to obtain 3, 5-diiodo-L-thyroxine 3.95mol, wherein the yield is 98.75%, and the purity is 99.20%;
step S3, preparation of L-thyroxine:
3, 5-diiodo-L-thyroxine, I 2 、NaI·2H 2 O、Na 2 SO 3 The molar ratio of (2) to (3) 2:0.45, wherein the molar ratio of 3, 5-diiodo-L-thyroxine is 2mol, and the concentration of dimethylamine aqueous solution is 35 percent
Adding 3, 5-diiodo-L-thyroxine into a reaction kettle 3, adding dimethylamine water solution to provide alkaline environment, and then dripping I 2 /NaI·2H 2 O in methanol is added dropwise for 3.0h, stirred for 1.0h at normal temperature, and Na is added 2 SO 3 Stirring, filtering, pumping the filtrate back to the reaction kettle 3, cooling to 10 ℃ with ice water, stirring for 10min, adjusting the pH=6 with hydrochloric acid, filtering, and drying the obtained solid to obtain 1.98mol of L-thyroxine with the yield of 99.00% and the purity of 95.33%;
step S4, preparing levothyroxine sodium:
the molar ratio of the L-thyroxine to the NaOH is 1:4, the concentration of the ethanol aqueous solution is 90%, the NaOH is prepared into a solution with the concentration of 30% and is added in two times, the molar ratio of the two times is 17:1 in sequence, and the L-thyroxine is 2mol;
adding L-thyroxine into a reaction kettle 4, adding a sufficient amount of ethanol water solution, heating to 80 ℃, adding NaOH water solution, preserving heat, stirring for 15min, cooling to room temperature, and suction filtering. Adding the filter cake into a reaction kettle 4, adding NaOH aqueous solution until the filter cake is completely dissolved, regulating the pH value of the solution to be 10 by hydrochloric acid, stirring the solution uniformly, carrying out suction filtration on the solution, and drying the obtained solid to obtain 1.48mol of levothyroxine sodium, wherein the yield is 74.00%, and the purity is 99.86%.
Example 3
Step S1, preparation of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester:
the mol ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the bis (4-methoxyphenyl) -iodine bromide to the triethylamine to the manganese chloride is 1:2.0:1.2:0.09, wherein the volume ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the ethanol to the petroleum ether to the water is 1:5:5;
sequentially adding N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester, di (4-methoxyphenyl) -iodine bromide, triethylamine, manganese chloride and other mixtures into a reaction kettle 1, adding a solvent methanol 50L, stirring for 48 hours at room temperature, removing methanol under reduced pressure, adding ethyl acetate 40L, stirring uniformly, removing solids through suction filtration, removing ethyl acetate under reduced pressure, adding ethanol 7L and petroleum ether/water mixed solution 70L into the reaction kettle, filtering, and drying the obtained solids to obtain 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester 4.11mol, wherein the yield is 82.2%, and the purity is 98.42%;
step S2, preparation of 3, 5-diiodo-L-thyroxine:
3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester, na 2 SO 3 Wherein the molar ratio of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester is 4 moles;
sequentially adding 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester, glacial acetic acid 5L and HBr5L solution into a reaction kettle 2, heating to reflux, stirring for 3.5h at a constant temperature, cooling to room temperature, reacting to remove acetyl groups, and adding Na into the reaction solution 2 SO 3 Quenching the reaction, stirring uniformly, filtering, and drying the obtained solid to obtain 3, 5-diiodo-L-thyroxine 3.58mol, wherein the yield is 89.50%, and the purity is 97.67%;
step S3, preparation of L-thyroxine:
3, 5-diiodo-L-thyroxine, I 2 、NaI·2H 2 O、Na 2 SO 3 The molar ratio of (2) to (3) 2:0.45, wherein the molar ratio of 3, 5-diiodo-L-thyroxine is 2mol, and the concentration of dimethylamine aqueous solution is 35 percent
Adding 3, 5-diiodo-L-thyroxine into a reaction kettle 3, adding dimethylamine water solution to provide alkaline environment, and then dripping I 2 /NaI·2H 2 O in methanol is added dropwise for 3.0h, stirred for 1.0h at normal temperature, and Na is added 2 SO 3 Stirring, filtering, pumping the filtrate back to the reaction kettle 3, cooling to 10 ℃ with ice water, stirring for 10min, adjusting the pH value of the solution to be=6 with hydrochloric acid, filtering, and drying the obtained solid to obtain 1.88mol of L-thyroxine, wherein the yield is 94% and the purity is 93.55%;
