CN104130258B - The method for transformation of a kind of dimer - Google Patents
The method for transformation of a kind of dimer Download PDFInfo
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- CN104130258B CN104130258B CN201410398340.4A CN201410398340A CN104130258B CN 104130258 B CN104130258 B CN 104130258B CN 201410398340 A CN201410398340 A CN 201410398340A CN 104130258 B CN104130258 B CN 104130258B
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- gelieting
- sodium
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- dimer
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
Abstract
The present invention relates to the method that the dimer of a kind of Li Gelieting is converted into Li Gelieting, under dimer is not less than at pH the alkaline condition of 8, under alkali effect, product Li Gelieting can be converted into, eliminating impurity, it is to increase receipts rates, technique is simple, reduce production cost, be conducive to suitability for industrialized production.
Description
Technical field
The present invention relates to the method for the trans-utilization of the dimer impurity of a kind of medicine, belong to pharmaceutical technology sectors.
Background technology
Li Gelieting (Linagliptin) is a kind of selectivity dipeptidyl peptidase enzyme 4 (DPP-4) inhibitor, can significantly control blood sugar, only needing every day once oral, the risk occurring hypoglycemia, cardiovascular event and body weight to increase is lower, good market prospect. Li Gelieting structure is as shown in the formula shown in (1):
Obtain in the preparation method of Li Gelieting at use acid Deprotection, easily generate a kind of dimer impurity, affect the quality of final product Li Gelieting. If directly impurity being removed, transferring by product to and abandoning, then receipts rate can be caused lower, the raising of production cost. If can be product Li Gelieting by impurity conversion, be then conducive to the quality control of product and lower manufacturing cost, be conducive to suitability for industrialized production.
Summary of the invention
In order to remove dimer impurity, and ensure receipts rate and the lower cost of product, inventors have developed a kind of method that dimer impurity is converted into product Li Gelieting.
Invention general introduction
The present invention provides a kind of method that dimer impurity in Li Gelieting production process is converted into Li Gelieting in the basic conditions.
Detailed Description Of The Invention
Obtaining in the preparation process of Li Gelieting at use acid Deprotection, easily generate a kind of dimer impurity compound (02), its content often can more than 5%, and its structure is as shown in the formula shown in (02):
Contriver, by research, develops a kind of method that this dimer impurity compound (02) is converted into Li Gelieting, can either remove impurity, reduce by product, turn improve receipts rate, is conducive to producing and cost control.
The described method that dimer impurity compound (02) is converted into Li Gelieting and compound (1) comprises: when adding alkali reagent, compound (02) is in reaction solvent, in the basic conditions, it is converted into Li Gelieting:
Described reaction solvent is: N, dinethylformamide, methylene dichloride, toluene, methyl alcohol, ethanol, Virahol, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, acetone, butanone, propione, ethyl acetate, water, or its combination. In some embodiments, described reaction solvent is the solvent dissolved each other with water. In some embodiments, moisture in described reaction solvent. In some embodiments, described reaction solvent is methyl alcohol, ethanol, Virahol, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, acetone, butanone, propione, ethyl acetate, water, or its combination. In some embodiments, described reaction solvent is methylene dichloride, toluene, ethanol, Virahol, acetonitrile, acetone, propione, ethyl acetate, water, or its combination.
Described alkali reagent is organic bases or mineral alkali, it is selected from: sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta, potassium tert.-butoxide, trimethyl carbinol lithium, sodium methylate, sodium ethylate, sodium amide, sodium hydride, hexamethyl two silicon base sodium amide, hexamethyl two silicon base Lithamide, hexamethyl two silicon base potassium amide, diethylamino lithium, lithium diisopropylamine, ammoniacal liquor, first amine, diethylamine, triethylamine, quadrol, diisopropyl ethyl amine, 1, 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), pyridine, pyrroles, N-methylmorpholine, or its combination. in some embodiments, described alkali is salt of wormwood, sodium hydroxide, potassium hydroxide, triethylamine, diisopropyl ethyl amine, or its combination. in some embodiments, described alkali is salt of wormwood, sodium hydroxide, potassium hydroxide, or its combination. in some embodiments, described alkali is triethylamine, diisopropyl ethyl amine, or its combination.
