CN112552281A - Synthetic process of trelagliptin succinate bulk drug - Google Patents
Synthetic process of trelagliptin succinate bulk drug Download PDFInfo
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- CN112552281A CN112552281A CN202011416566.4A CN202011416566A CN112552281A CN 112552281 A CN112552281 A CN 112552281A CN 202011416566 A CN202011416566 A CN 202011416566A CN 112552281 A CN112552281 A CN 112552281A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
Abstract
The invention discloses a synthetic process of a trelagliptin succinate bulk drug, and relates to the field of pharmacy. The method comprises the following steps: (1) SM1, SM2, an acid binding agent and a solvent, and reacting at 25-100 ℃ to obtain INT 1; (2) INT1, SM3, a solvent and an acid-binding agent are reacted at 25-100 ℃ to obtain INT 2; (3) heating succinic acid and solvent to dissolve to obtain a standby solution; INT2 adding solvent, heating to dissolve, pouring the solution for use, and reacting at 25-100 ℃ to obtain trelagliptin succinate. Condensation and ammoniation reaction, wherein the solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide, isopropanol, ethyl acetate, tetrahydrofuran and acetonitrile; the acid-binding agent is liquid or solid, the liquid is diisopropylethylamine, triethylamine or pyridine, and the solid is potassium carbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; the salt-forming solvent is one or more of isopropanol, ethanol, methanol, ethyl acetate, acetonitrile, acetone and dichloromethane. The method has the advantages of easily available raw materials, mild and controllable reaction conditions, convenient recovery and reuse of the solvent, safety, reliability, environmental protection, higher yield and product purity, and easy industrial production.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to a synthesis process of a hypoglycemic drug trelagliptin succinate.
Background
Trelagliptin succinate (a long-acting dipeptidyl peptidase IV (DPP-4) inhibitor researched and developed by Nippon Wutian pharmaceutical company is mainly used for treating type II diabetes.
Trelagliptin succinate is a type II hypoglycemic drug once a week, and realizes the control of blood sugar level by selectively and continuously inhibiting DPP-4. DPP-4 is an enzyme that triggers the inactivation of incretin and glucose-dependent insulinotropic polypeptides, whereas these 2 incretins play an important role in blood glucose regulation. Inhibiting DPP-4 can increase blood sugar level dependent insulin secretion, thereby controlling blood sugar level.
DPP-4 inhibitors are known to be a first group of novel type II diabetes drugs that can control blood glucose levels by improving the body's own ability, either as single drugs or in combination with other oral hypoglycemic agents. The medicine has unique action mechanism, has the unique advantages of no hypoglycemia, no weight increase, small side effect and the like, and has low incidence of gastrointestinal adverse reactions.
The synthetic patents of Wutian corporation CN1926128 and CN101360723 comprise the following synthetic process routes:
2-bromo-5-fluorotoluene is used as an initial material, and is subjected to cyanidation, bromination, condensation, ammoniation and salt formation reaction to synthesize trelagliptin succinate. In the reaction process, a high-toxicity reagent cuprous cyanide is needed for cyanidation, a carbon tetrachloride toxic solvent is used for bromination reaction, high-temperature reaction is needed for condensation reaction in a closed reactor, and a product needs to be purified by a chromatographic column. The reaction conditions are harsh, the safety and environmental protection are poor, the overall reaction yield is low, the product purity is not high, and the industrial production is not facilitated.