step S4, preparing levothyroxine sodium:
the molar ratio of the L-thyroxine to the NaOH is 1:4, the concentration of the ethanol aqueous solution is 90%, the NaOH is prepared into a solution with the concentration of 30% and is added in two times, the molar ratio of the two times is 17:1 in sequence, and the L-thyroxine is 2mol;
adding L-thyroxine into a reaction kettle 4, adding a sufficient amount of ethanol water solution, heating to 80 ℃, adding NaOH water solution, preserving heat, stirring for 15min, cooling to room temperature, and suction filtering. Adding the filter cake into a reaction kettle 4, adding NaOH aqueous solution until the filter cake is completely dissolved, regulating the pH value of the solution to be 10 by hydrochloric acid, stirring the solution uniformly, carrying out suction filtration on the solution, and drying the obtained solid to obtain 1.37mol of levothyroxine sodium, wherein the yield is 68.50%, and the purity is 97.46%.
Example 4
Step S1, preparation of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester:
the mol ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the bis (4-methoxyphenyl) -iodine bromide to the triethylamine to the manganese chloride is 1:2.0:1.2:0.09, wherein the volume ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the ethanol to the petroleum ether to the water is 1:5:5;
sequentially adding N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester, di (4-methoxyphenyl) -iodine bromide, triethylamine, manganese chloride and other mixtures into a reaction kettle 1, adding a solvent methanol 50L, stirring for 48 hours at room temperature, removing methanol under reduced pressure, adding ethyl acetate 40L, stirring uniformly, removing solids through suction filtration, removing ethyl acetate under reduced pressure, adding ethanol 7L and petroleum ether/water mixed solution 70L into the reaction kettle, filtering, and drying the obtained solids to obtain 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester 4.11mol, wherein the yield is 82.2%, and the purity is 98.42%;
step S2, preparation of 3, 5-diiodo-L-thyroxine:
3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester, naI.2H 2 O is 1:0.35, wherein the mol ratio of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester is 4mol;
sequentially adding 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester and NaI.2H into a reaction kettle 2 2 Heating O, glacial acetic acid 5L and HBr5L solution to reflux, keeping the temperature and stirring for 3.5h, cooling to room temperature, reacting to remove acetyl, stirring uniformly, filtering, drying the obtained solid to obtain 3, 5-diiodo-L-thyroxine 3.75mol, with the yield of 93.75% and the purity of 98.42%;
step S3, preparation of L-thyroxine:
3, 5-diiodo-L-thyroxine, I 2 、NaI·2H 2 The molar ratio of O is 1:2.2:3.2, wherein the mol ratio of 3, 5-diiodo-L-thyroxine is 2mol, and the concentration of dimethylamine aqueous solution is 35 percent
Adding 3, 5-diiodo-L-thyroxine into a reaction kettle 3, adding dimethylamine water solution to provide alkaline environment, and then dripping I 2 /NaI·2H 2 Dropwise adding a methanol solution of O for 3.0h, stirring for 1.0h at normal temperature, filtering, pumping the filtrate back to a reaction kettle 3, cooling to 10 ℃ with ice water, stirring for 10min, adjusting the pH value of the solution to be 6 with hydrochloric acid, filtering, and drying the obtained solid to obtain 1.91mol of L-thyroxine with the yield of 95.5% and the purity of 94.10%;
step S4, preparing levothyroxine sodium:
the molar ratio of the L-thyroxine to the NaOH is 1:4, the concentration of the ethanol aqueous solution is 90%, the NaOH is prepared into a solution with the concentration of 30% and is added in two times, the molar ratio of the two times is 17:1 in sequence, and the L-thyroxine is 2mol;
adding L-thyroxine into a reaction kettle 4, adding a sufficient amount of ethanol water solution, heating to 80 ℃, adding NaOH water solution, preserving heat, stirring for 15min, cooling to room temperature, and suction filtering. Adding the filter cake into a reaction kettle 4, adding NaOH aqueous solution until the filter cake is completely dissolved, regulating the pH value of the solution to be 10 by hydrochloric acid, stirring the solution uniformly, carrying out suction filtration on the solution, and drying the obtained solid to obtain 1.40mol of levothyroxine sodium, wherein the yield is 70.00%, and the purity is 98.68%.