The pH that described alkaline condition is reaction system is greater than 7. In some embodiments, described alkaline condition is that the pH of reaction system is not less than 8. In some embodiments, described alkaline condition is that the pH of reaction system is not less than 9. In some embodiments, described alkaline condition is that the pH of reaction system is not less than 10.
Dimer is converted into the reaction of Li Gelieting under alkali reagent effect, it is possible to carry out at ambient temperature, it is also possible to heat to promote that reaction carries out sooner. In some embodiments, dimer is converted into the reaction of Li Gelieting under reagent alkali effect, and temperature of reaction is-5 DEG C-60 DEG C. In some embodiments, dimer is converted into the reaction of Li Gelieting under alkali reagent effect, and temperature of reaction is 15 DEG C-40 DEG C. In some embodiments, dimer is converted into the reaction of Li Gelieting under alkali reagent effect, and temperature of reaction is the reflux temperature of solvent.
In reaction process, by the amount of compound (02) in HPLC detection system, the amount at compound (02) reacts completely lower than thinking when 3%. In some embodiments, the amount of compound (02) reacts completely lower than thinking when 2%. In some embodiments, the amount of compound (02) reacts completely lower than thinking when 1%. In some embodiments, the amount of compound (02) reacts completely lower than thinking when 0.5%. In some embodiments, the amount of compound (02) reacts completely lower than thinking when 0.1%.
In some embodiments, dimer is converted into Li Gelieting and reacted completely at 0.5 hour-24 hours. In some embodiments, dimer is converted into Li Gelieting and reacted completely at 2 hours-10 hours. In some embodiments, dimer is converted into Li Gelieting and reacted completely at 2 hours-5 hours.
Upon reaction completion, caning be passed through aftertreatment and obtain product Li Gelieting, solvent and alkali remove by distillation, then directly obtain or crystallization and obtain Li Gelieting; Can also using the pH of acid regulation system, the system pH of making is greater than 7 lower than 9, and then crystallization obtains Li Gelieting.
In some embodiments, compound (02) in organic solvent, adds organic bases, makes reaction system be not less than 8, reacts in a heated condition, after reacting completely, obtains Li Gelieting through aftertreatment.
In some embodiments, compound (02) in organic solvent, adds triethylamine, or diisopropyl ethyl amine, makes pH value of reaction system be not less than 8, reacts in a heated condition, after reacting completely, obtains Li Gelieting through aftertreatment.
In some embodiments, compound (02) is in water-containing solvent, and under alkali reagent exists, reaction system pH reacts under being not less than 9 conditions, after reacting completely, obtains Li Gelieting through aftertreatment.
In some embodiments, compound (02) is dissolved in ethanol, adds the aqueous solution of sodium hydroxide or potassium hydroxide, pH value of reaction system is made to be not less than 10, react under 15 DEG C of-40 DEG C of conditions, after reacting completely, obtain Li Gelieting through aftertreatment.
Dimer can be converted into product Li Gelieting by the inventive method, eliminate impurity, it is to increase receipts rates, reduces costs, is conducive to suitability for industrialized production.
Embodiment
In order to make the technician of this area understand the technical scheme of the present invention better, below disclose further some unrestricted embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, g represents gram, and mL represents milliliter.
Embodiment 1
In reaction flask, add the Li Gelieting crude product 2.8g of the dipolymer containing 13.8%, add 15mL methylene dichloride, the pH adding triethylamine 1.5mL regulation system is 8-9, reflux 24 hours, HPLC detection, containing the dimer of 1.36%, stops heating, it is transferred in room temperature and stirs 0.5 hour, then being cooled to 0 DEG C, brilliant 1 hour of analysis, then filters, drying, obtains solid product Li Gelieting 2.5g; HPLC detects in product not containing dimer.
Embodiment 2
Get the Li Gelieting crude product that 1.0g contains the dimer compound (02) of 30.82%, add 15mL acetonitrile; Being about 9-10 with the pH of the wet chemical regulation system of 5% (massfraction), be heated to 45 DEG C of reactions 10 hours, HPLC detection, containing the dimer of 0.05%, stops heating. Adding 30mL dichloromethane extraction, once, dichloromethane layer concentrates and obtains solid Li Gelieting 0.9g to dry in 10mL water washing; HPLC detects, not containing dimer in product.