Patents EP2682110 and WO2012118180 are optimized on the original basis, and the process route is as follows:
the trelagliptin succinate is prepared by taking 3-methyl-6-chlorouracil and 2-cyano-5-fluorobenzyl bromide as starting materials and performing condensation, ammoniation and salt forming reactions. The condensation reaction uses N-methyl pyrrolidone as a high boiling point solvent, and the post-treatment adopts a method of adding water to separate out a product, so that a large amount of organic wastewater is generated, and the purity of the product is not easy to control. The salifying reaction solvent is a mixed solvent of tetrahydrofuran and isopropanol, the tetrahydrofuran is a second-class solvent and has a lower boiling point, the amplification production is not beneficial to the operation of personnel, and simultaneously, the residual of the medicine solvent is easy to exceed the standard.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a synthetic process of a trelagliptin succinate raw material drug, which has the advantages of easily available reaction raw materials, mild and controllable reaction conditions, convenient recovery and reuse of a solvent, safety, reliability, environmental protection, higher reaction yield and product purity, and easiness in industrial expanded production.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows: a synthetic process of a trelagliptin succinate bulk drug comprises the following steps:
(1) condensation reaction:
adding an acid-binding agent and a solvent into 3-methyl-6-chlorouracil SM1 and 2-cyano-5-fluorobenzyl bromide SM2 serving as starting materials, uniformly stirring, and stirring for reaction at a reaction temperature of 25-100 ℃ until the reaction is finished to obtain INT 1;
(2) ammoniation reaction: adding INT1, R-3-aminopiperidine dihydrochloride SM3, a solvent and an acid-binding agent, stirring, reacting at the reaction temperature of 25-100 ℃ until the reaction is finished to obtain INT 2;
(3) salt forming reaction: adding succinic acid and solvent, stirring, heating for dissolving completely to obtain a solution; INT2 adding solvent, heating to dissolve the solid completely, pouring into the solution, and stirring at 25-100 deg.C to obtain the product, i.e. trelagliptin succinate.
The reaction formula is as follows:
in the condensation reaction and the ammoniation reaction, the solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide, isopropanol, ethyl acetate, tetrahydrofuran and acetonitrile; the acid binding agent is a liquid reagent or a solid reagent, the liquid reagent is diisopropylethylamine, triethylamine or pyridine, and the solid reagent is potassium carbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide;
in the salt forming reaction, the solvent is one or more of isopropanol, ethanol, methanol, ethyl acetate, acetonitrile, acetone and dichloromethane.
Preferably, in the condensation reaction, the solvent is N, N-dimethylformamide, and the acid-binding agent is solid reagent potassium carbonate.
Preferably, in the ammoniation reaction, the solvent is isopropanol, and the acid-binding agent is solid reagent potassium carbonate.
Preferably, in the condensation reaction, the dosage of the acid-binding agent is 1.0-3.0 times of the molar weight of SM1, and the reaction time is 2-20 h; in the ammoniation reaction, the dosage of the acid-binding agent is 1.0 to 5.0 times of the molar weight of INT1, and the reaction time is 2 to 20 hours.
Further preferably, in the condensation reaction, the dosage of the acid-binding agent is 1.2 times of the molar weight of SM 1; in the ammoniation reaction, the dosage of the acid-binding agent is 2.0 times of the molar weight of INT 1.
Preferably, the condensation reaction and the amination reaction are carried out at a temperature of from 50 to 60 ℃.
Preferably, INT1 is obtained by filtering in the post-treatment in the condensation reaction, recovering the solvent by concentrating the filtrate under reduced pressure, and then purifying the solvent with methanol.
Preferably, in the amination, the solvent is recovered by concentration under reduced pressure in the post-treatment, then dichloromethane is added for dissolution, water and a hydrochloric acid solution are added for purification by a hydrochloride formation method, and finally alkali is added for adjusting the pH value to 9-10 to obtain the product INT2 which is recrystallized by methanol.
Preferably, in the salt-forming reaction, the solvent is methanol.
Preferably, in the salt forming reaction, the reaction temperature is 55-65 ℃, and the reaction time is 0.5-4 h; and cooling, crystallizing, filtering and drying the product to obtain the trelagliptin succinate.
