CN112961155A - Preparation method of linagliptin - Google Patents
Preparation method of linagliptin Download PDFInfo
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- CN112961155A CN112961155A CN202110280677.5A CN202110280677A CN112961155A CN 112961155 A CN112961155 A CN 112961155A CN 202110280677 A CN202110280677 A CN 202110280677A CN 112961155 A CN112961155 A CN 112961155A
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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
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- 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
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- 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
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Abstract
The invention relates to a preparation method of linagliptin, which comprises the following steps of: 2-chloromethyl-4-methyl quinazoline and raw material II: 8-bromo-7- (2-butynyl) -3-methyl-1H-purine-2, 6(3H,7H) -dione is used as a raw material, and an intermediate III is obtained through reaction: 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1- [ (4-methylquinazolin-2-yl) -methyl ] -1H-purine-2, 6-dione, in turn, with the starting material IV: and (R) -3-aminopiperidine hydrochloride reacts to prepare the target product. The method does not need to add a protecting group in the reaction process, saves the step of removing the protecting group after the reaction is finished, and reduces the generation of reaction byproducts during the protecting group removal. The solvent used in the invention is beneficial to recycle, has low price, is environment-friendly, green and environment-friendly, and the obtained product has high yield and high purity, and is suitable for large-scale production.
Description
Technical Field
The invention relates to a preparation method of linagliptin, and belongs to the technical field of medicines.
Background
Linagliptin is a new generation of drug for treating type II diabetes, belongs to a dipeptidyl peptidase (DDP-4) inhibitor, is developed by Boringer Yiger, and has a structural formula shown as follows:
the reagent 2-aminopiperidine used in the preparation process of linagliptin generally protects 2-amino group, and deprotection reaction is carried out after the reaction is finished. The patent WO2004018468 and other patents use boc-2-aminopiperidine, and after the 2-aminopiperidine reaction using a protecting group is finished, the protecting group needs to be removed; the removal of the protecting group requires the use of trifluoroacetic acid or the like, and the complete removal of the protecting group is difficult and more by-products are easily produced. The (R) -3-phthalimide piperidine has higher use cost, more protective byproducts are removed, and reaction reagents such as hydrazine hydrate and the like are needed. The process for directly preparing linagliptin by developing the 2-aminopiperidine compound has important significance.
2-aminopiperidine has similar activity as the primary amine group at the 2-position and the secondary amine group on piperidine, so the reaction specificity is poor, and two active functional groups are likely to participate in the reaction. Commercially available 2-aminopiperidines are usually present in the form of the hydrochloride salt. And 2-aminopiperidine or hydrochloride are more polar; during the reaction, solvents with high polarity such as dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), methyl isobutyl ketone (MIBK) and the like are needed, a large amount of water is needed during the post-reaction treatment of the solvents with high polarity, then samples are extracted, and due to the high polarity and high boiling point, the solvents are difficult to recover, and a large amount of aqueous solution containing the solvents with high polarity is difficult to treat.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of linagliptin.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method of linagliptin comprises the steps of mixing a raw material I and a raw material II with an inorganic base A, a solvent A and water to prepare an intermediate III, and mixing the intermediate III and the raw material IV with an inorganic base B, a solvent B and water to prepare a product V; the reaction scheme is as follows:
the product V is linagliptin, and the chemical names of the raw material I, the raw material II, the intermediate III and the raw material IV are respectively as follows:
raw material I: 2-chloromethyl-4-methyl quinazoline;
raw material II: 8-bromo-7- (2-butynyl) -3-methyl-1H-purine-2, 6(3H,7H) -dione;
intermediate III: 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1- [ (4-methylquinazolin-2-yl) -methyl ] -1H-purine-2, 6-dione;
raw material IV: (R) -3-aminopiperidine hydrochloride.
The inorganic base A and the inorganic base B are both acid-binding agents, and the acid-binding agents are any one or a mixture of two or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
The solvent A and the solvent B are both polar organic solvents, and the polar organic solvents are any one or a mixture of two or more of acetonitrile, acetone, methanol, ethanol, isopropanol and tetrahydrofuran.
In the reaction process of preparing the intermediate III by the raw materials I and II, the molar ratio of the raw materials I to II is 1.05-1.2: 1, the molar ratio of the inorganic base A to the raw material II is 1.5-3.0: 1, the volume-to-mass ratio (mL/g) of the solvent A to the raw material II is 8-15: 1; the volume ratio of water to the solvent A is 0.05-0.3: 1; the reaction temperature is 70-80 ℃, and the reaction time is 5-6 h.