Example 5
Step S1, preparation of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester:
the mol ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the bis (4-methoxyphenyl) -iodine bromide to the triethylamine to the manganese chloride is 1:2.0:1.2:0.09, wherein the volume ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the ethanol to the petroleum ether to the water is 1:5:5;
sequentially adding N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester, di (4-methoxyphenyl) -iodine bromide, triethylamine, manganese chloride and other mixtures into a reaction kettle 1, adding a solvent methanol 50L, stirring for 48 hours at room temperature, removing methanol under reduced pressure, adding ethyl acetate 40L, stirring uniformly, removing solids through suction filtration, removing ethyl acetate under reduced pressure, adding ethanol 7L and petroleum ether/water mixed solution 70L into the reaction kettle, filtering, and drying the obtained solids to obtain 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester 4.11mol, wherein the yield is 82.2%, and the purity is 98.42%;
step S2, preparation of 3, 5-diiodo-L-thyroxine:
3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester, naI.2H 2 O、Na 2 SO 3 Wherein the molar ratio of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester is 4 moles;
sequentially adding 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester and NaI.2H into a reaction kettle 2 2 Heating O, glacial acetic acid 5L and HBr5L solution to reflux, stirring for 3.5h at a constant temperature, cooling to room temperature, removing acetyl by reaction, and adding Na into the reaction solution 2 SO 3 Quenching the reaction, stirring uniformly, filtering, and drying the obtained solid to obtain 3, 5-diiodo-L-thyroxine 3.95mol, wherein the yield is 98.75%, and the purity is 99.20%;
step S3, preparation of L-thyroxine:
3, 5-diiodo-L-thyroxine, I 2 、NaI·2H 2 The molar ratio of O is 1:2.2:3.2, wherein the mol ratio of 3, 5-diiodo-L-thyroxine is 2mol, and the concentration of dimethylamine aqueous solution is 35 percent
Adding 3, 5-diiodo-L-thyroxine into a reaction kettle 3, adding dimethylamine water solution to provide alkaline environment, and then dripping I 2 /NaI·2H 2 Dropwise adding a methanol solution of O for 3.0h, stirring for 1.0h at normal temperature, filtering, pumping the filtrate back to a reaction kettle 3, cooling to 10 ℃ with ice water, stirring for 10min, adjusting the pH value of the solution to be 6 with hydrochloric acid, filtering, and drying the obtained solid to obtain 1.94mol of L-thyroxine with the yield of 97.00% and the purity of 94.76%;
step S4, preparing levothyroxine sodium:
the molar ratio of the L-thyroxine to the NaOH is 1:4, the concentration of the ethanol aqueous solution is 90%, the NaOH is prepared into a solution with the concentration of 30% and is added in two times, the molar ratio of the two times is 17:1 in sequence, and the L-thyroxine is 2mol;
adding L-thyroxine into a reaction kettle 4, adding a sufficient amount of ethanol water solution, heating to 80 ℃, adding NaOH water solution, preserving heat, stirring for 15min, cooling to room temperature, and suction filtering. Adding the filter cake into a reaction kettle 4, adding NaOH aqueous solution until the filter cake is completely dissolved, regulating the pH value of the solution to be 10 by hydrochloric acid, stirring the solution uniformly, carrying out suction filtration on the solution, and drying the obtained solid to obtain 1.45mol of levothyroxine sodium, wherein the yield is 72.50%, and the purity is 99.17%.