Adopt the produced beneficial effect of above-mentioned technical scheme to lie in:
the invention adopts the route described in patent EP2682110, and improves the operability, safety and environmental protection of the synthesis process by optimizing reaction conditions and a post-treatment method. The trelagliptin succinate is prepared by taking 3-methyl-6-chlorouracil and 2-cyano-5-fluorobenzyl bromide as starting materials and performing condensation, ammoniation and salt forming reactions. The method avoids the use of solvents with high boiling points and difficult recovery, reduces the types of solvents in a reaction route, optimizes the solid alkali to replace liquid alkali, is easy to transport, and reduces the reaction cost. The salifying reaction adopts single solvent for recrystallization, so that the product purity is improved, the process operation is simplified, and the inspection cost is reduced. The overall reaction yield is 70-80%, the product purity is not lower than 99.5%, and the optical purity is not lower than 99.9%.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments.
Example 1
(1) INT1 Synthesis
1.00kg of 3-methyl-6-chlorouracil, 1.47kg of 2-cyano-5-fluorobenzyl bromide, 1.03kg of potassium carbonate and 8L of N, N-dimethylformamide are sequentially added at room temperature, and the mixture is stirred to be uniformly dispersed. Slowly heating the reaction system to 50-60 ℃, stirring and reacting for 4-5h, gradually changing the reaction liquid from white turbid liquid to dark turbid liquid, and monitoring the reaction end point by TLC (developing agent PE/EA ═ 1:1, 254 color development).
After the reaction, the reaction solution is filtered while hot, the filter cake is washed with N, N-dimethylformamide for 2 times at 50-60 ℃, the filtrates are combined, and the solvent is evaporated by decompression concentration. Washing the solid obtained by evaporation by using methanol slurry, controlling the temperature to be 50-60 ℃, stirring for 1h, cooling, filtering, and drying the filter cake by blowing air to obtain a white-like solid, namely INT1, wherein the yield is 96 percent, and the product purity is 98.2 percent.
(2) INT2 Synthesis
Adding INT11.00kg, R-3-aminopiperidine dihydrochloride 648g, isopropanol 8L and potassium carbonate 941g in sequence at room temperature, slowly heating to 50-60 ℃ under stirring, and reacting for 5-6h, wherein the reaction solution is changed from white turbid solution to light yellow turbid solution. The end of the reaction was monitored by TLC (developer EA: PE: 1: 254 color).
After the reaction, the isopropanol was concentrated under reduced pressure to dryness to obtain a pale yellow solid, and 7L of dichloromethane was added and dissolved by stirring. Filtering to obtain a yellow organic phase, adding 6L of water into the organic phase, adding 2L of 2mol/L hydrochloric acid solution while stirring, separating out a solid, filtering, and rinsing a filter cake by using 2L of dichloromethane. The filter cake was dissolved with 3L of water under heating, 3L of dichloromethane was added, 2.1L of 2mol/L NaOH solution was slowly added, PH was adjusted to 9-10, stirring was carried out, liquid separation was carried out, the aqueous phase was extracted 1 time with dichloromethane, the organic phases were combined, and the organic phase was dried with anhydrous sodium sulfate. Filtering, removing the drying agent, decompressing and concentrating the filtrate, evaporating the solvent to dryness, and recrystallizing with methanol to obtain an off-white solid, namely INT2, with the yield of 86% and the product purity of 99.6%.
(3) Synthesis of finished product
278g of succinic acid and 1.5L of methanol were added to the flask, and the mixture was heated to be completely dissolved with stirring and was reserved.
Adding INT 2800 g into a flask, adding 4.5L of methanol, heating to 60 deg.C to dissolve the solid completely, pouring the solution into the reaction system, stirring for reaction for 30min, cooling, and crystallizing for 1-2 h. Filtering, washing a filter cake by using cold methanol, and drying in vacuum to obtain the product, namely the trelagliptin succinate with the yield of 79 percent, the product purity of 99.9 percent and the optical purity of 100 percent.
The reaction formula is as follows:
example 2
(1) INT1 Synthesis
1.00kg of 3-methyl-6-chlorouracil, 1.47kg of 2-cyano-5-fluorobenzyl bromide, 1.03kg of potassium carbonate and 8L of dimethyl sulfoxide are sequentially added at room temperature, and the materials are stirred to be uniformly dispersed. Slowly heating the reaction system to 50-60 ℃, stirring and reacting for 5-6h, gradually changing the reaction liquid from white turbid liquid to dark turbid liquid, and monitoring the reaction end point by TLC (developing agent PE/EA is 1:1, 254 is developed).
