CN112480075A - Refining method of trelagliptin succinate - Google Patents
Refining method of trelagliptin succinate Download PDFInfo
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- CN112480075A CN112480075A CN202011516788.3A CN202011516788A CN112480075A CN 112480075 A CN112480075 A CN 112480075A CN 202011516788 A CN202011516788 A CN 202011516788A CN 112480075 A CN112480075 A CN 112480075A
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- trelagliptin succinate
- trelagliptin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
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- Oil, Petroleum & Natural Gas (AREA)
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Abstract
The invention discloses a refining method of trelagliptin succinate, which is characterized by comprising the following steps: taking a crude product of trelagliptin succinate (with the purity of 99.76%) as an initial raw material, adding an organic solvent to dissolve the crude product of trelagliptin succinate, cooling and crystallizing to obtain a high-purity target product of trelagliptin succinate solid, wherein the purity can reach 99.99% through HPLC detection. Compared with the prior art, the used solvent has lower toxicity, the mother solution solvent can be recycled, and the environmental pollution is less; and the operation is simple and easy, and the industrial scale production is convenient.
Description
Technical Field
The invention relates to a refining method of trelagliptin succinate, belonging to the technical field of medicines and chemical industry.
Background
Trelagliptin succinate is an ultra-long-acting dipeptidyl peptidase IV (DPP-4) inhibitor which controls blood sugar levels by selectively and continuously inhibiting DPP-4. Trelagliptin is the first once-weekly hypoglycemic drug on the global market, while the similar DPP-4 inhibitor on the market needs to be orally taken once a day, the medication advantage of Zafatek undoubtedly provides more convenient treatment options for diabetic patients, and greatly improves the convenience and compliance of the patients.
Trelagliptin succinate tablet was manufactured by Takeda, Inc. under the trade name
The tablet is 100 mg/tablet, and can be used for treating type 2 diabetes. The product is approved by Japan health and labour welfare department (MHLW) to be marketed at 26.3.2015, and is used for treating type 2 diabetes. Zafatek is marked as the first once-weekly oral hypoglycemic agent on the world market, and also represents a heavy pound bomb thrown by wutian in the diabetes market.
English name of trelagliptin succinate: trelagliptin Succinate
Chemical name of Chinese: 2- ({6- [ (3R) -3-aminopiperidin-1-yl ] -3-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl } methyl) -4-fluorobenzonitrile, succinic acid (1:1) (I)
Chemical name of English: 2- [ [6- [ (3R) -3-aminoperidin-1-yl ] -3-methyl-2, 4-dioxoperidin-1-yl ] methyl ] -4-fluoronitrile Succinate (I)
CAS number: 1029877-94-8
Structural formula (xvi):
disclosure of Invention
Aiming at the defects of the prior art, the invention provides a refining method of trelagliptin succinate, and finally the trelagliptin succinate with the purity of 99.99 percent can be obtained.
The refining method of the trelagliptin succinate provided by the invention takes a crude trelagliptin succinate (with the purity of 99.76%) as an initial raw material, the crude trelagliptin succinate is dissolved in an organic solvent, and is cooled and crystallized to obtain a high-purity target product, namely the trelagliptin succinate solid, and the purity can reach 99.99% through HPLC detection.
In the purification method of trelagliptin succinate, the purification solvents acetonitrile and acetonitrile-ethanol (1:1) are preferably acetonitrile-ethanol (1: 1).
In the refining method of trelagliptin succinate, the heating and dissolving temperature is 40-70 ℃, and preferably 50-60 ℃.
In the refining method of trelagliptin succinate, the crystallization temperature is-10 ℃, and preferably 0-10 ℃.
The refining method of trelagliptin succinate has the highest purity of 99.99 percent, and compared with the prior art, the refining method of trelagliptin succinate uses a solvent, has low toxicity, can recycle a mother solution solvent, and has little environmental pollution; and the operation is simple and easy, and the industrial scale production is convenient.