Example 6
Step S1, preparation of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester:
the mol ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the bis (4-methoxyphenyl) -iodine bromide to the triethylamine to the manganese chloride is 1:2.0:1.2:0.09, wherein the volume ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the ethanol to the petroleum ether to the water is 1:5:5;
sequentially adding N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester, di (4-methoxyphenyl) -iodine bromide, triethylamine, manganese chloride and other mixtures into a reaction kettle 1, adding a solvent methanol 50L, stirring for 48 hours at room temperature, removing methanol under reduced pressure, adding ethyl acetate 40L, stirring uniformly, removing solids through suction filtration, removing ethyl acetate under reduced pressure, adding ethanol 7L and petroleum ether/water mixed solution 70L into the reaction kettle, filtering, and drying the obtained solids to obtain 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester 4.11mol, wherein the yield is 82.2%, and the purity is 98.42%;
step S2, preparation of 3, 5-diiodo-L-thyroxine:
3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester, naI.2H 2 O、Na 2 SO 3 Wherein the molar ratio of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester is 4 moles;
sequentially adding 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester and NaI.2H into a reaction kettle 2 2 Heating O, glacial acetic acid 5L and HBr5L solution to reflux, stirring for 3.5h at a constant temperature, cooling to room temperature, removing acetyl by reaction, and adding Na into the reaction solution 2 SO 3 Quenching the reaction, stirring uniformly, filtering, and drying the obtained solid to obtain 3, 5-diiodo-L-thyroxine 3.95mol, wherein the yield is 98.75%, and the purity is 99.20%;
step S3, preparation of L-thyroxine:
3, 5-diiodo-L-thyroxine, I 2 、NaI·2H 2 O、Na 2 SO 3 The molar ratio of (2) to (3) 2:0.45, wherein the molar ratio of 3, 5-diiodo-L-thyroxine is 2mol, and the concentration of dimethylamine aqueous solution is 35 percent
Adding 3, 5-diiodo-L-thyroxine into a reaction kettle 3, adding dimethylamine water solution to provide alkaline environment, and then dripping I 2 /NaI·2H 2 O in methanol is added dropwise for 3.0h, stirred for 1.0h at normal temperature, and Na is added 2 SO 3 Stirring, filtering, pumping the filtrate back to the reaction kettle 3, cooling to 10 ℃ with ice water, stirring for 10min, adjusting the pH=6 with hydrochloric acid, filtering, and drying the obtained solid to obtain 1.98mol of L-thyroxine with the yield of 99.00% and the purity of 95.33%;
step S4, preparing levothyroxine sodium:
the molar ratio of the L-thyroxine to the NaOH is 1:4, the NaOH is prepared into a solution with the concentration of 30 percent, the solution is added in two times, the molar ratio of the two times of addition is 17:1 in sequence, and the L-thyroxine is 2mol;
adding L-thyroxine into a reaction kettle 4, heating to 80 ℃, adding NaOH aqueous solution, preserving heat, stirring for 15min, cooling to room temperature, and suction filtering. Adding the filter cake into a reaction kettle 4, adding NaOH aqueous solution until the filter cake is completely dissolved, regulating the pH value of the solution to be 10 by hydrochloric acid, stirring the solution uniformly, carrying out suction filtration on the solution, and drying the obtained solid to obtain 1.44mol of levothyroxine sodium, wherein the yield is 72.00%, and the purity is 99.25%.