After the reaction, the reaction solution is filtered while hot, the filter cake is washed with dimethyl sulfoxide at 50-60 ℃ for 2 times, the filtrates are combined, and the solvent is evaporated by decompression concentration. Washing the solid obtained by evaporation by using methanol slurry, controlling the temperature to be 50-60 ℃, stirring for 1h, cooling, filtering, and drying the filter cake by blowing air to obtain a white-like solid, namely INT1, wherein the yield is 89%, and the product purity is 97.5%.
(2) INT2 Synthesis
Adding INT11.00kg, R-3-aminopiperidine dihydrochloride 648g, ethanol 8L and potassium carbonate 941g in sequence at room temperature, slowly heating to 50-60 ℃ under stirring, and reacting for 7-8h, wherein the reaction solution is changed from white turbid solution to light yellow turbid solution. The end of the reaction was monitored by TLC (developer EA: PE: 1: 254 color).
After the reaction is finished, concentrating under reduced pressure and evaporating ethanol to dryness to obtain a light yellow solid, and adding 7L of dichloromethane, stirring and dissolving. Filtering to obtain a yellow organic phase, adding 6L of water into the organic phase, adding 2L of 2mol/L hydrochloric acid solution while stirring, separating out a solid, filtering, and rinsing a filter cake by using 2L of dichloromethane. The filter cake was dissolved with 3L of water under heating, 3L of dichloromethane was added, 2.1L of 2mol/L NaOH solution was slowly added, PH was adjusted to 9-10, stirring was carried out, the layers were separated, the aqueous phase was extracted 1 time with DCM, the organic phases were combined and dried over anhydrous sodium sulfate. Filtering, removing the drying agent, decompressing and concentrating the filtrate, evaporating the solvent to dryness, and recrystallizing with methanol to obtain an off-white solid, namely INT2, with the yield of 81 percent and the product purity of 99.2 percent.
(3) Synthesis of finished product
278g of succinic acid and 2L of isopropyl alcohol were added to the flask, and the mixture was heated to be completely dissolved with stirring and was used.
INT 2800 g and 6L of isopropanol are added into the flask, the solid is heated to 63 ℃ and completely dissolved, then the standby liquid is quickly poured into a reaction system, stirred and reacted for 30min, and cooled and crystallized for 1-2 h. Filtering, washing the filter cake with cold isopropanol, and vacuum drying to obtain the product, namely trelagliptin succinate with the yield of 69%, the product purity of 99.9% and the optical purity of 100%.
Example 3
(1) INT1 Synthesis
1.00kg of 3-methyl-6-chlorouracil, 1.47kg of 2-cyano-5-fluorobenzyl bromide, 807g of sodium bicarbonate and 8L of N, N-dimethylformamide are sequentially added at room temperature, and the materials are stirred to be uniformly dispersed. Slowly heating the reaction system to 50-60 ℃, stirring and reacting for 5-6h, gradually changing the reaction liquid from white turbid liquid to dark turbid liquid, and monitoring the reaction end point by TLC (developing agent PE/EA is 1:1, 254 is developed).
After the reaction, the reaction solution is filtered while hot, the filter cake is washed with N, N-dimethylformamide for 2 times at 50-60 ℃, the filtrates are combined, and the solvent is evaporated by decompression concentration. Washing the solid obtained by evaporation by using methanol slurry, controlling the temperature to be 50-60 ℃, stirring for 1h, cooling, filtering, and drying the filter cake by blowing air to obtain a white-like solid, namely INT1, wherein the yield is 91%, and the product purity is 97.8%.