Embodiment 3
The Li Gelieting crude product 1.2kg of the dipolymer containing 26.06%, adds the aqueous solution 6.0kg containing concentrated hydrochloric acid 220mL, stirs, add ethanol 7.2kg, adjusting pH to 11 with 40% (massfraction) aqueous sodium hydroxide solution, react 3 hours at 25 DEG C-35 DEG C, HPLC detects without dimer. Adding acid for adjusting pH to 8-9, underpressure distillation, removes major part ethanol. Then residual solution is cooled to 0 DEG C-5 DEG C stirrings 3 hours, filters, and gained solid use water 3.0kg washs once, and drying obtains Li Gelieting 1.1kg except after desolventizing; HPLC detects, not containing dimer.
Embodiment 4
Get the Li Gelieting crude product that 1.0g contains the dimer compound (02) of 30.82%, add 15mL acetonitrile; Being no more than 8,25 DEG C with the pH of the aqueous sodium hydroxide solution regulation system of 5% (massfraction) to stir 4 hours, HPLC detects dimer content without obvious minimizing, substantially reactionless; Continue to drip add 5% pH to 9-10,25 DEG C of the aqueous sodium hydroxide solution regulation system reaction 4 hours of (massfraction); HPLC detects, and dimer content is reduced to less than 4%.
The method of the present invention is described by better embodiment, and methods and applications as herein described obviously can be changed in content of the present invention, spirit and scope or suitably change and combination by related personnel, realize and apply the technology of the present invention. Those skilled in the art can use for reference content herein, and suitable improving technique parameter realizes. Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (5)
1. the method that compound (02) is converted into compound (1), comprising: when adding alkali reagent, and compound (02) is obtained by reacting Li Gelieting in the basic conditions in reaction solvent:
The pH that described alkaline condition is reaction system is not less than 8; Described reaction solvent is N, dinethylformamide, methylene dichloride, toluene, methyl alcohol, ethanol, Virahol, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, acetone, butanone, propione, ethyl acetate, water, or its combination.
2. method according to claim 1, described alkali reagent is sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta, potassium tert.-butoxide, trimethyl carbinol lithium, sodium methylate, sodium ethylate, sodium amide, sodium hydride, hexamethyl two silicon base sodium amide, hexamethyl two silicon base Lithamide, hexamethyl two silicon base potassium amide, diethylamino lithium, lithium diisopropylamine, ammoniacal liquor, first amine, diethylamine, triethylamine, quadrol, diisopropyl ethyl amine, pyridine, pyrroles, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] 11 carbon-7-alkene, or its combination.
3. method according to claim 1, described alkali reagent is salt of wormwood, sodium hydroxide, potassium hydroxide, triethylamine, diisopropyl ethyl amine, or its combination, and the pH that described alkaline condition is reaction system is not less than 9.
4. method according to claim 3, described reaction solvent is methylene dichloride, ethanol, acetonitrile, ethyl acetate, water, or its combination.
5. method according to claim 4, comprising: compound (02), in second alcohol and water, adds salt of wormwood, sodium hydroxide or potassium hydroxide, reacts in the basic conditions, obtain Li Gelieting; The pH that described alkaline condition is reaction system is not less than 9, and temperature of reaction is 15 DEG C-40 DEG C.
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| CN201410398340.4A CN104130258B (en) | 2014-08-13 | 2014-08-13 | The method for transformation of a kind of dimer |
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| CN104130258B true CN104130258B (en) | 2016-06-01 |
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PE20080251A1 (en) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | USES OF DPP IV INHIBITORS |
| EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
| MX2008014024A (en) | 2006-05-04 | 2008-11-14 | Boehringer Ingelheim Int | Polymorphs. |
| PE20091730A1 (en) | 2008-04-03 | 2009-12-10 | Boehringer Ingelheim Int | FORMULATIONS INVOLVING A DPP4 INHIBITOR |
| US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
| US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
| HUE043540T2 (en) | 2011-07-15 | 2019-08-28 | Boehringer Ingelheim Int | Substituted dimeric quinazoline derivative, its preparation and its use in pharmaceutical compositions for the treatment of type i and ii diabetes |
| CN104672238B (en) * | 2015-02-17 | 2017-12-08 | 华润赛科药业有限责任公司 | A kind of Li Gelieting preparation method |
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Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |
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