Example 7
Step S1, preparation of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester:
the mol ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the bis (4-methoxyphenyl) -iodine bromide to the triethylamine to the manganese chloride is 1:2.0:1.2:0.09, wherein the volume ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester to the ethanol to the petroleum ether to the water is 1:5:5;
sequentially adding N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester, di (4-methoxyphenyl) -iodine bromide, triethylamine, manganese chloride and other mixtures into a reaction kettle 1, adding a solvent methanol 50L, stirring for 48 hours at room temperature, removing methanol under reduced pressure, adding ethyl acetate 40L, stirring uniformly, removing solids through suction filtration, removing ethyl acetate under reduced pressure, adding ethanol 7L and petroleum ether/water mixed solution 70L into the reaction kettle, filtering, and drying the obtained solids to obtain 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester 4.11mol, wherein the yield is 82.2%, and the purity is 98.42%;
step S2, preparation of 3, 5-diiodo-L-thyroxine:
3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester, naI.2H 2 O、Na 2 SO 3 Wherein the molar ratio of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester is 4 moles;
sequentially adding 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester and NaI.2H into a reaction kettle 2 2 Heating O, glacial acetic acid 5L and HBr5L solution to reflux, stirring for 3.5h at a constant temperature, cooling to room temperature, removing acetyl by reaction, and adding Na into the reaction solution 2 SO 3 Quenching the reaction, stirring uniformly, filtering, and drying the obtained solid to obtain 3, 5-diiodo-L-thyroxine 3.95mol, wherein the yield is 98.75%, and the purity is 99.20%;
step S3, preparation of L-thyroxine:
3, 5-diiodo-L-thyroxine, I 2 、NaI·2H 2 O、Na 2 SO 3 The molar ratio of (2) to (3) 2:0.45, wherein the molar ratio of 3, 5-diiodo-L-thyroxine is 2mol, and the concentration of dimethylamine aqueous solution is 35 percent
Adding 3, 5-diiodo-L-thyroxine into a reaction kettle 3, adding dimethylamine water solution to provide alkaline environment, and then dripping I 2 /NaI·2H 2 O in methanol is added dropwise for 3.0h, stirred for 1.0h at normal temperature, and Na is added 2 SO 3 Stirring, filtering, pumping the filtrate back to the reaction kettle 3, cooling to 10 ℃ with ice water, stirring for 10min, adjusting the pH=6 with hydrochloric acid, filtering, and drying the obtained solid to obtain 1.98mol of L-thyroxine with the yield of 99.00% and the purity of 95.33%;
step S4, preparing levothyroxine sodium:
the molar ratio of the L-thyroxine to the NaOH is 1:4, the concentration of the ethanol water solution is 90 percent, and the NaOH is prepared into a solution with the concentration of 30 percent, wherein the L-thyroxine is 2mol;
adding L-thyroxine into a reaction kettle 4, adding enough ethanol water solution, heating to 80 ℃, adding NaOH water solution, keeping the temperature, stirring for 15min, cooling to room temperature, regulating the pH value of the solution to be 10 by hydrochloric acid, stirring uniformly, filtering the solution, and drying the obtained solid to obtain 1.41mol of levothyroxine sodium with the yield of 70.50% and the purity of 96.83%.