(2) INT2 Synthesis
INT11.00kg, R-3-aminopiperidine dihydrochloride 648g, isopropanol 8L and sodium bicarbonate 573g are sequentially added at room temperature, the temperature is slowly raised to 50-60 ℃ under stirring, the reaction is carried out for 7-8h, and the reaction solution is changed from white turbid solution to light yellow turbid solution. The end of the reaction was monitored by TLC (developer EA: PE: 1: 254 color).
After the reaction, the isopropanol was concentrated under reduced pressure to dryness to obtain a pale yellow solid, and 7L of dichloromethane was added and dissolved by stirring. Filtering to obtain a yellow organic phase, adding 6L of water into the organic phase, adding 2L of 2mol/L hydrochloric acid solution while stirring, separating out a solid, filtering, and rinsing a filter cake by using 2L of dichloromethane. The filter cake was dissolved with 3L of water under heating, 3L of dichloromethane was added, 2.1L of 2mol/L NaOH solution was slowly added, PH was adjusted to 9-10, stirring was carried out, liquid separation was carried out, the aqueous phase was extracted 1 time with dichloromethane, the organic phases were combined, and the organic phase was dried with anhydrous sodium sulfate. Filtering, removing the drying agent, decompressing and concentrating the filtrate, evaporating the solvent to dryness, and recrystallizing with methanol to obtain an off-white solid, namely INT2, with the yield of 80 percent and the product purity of 99.5 percent.
(3) Synthesis of finished product
278g of succinic acid and 2L of ethanol were added to the flask, and the mixture was heated to be completely dissolved with stirring for use.
Adding INT 2800 g into a flask, adding 6L ethanol, heating to 57 deg.C to dissolve the solid completely, then quickly pouring the solution into the reaction system, stirring for reaction for 30min, and cooling for crystallization for 1-2 h. Filtering, washing a filter cake by using cold ethanol, and drying in vacuum to obtain the product, namely the trelagliptin succinate with the yield of 72 percent, the product purity of 99.9 percent and the optical purity of 100 percent.
In conclusion, in the synthesis of the trelagliptin succinate, a reaction solvent N, N-dimethylformamide is preferably selected for condensation reaction, a solid reagent potassium carbonate is preferably selected as an acid binding agent, the dosage of the solid reagent potassium carbonate is 1.2 times of the molar weight of SM1, the reaction temperature is 50-60 ℃, and a methanol slurry washing mode is adopted for refining; the reaction solvent isopropanol is preferably selected in the ammoniation reaction, the solid reagent potassium carbonate is preferably selected as the acid-binding agent, the dosage of the acid-binding agent is 2.0 times of INT1 molar weight, the reaction temperature is 50-60 ℃, and the refining adopts a recrystallization mode of salifying acid salt and methanol for refining; the preferable reaction solvent for the salt-forming reaction is methanol, and the reaction temperature is 55-65 ℃. The reaction solvent can be recycled and reused, the reaction conditions are mild and easy to control, the overall yield is high, the method is suitable for industrial production, the product quality is controllable, and the requirements of raw material medicines are met.
The above embodiments are provided to aid in understanding the present invention and to enable those skilled in the art to make and use the invention, and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A synthetic process of a trelagliptin succinate bulk drug is characterized by comprising the following steps: the method comprises the following steps:
(1) condensation reaction:
adding an acid-binding agent and a solvent into 3-methyl-6-chlorouracil (SM1) and 2-cyano-5-fluorobenzyl bromide (SM2) serving as starting materials, uniformly stirring, and stirring for reaction at a reaction temperature of 25-100 ℃ until the reaction is finished to obtain INT 1;
(2) ammoniation reaction: adding INT1, R-3-aminopiperidine dihydrochloride (SM3), a solvent and an acid-binding agent, stirring, reacting at the reaction temperature of 25-100 ℃ until the reaction is finished to obtain INT 2;
(3) salt forming reaction: adding succinic acid and solvent, stirring, heating for dissolving completely to obtain a solution; INT2 adding solvent, heating to dissolve solid completely, adding the solution, stirring at 25-100 deg.C for reaction, cooling, and crystallizing to obtain Trelagliptin succinate (API); the reaction formula is as follows:
in the condensation reaction and the ammoniation reaction, a solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide, isopropanol, ethyl acetate, tetrahydrofuran and acetonitrile; the acid binding agent is a liquid reagent or a solid reagent, the liquid reagent is diisopropylethylamine, triethylamine or pyridine, and the solid reagent is potassium carbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide;
in the salt forming reaction, the solvent is one or more of isopropanol, ethanol, methanol, ethyl acetate, acetonitrile, acetone and dichloromethane.
