CN109705122B - Preparation method of linagliptin intermediate for treating type II diabetes - Google Patents
Preparation method of linagliptin intermediate for treating type II diabetes Download PDFInfo
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Abstract
The invention provides a preparation method of a linagliptin intermediate for treating type II diabetes, a preparation method of an intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione, 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione and 2-butyne react in an organic solvent in the presence of a copper catalyst and a cocatalyst to prepare 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione, the operation is simple, the conditions are mild, and higher yield and purity are obtained, is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to a preparation method of a linagliptin intermediate, belonging to the technical field of preparation of raw material medicines.
Technical Field
Linagliptin (English name is Linagliptin), has a chemical name of [ (3R) -3-amino-1-piperidyl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, is a dipeptidyl peptidase-4 (DPP-4) inhibitor, and can improve the blood glucose control level of adult patients with type 2 diabetes (T2DM) on the basis of diet control and physical exercise. Linagliptin has excellent renal safety relative to other gliptin drugs. It does not need to adjust dosage for patients with renal function impairment or the elderly with the age of more than 75 years, thereby greatly expanding the range of drug-taking population and improving the drug-taking compliance of patients. The food and drug administration 2011 5.month 2 approved linagliptin tablets for marketing.
Currently, many researches are made on preparation methods of linagliptin, such as CN104496989A, CN104387390A, CN104844602A, CN104672238A, CN104844603A and the like, and all of the processes have the disadvantages of complex operation, low product yield, high production cost and the like, and are not suitable for industrial mass production. Wherein, the key intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione prepared by linagliptin has less reports on the preparation of the key intermediate. The current method for preparing the intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione is generally to use 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione followed by reaction with a haloalkyne under basic conditions to form the intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione. The method has low yield of the obtained product and difficult purification due to the close nature of isomers.
In view of the above problems in the prior art for the preparation of linagliptin intermediates, it is necessary to develop a novel method for preparing linagliptin intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione.
Disclosure of Invention
In order to solve the technical problem of preparation of the linagliptin intermediate, the invention provides a preparation method of the linagliptin intermediate, which is simple to operate, simple and easily available in raw materials, high in yield and suitable for large-scale industrial production.
The invention provides a preparation method of a linagliptin intermediate, which comprises the following steps:
a preparation method of a linagliptin intermediate is characterized in that 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione and 2-butyne react in an organic solvent in the presence of a copper catalyst and a cocatalyst to prepare 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione.
According to the preparation method of the linagliptin intermediate, the catalyst is copper perchlorate, and the cocatalyst is tetramethylethylenediamine.
The preparation method of the linagliptin intermediate comprises the step of preparing the linagliptin intermediate by using an organic solvent, wherein the organic solvent is selected from methanol, ethanol, DMF (dimethyl formamide), DMSO (dimethyl sulfoxide), acetonitrile and the like.
In the preparation method of the linagliptin intermediate, the molar ratio of the 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione to the 2-butyne is 1: 1 to 2.
In the preparation method of the linagliptin intermediate, the molar ratio of the 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione to the copper perchlorate to the tetramethylethylenediamine is 1: 0.1-1: 0.1 to 1.
In the preparation method of the linagliptin intermediate, the reaction temperature is 50-70 ℃, and preferably 55-65 ℃.
The reaction time of the preparation method of the linagliptin intermediate is 2 to 10 hours, preferably 4 to 6 hours.
According to the preparation method of the linagliptin intermediate, the reaction process is protected by nitrogen.
A preparation method of a linagliptin intermediate comprises the following steps of dissolving 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione in an organic solvent, adding an organic solvent solution of copper perchlorate and tetramethylethylenediamine, uniformly mixing, adding a DMF (dimethyl formamide) solution of 2-butyne for reaction, and performing post-treatment after the reaction is completed to obtain a linagliptin intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione.
After the reaction is finished, pouring the reaction liquid into water, extracting with dichloromethane, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, recrystallizing, filtering and drying to obtain the gliptin intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione. It is preferable to recrystallize in a mixed solvent of petroleum ether and methylene chloride.
The preparation method provided by the invention is simple to operate and mild in conditions, the linagliptin intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione is obtained, and the yield and purity are high, so that the preparation method is suitable for large-scale industrial production.
Detailed Description
In order to better understand the present invention, the following examples are included to further illustrate the present invention. However, the present invention is not limited to the following examples.
Example 1
A preparation method of a linagliptin intermediate comprises the following steps:
dissolving 100mmol of 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione in 200ml of DMF under the protection of nitrogen, adding a solution of copper perchlorate (20mmol) and tetramethylethylenediamine (20mmol) in DMF, uniformly mixing, then dropwise adding a solution of 2-butyne in DMF (containing 150mmol of 2-butyne), reacting at 50 ℃ for 4 hours, then pouring the reaction solution into water, extracting with dichloromethane, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating, then recrystallizing in a mixed solvent of petroleum ether and dichloromethane with a volume ratio of 20:1, filtering, drying to obtain the gliptin intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione in 93.2% yield and 99.96% purity (HPLC area normalization).
Example 2
A preparation method of a linagliptin intermediate comprises the following steps:
dissolving 100mmol of 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione in 200ml of DMF under the protection of nitrogen, adding a solution of copper perchlorate (15mmol) and tetramethylethylenediamine (15mmol) in DMF, uniformly mixing, then dropwise adding a solution of 2-butyne in DMF (containing 200mmol of 2-butyne), reacting at 50 ℃ for 4 hours, then pouring the reaction solution into water, extracting with dichloromethane, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating, then recrystallizing in a mixed solvent of petroleum ether and dichloromethane with a volume ratio of 20:1, filtering, drying to obtain the gliptin intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione in 93.5% yield and 99.93% purity (HPLC area normalization).