Detailed Description
Example 1:
the method comprises the following steps: preparation of 2- [ (6-chloro-3, 4-dihydro-3-methyl-2, 4-dioxo-1 (2H) -pyrimidinyl) methyl ] -4-fluorobenzonitrile
To a reaction flask were added 100g of 3-methyl-6-chlorouracil, 140g of 2-cyano-5-fluorobenzyl bromide (1.05 eq), 800ml of toluene, and 38.4g of potassium hydroxide (1.1 eq). Stirring the mixture at 40-50 ℃ for reaction, detecting by TLC, reacting completely within 3 hours, and directly using the product in the next reaction.
Step two: preparation of Trelagliptin
113.2g of (R) -3-aminopiperidine dihydrochloride (1.05 equivalent) was added to the first-step reaction flask, and the mixture was stirred at 40 to 50 ℃ for reaction, followed by TLC detection, and the reaction was completed in 2 hours. Filtering, and evaporating the solvent of the filtrate to dryness to obtain the trelagliptin.
Step three: preparation of trelagliptin succinate
600ml of ethanol and 73.5g of succinic acid were added to the above second-step reaction flask, and the reaction was terminated by refluxing for 1 hour. Cooled to room temperature and stirred for 1 hour, filtered and washed with a little ethanol. Vacuum drying at 50 ℃ to obtain 198.4g of a white solid crude trelagliptin succinate. The total yield of the three-step reaction is 67 percent, and the HPLC purity is 99.76 percent.
Example 2:
adding 100g of the trelagliptin succinate crude product into 300ml of acetonitrile-ethanol (1:1), heating to 50-60 ℃, dissolving, stirring for half an hour, cooling to 0-10 ℃, stirring for 2h, crystallizing, filtering, and washing the solid with a small amount of cold acetonitrile-ethanol (1: 1). Air-blast drying at 50 ℃. The yield was 95.2% and the HPLC purity was 99.99%.
Example 3:
adding 100g of the trelagliptin succinate crude product into 300ml of acetonitrile-ethanol (1:1), heating to 50-60 ℃, dissolving, stirring for half an hour, cooling to-10-0 ℃, stirring for 2h, crystallizing, filtering, and washing the solid with a small amount of cold acetonitrile-ethanol (1: 1). Air-blast drying at 50 ℃. The yield was 96.3% and the HPLC purity was 99.97%.
Example 4:
adding 100g of the trelagliptin succinate crude product into 300ml of acetonitrile, heating to 50-60 ℃, dissolving, stirring for half an hour, cooling to 0-10 ℃, stirring for 2h, crystallizing, filtering, and washing the solid with a small amount of cold acetonitrile. Air-blast drying at 50 ℃. The yield was 95.8% and the HPLC purity was 99.96%.
Example 5:
adding 100g of the trelagliptin succinate crude product into 300ml of acetonitrile, heating to 50-60 ℃, dissolving, stirring for half an hour, cooling to-10-0 ℃, stirring for 2h, crystallizing, filtering, and washing the solid with a small amount of cold acetonitrile. Air-blast drying at 50 ℃. The yield was 96.7% and the HPLC purity was 99.93%.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.
Claims (4)
1. The refining method of trelagliptin succinate is characterized by comprising the following steps: taking a crude product of trelagliptin succinate (with the purity of 99.76%) as an initial raw material, adding an organic solvent to dissolve the crude product of trelagliptin succinate, cooling and crystallizing to obtain a high-purity target product of trelagliptin succinate solid, wherein the purity can reach 99.99% through HPLC detection.
2. The method for refining trelagliptin succinate according to claim 1, wherein: the refined solvents acetonitrile and acetonitrile-ethanol (1:1), preferably acetonitrile-ethanol (1: 1).
3. The method for refining trelagliptin succinate according to claim 1, wherein: the heating and dissolving temperature is 40-70 ℃, preferably 50-60 ℃.
4. In the refining method of trelagliptin succinate, the crystallization temperature is-10 ℃, and preferably 0-10 ℃.
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| CN202011516788.3A CN112480075A (en) | 2020-12-22 | 2020-12-22 | Refining method of trelagliptin succinate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112574186A (en) * | 2020-12-22 | 2021-03-30 | 山东永丞制药有限公司 | Refining method of engagliflozin |
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