2. The synthetic process of trelagliptin succinate raw material medicine according to claim 1, characterized in that in the condensation reaction, a solvent is N, N-dimethylformamide, and an acid-binding agent is solid reagent potassium carbonate.
3. The synthetic process of trelagliptin succinate bulk drug according to claim 1, characterized in that in the ammoniation reaction, a solvent is isopropanol, and an acid-binding agent is a solid reagent potassium carbonate.
4. The synthetic process of trelagliptin succinate bulk drug according to claim 1, characterized in that in the condensation reaction, the dosage of an acid-binding agent is 1.0-3.0 times of the molar amount of SM1, and the reaction time is 2-20 h; in the ammoniation reaction, the dosage of the acid-binding agent is 1.0-5.0 times of the molar weight of INT1, and the reaction time is 2-20 h.
5. The synthetic process of trelagliptin succinate bulk drug according to claim 4, characterized in that in the condensation reaction, the dosage of the acid-binding agent is 1.2 times of the molar weight of SM 1; in the ammoniation reaction, the dosage of the acid-binding agent is 2.0 times of the molar weight of INT 1.
6. The synthetic process of trelagliptin succinate bulk drug according to claim 1, characterized in that the reaction temperature is 50-60 ℃ in the condensation reaction and the ammoniation reaction.
7. The process for synthesizing the trelagliptin succinate bulk drug according to claim 1, wherein in the condensation reaction, the post-treatment is filtration, the filtrate is subjected to reduced pressure concentration to recover the solvent, and then the solvent is refined by methanol to obtain INT 1.
8. The process for synthesizing trelagliptin succinate bulk drug according to claim 1, wherein in the ammoniation reaction, the solvent is recovered by decompression concentration after the post-treatment, then dichloromethane is added for dissolution, water and hydrochloric acid solution are added, the product is refined by a hydrochloride forming mode, and finally alkali is added to adjust the pH value to be 9-10, so that the product INT2 is obtained and recrystallized by methanol.
9. The synthetic process of trelagliptin succinate bulk drug according to claim 1, characterized in that in the salt-forming reaction, the solvent is methanol.
10. The synthetic process of trelagliptin succinate bulk drug according to claim 1, characterized in that in the salt forming reaction, the reaction temperature is 55-65 ℃, and the reaction time is 0.5-4 h; and filtering the post-treatment, washing a filter cake by using a solvent, and drying to obtain the trelagliptin succinate.
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WO2014127735A1 (en) * | 2013-02-22 | 2014-08-28 | 四川海思科制药有限公司 | Solid forms of trelagliptin, preparation method and applications thereof |
CN106632241A (en) * | 2016-12-06 | 2017-05-10 | 安徽省金楠医疗科技有限公司 | Preparation method of trelagliptin succinate |
CN108822080A (en) * | 2018-08-31 | 2018-11-16 | 四川新斯顿制药股份有限公司 | The preparation method of amber love song Ge Lieting |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US20140023708A1 (en) * | 2011-03-03 | 2014-01-23 | Takeda Pharmaceutical Company Limited | Laminated tablet and manufacturing method therefor |
WO2014127735A1 (en) * | 2013-02-22 | 2014-08-28 | 四川海思科制药有限公司 | Solid forms of trelagliptin, preparation method and applications thereof |
CN106632241A (en) * | 2016-12-06 | 2017-05-10 | 安徽省金楠医疗科技有限公司 | Preparation method of trelagliptin succinate |
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