Claims (9)
1. The production process of the levothyroxine sodium is characterized by comprising the following steps of:
step S1, preparation of 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester:
sequentially adding N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester, di (4-methoxyphenyl) -iodine bromide, triethylamine, manganese chloride and other mixtures into a reaction kettle 1, adding solvent methanol, stirring uniformly, removing methanol under reduced pressure, adding ethyl acetate, stirring uniformly, filtering to remove solids, removing ethyl acetate under reduced pressure, adding ethanol and petroleum ether/water mixed solution into the reaction kettle, filtering, and drying the obtained solids to obtain 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester;
step S2, preparation of 3, 5-diiodo-L-thyroxine:
sequentially adding 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester and NaI.2H into a reaction kettle 2 2 Heating O, glacial acetic acid and HBr solution to reflux, maintaining the temperature, stirring for a period of time, cooling to room temperature, removing acetyl by reaction, and adding Na into the reaction solution 2 SO 3 Quenching the reaction, stirring uniformly, filtering, and drying the obtained solid to obtain 3, 5-diiodo-L-thyroxine;
step S3, preparation of L-thyroxine:
adding 3, 5-diiodo-L-thyroxine into a reaction kettle 3, adding dimethylamine water solution to provide alkaline environment, and then dripping I 2 /NaI·2H 2 O methanol solution is stirred evenly at normal temperature after being added dropwise, and Na is added 2 SO 3 Stirring, filtering, pumping the filtrate back to the reaction kettle 3, regulating the pH of the solution to be weak acid, filtering, and drying the obtained solid to obtain the L-thyroxine;
step S4, preparing levothyroxine sodium:
adding L-thyroxine into a reaction kettle 4, adding a sufficient amount of ethanol water solution, heating, adding NaOH water solution, keeping the temperature, stirring, cooling to room temperature, and carrying out suction filtration. Adding the filter cake into a reaction kettle 4, adding NaOH aqueous solution until the filter cake is completely dissolved, adjusting the pH value of the solution to be 8-10, stirring the solution uniformly, filtering the solution, and drying the obtained solid to obtain the levothyroxine sodium.
2. The production process of the levothyroxine sodium according to claim 1, wherein the production process is characterized by comprising the following steps of: in the step S1, the mol ratio of the N-acetyl-3, 5-diiodo-L-tyrosine ethyl ester, the di (4-methoxyphenyl) -iodine bromide, the triethylamine and the manganese chloride is 1:1.8-2.0:1-1.2:0.07-0.09.
3. The production process of the levothyroxine sodium according to claim 1, wherein the production process is characterized by comprising the following steps of: and (2) adding the solvent methanol in the step (S1), and stirring for 48 hours at room temperature, wherein the volume ratio of the ethanol to the petroleum ether to the water is 1:5:5.
4. The production process of the levothyroxine sodium according to claim 1, wherein the production process is characterized by comprising the following steps of: the step S2 is performed by using 3, 5-diiodo-4- (4-methoxyphenoxy) -N-acetyl-L-phenylalanine ethyl ester and NaI.2H 2 O、Na 2 SO 3 The mol ratio of (3) is 1:0.3-0.35:0.23-0.25, and the heat preservation and stirring time is 3.5h.
5. The production process of the levothyroxine sodium according to claim 1, wherein the production process is characterized by comprising the following steps of: 3, 5-diiodo-L-thyroxine, I in step S3 2 、NaI·2H 2 O、Na 2 SO 3 The molar ratio of (2) to (3) 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 the levothyroxine sodium according to claim 1, wherein the production process is characterized by comprising the following steps of: the dripping time of the methanol solution of I2/NaI.2H2O in the step S3 is 2.5-3.0H, and the mixture is stirred for 1.0H at normal temperature after the dripping is finished.
7. The production process of the levothyroxine sodium according to claim 1, wherein the production process is characterized by comprising the following steps of: in the step S3, the filtrate is pumped back to the reaction kettle 3, cooled to 0-10 ℃ by ice water, stirred for 10min, and the pH=6 of the solution is regulated by hydrochloric acid.
8. The production process of the levothyroxine sodium according to claim 1, wherein the production process is characterized by comprising the following steps of: in the step S4, the molar ratio of the L-thyroxine to the NaOH is 1:4, the concentration of the ethanol aqueous solution is 85-90%, the NaOH is prepared into a solution with the concentration of 30% and is added in two times, and the molar ratio of the two times of addition is 16-17:1 in sequence.
9. The production process of the levothyroxine sodium according to claim 1, wherein the production process is characterized by comprising the following steps of: in the step S4, the temperature is raised to 80 ℃, naOH aqueous solution is added, the temperature is kept and stirred for 10 to 15min, the temperature is cooled to room temperature, and hydrochloric acid is used for adjusting the pH value of the solution to be 8 to 10.
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