Example 3
A preparation method of a linagliptin intermediate comprises the following steps:
dissolving 100mmol of 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione in 200ml of DMF under the protection of nitrogen, adding a solution of copper perchlorate (20mmol) and tetramethylethylenediamine (40mmol) in DMF, uniformly mixing, then dropwise adding a solution of 2-butyne in DMF (containing 150mmol of 2-butyne), reacting at 50 ℃ for 4 hours, then pouring the reaction solution into water, extracting with dichloromethane, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating, then recrystallizing in a mixed solvent of petroleum ether and dichloromethane with a volume ratio of 20:1, filtering, drying to obtain the gliptin intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione in 95.1% yield and 99.95% purity (HPLC area normalization).
Example 4
A preparation method of a linagliptin intermediate comprises the following steps:
under the protection of nitrogen, dissolving 100mmol of 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione in 200ml of DMF, adding a solution of copper perchlorate (20mmol) and tetramethylethylenediamine (10mmol) in DMF, uniformly mixing, then dropwise adding a solution of 2-butyne in DMF (containing 100mmol of 2-butyne), reacting at 60 ℃ for 5 hours, then pouring the reaction solution into water, extracting with dichloromethane, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating, then recrystallizing in a mixed solvent of petroleum ether and dichloromethane with a volume ratio of 20:1, filtering, drying to obtain the gliptin intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione, yield 90.3%.
Example 5
A preparation method of a linagliptin intermediate comprises the following steps:
dissolving 100mmol of 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione in 200ml of DMF under the protection of nitrogen, adding a solution of copper perchlorate (20mmol) and tetramethylethylenediamine (30mmol) in DMF, uniformly mixing, then dropwise adding a solution of 2-butyne in DMF (containing 150mmol of 2-butyne), reacting at 60 ℃ for 8 hours, then pouring the reaction solution into water, extracting with dichloromethane, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating, then recrystallizing in a mixed solvent of petroleum ether and dichloromethane with a volume ratio of 20:1, filtering, drying to obtain the gliptin intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione, yield 93.6%.
The above examples show that the linagliptin intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-dione prepared by the preparation method provided by the invention has the advantages of high yield and purity, simple operation, mild conditions, suitability for large-scale industrial production, and important industrial technical significance and application value.
The use of the above examples is merely illustrative of the present invention and is not intended to limit the scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (3)
1. A preparation method of a linagliptin intermediate is characterized in that under the protection of nitrogen, 100mmol of 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione is dissolved in 200ml of DMF, 20mmol of copper perchlorate and 20mmol of tetramethylethylenediamine are added into DMF solution and mixed uniformly, then 2-butyne containing DMF solution is dripped into the DMF solution and reacted for 4 hours at 50 ℃, then the reaction solution is poured into water and extracted by dichloromethane, washed by saturated saline solution, dried by anhydrous sodium sulfate and concentrated, then recrystallized in a mixed solvent of petroleum ether and dichloromethane with the volume ratio of 20:1, filtered and dried to obtain the linagliptin intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-diketones.
2. A preparation method of a linagliptin intermediate is characterized in that under the protection of nitrogen, 100mmol of 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione is dissolved in 200ml of DMF, a DMF solution containing 15mmol of copper perchlorate and 15mmol of tetramethylethylenediamine is added and mixed uniformly, then a DMF solution containing 2-butyne is added dropwise, the mixture is reacted for 4 hours at 50 ℃, then the reaction liquid is poured into water, dichloromethane is extracted, saturated saline solution is washed, anhydrous sodium sulfate is dried and concentrated, then the mixture is recrystallized in a mixed solvent of petroleum ether and dichloromethane with the volume ratio of 20:1, filtered and dried to obtain the linagliptin intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-diketones.
3. A preparation method of a linagliptin intermediate is characterized in that under the protection of nitrogen, 100mmol of 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione is dissolved in 200ml of DMF, 20mmol of copper perchlorate and 40mmol of tetramethylethylenediamine DMF solution are added and mixed uniformly, then 2-butyne DMF solution is dripped, 150mmol of 2-butyne is contained, the reaction solution is reacted for 4 hours at 50 ℃, then the reaction solution is poured into water, dichloromethane is extracted, saturated saline solution is washed, anhydrous sodium sulfate is dried and concentrated, then the recrystallization is carried out in a mixed solvent of petroleum ether and dichloromethane with the volume ratio of 20:1, the filtration and the drying are carried out to obtain the linagliptin intermediate 8-bromo-3, 7-dihydro-3-methyl-9- (2-butynyl) -1H-purine-2, 6-diketones.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015067539A1 (en) * | 2013-11-06 | 2015-05-14 | Chemelectiva S.R.L. | Process and intermediates for the preparation of linagliptin |
| CN105968112A (en) * | 2016-05-16 | 2016-09-28 | 青岛云天生物技术有限公司 | Method for preparing linagliptin intermediate for treating II-type diabetis |
| CN107936023A (en) * | 2017-12-28 | 2018-04-20 | 安庆奇创药业有限公司 | A kind of synthetic method of Li Gelieting intermediates |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015067539A1 (en) * | 2013-11-06 | 2015-05-14 | Chemelectiva S.R.L. | Process and intermediates for the preparation of linagliptin |
| CN105968112A (en) * | 2016-05-16 | 2016-09-28 | 青岛云天生物技术有限公司 | Method for preparing linagliptin intermediate for treating II-type diabetis |
| CN107936023A (en) * | 2017-12-28 | 2018-04-20 | 安庆奇创药业有限公司 | A kind of synthetic method of Li Gelieting intermediates |
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