In the reaction process of preparing the product V linagliptin from the raw material IV and the intermediate III, the molar ratio of the raw material IV to the intermediate III is 1.3-1.1: 1, the molar ratio of the inorganic base B to the intermediate III is 3.5-5.0: 1, the volume-to-mass ratio (mL/g) of the solvent B to the intermediate III is 8-15: 1; the volume ratio of the water to the solvent B is 0.05-0.30: 1; the reaction temperature is 70-80 ℃, and the reaction time is 7-8 h.
After the reaction of preparing the intermediate III from the raw material I and the raw material II is finished, regulating the pH value of the solution to 8 by hydrochloric acid, concentrating under reduced pressure at 60 ℃ to evaporate the organic solvent, adding water into the residue, extracting with dichloromethane for 2 times, adding anhydrous sodium sulfate, drying overnight, filtering, washing the filter cake with dichloromethane, and concentrating the filtrate to obtain the intermediate III.
After the reaction of preparing the product V linagliptin from the raw material IV and the intermediate III is finished, regulating the pH value of the solution to 8 by using hydrochloric acid, concentrating under reduced pressure at 60 ℃ to evaporate an organic solvent, adding water into the residue, extracting with dichloromethane for 2 times, adding anhydrous sodium sulfate, drying overnight, performing suction filtration, washing a filter cake with dichloromethane, and concentrating the filtrate to obtain a white-like solid; adding isopropyl ether into the obtained white-like solid, stirring for 1h, carrying out suction filtration, washing a filter cake with isopropyl ether, and drying for more than 12h at 50 ℃ under a vacuum condition to obtain the product V linagliptin.
The invention has the beneficial effects that:
the invention relates to a preparation method of linagliptin, which does not need to protect 2-amino by a protective group in the reaction process, omits the step of deprotection after the reaction is finished, and reduces the generation of reaction byproducts in the process of deprotection and the problems of recycling of solvents with larger polarity.
The solvent used in the invention is beneficial to recycle, has low price, is environment-friendly, is green and environment-friendly, and is suitable for large-scale production. The solvent used in the reaction is a low-boiling-point organic solvent which is easily dissolved in water, and after the reaction is finished, the organic solvent can be concentrated and separated from the mixed solvent under reduced pressure; the solvent used in the post-treatment extraction is not soluble with water, and after the product is extracted, the solvent obtained after the reduced pressure concentration can still be repeatedly used, thereby reducing the discharge of waste liquid.
The acid-binding agent used in the invention is inorganic base with low price, and the inorganic base can be converted into sodium chloride (or potassium chloride) and sodium sulfate (or potassium sulfate) after reaction, and the by-product is less. The product prepared by the preparation method of linagliptin has higher yield and purity.
Drawings
FIG. 1 shows the preparation of linagliptin according to an embodiment of the present invention1H-NMR。
Wherein, the number of the hydrogen in the low field is 4, the number of the hydrogen is 8.250-8.234(1H, m), the number of the hydrogen in the delta 7.932-7.902(1H, m), the number of the hydrogen in the delta 7.833-7.817(1H, m), the number of the hydrogen in the delta 7.689-7.659(1H, m) and the target moleculeAnd (5) the consistency is achieved. δ 5.363, δ 4.935, two methylene peaks attached to the nitrogen atom; delta 3.710-3.623(2H, m), delta 3.430(3H, s, -CH)3)，δ3.063-3.019(1H,m)，δ2.901(3H,s,-CH3)，δ2.882-2.784(2H,m)，δ1.913-1.890(3H,s,-CH3) δ 1.808, δ 1.699-1.655, δ 1.302-1.284 for a total of 22 hydrogens; the number of the active hydrogen in the target molecule is consistent with that of the hydrogen in the target molecule; the delta 2.006 position hydrogen signal is an active hydrogen signal; hydrogen signal and target molecule C25H28N8O2And (5) the consistency is achieved.
FIG. 2 shows the preparation of linagliptin according to the first embodiment of the present invention13C-NMR。
Wherein, δ 168.660, δ 160.920, δ 0156.043, δ 1153.152, δ 2150.848, δ 3148.969, δ 4147.652, δ 5133.895, δ 6127.761, δ 7126.972, δ 8125.553, δ 9122.380 and δ 103.120 are carbon spectra positioned in a low field region, wherein δ 0168.66 and δ 1160.92 are carbonyl carbons, δ 2122.380 and δ 3103.120 are alkynyl carbons, and other 8 carbon signals are aromatic ring carbon signals and are consistent with target molecules; δ 481.029, δ 573.681, δ 657.505, δ 749.473, δ 847.181, δ 945.481, δ 35.405, δ 033.133, δ 29.299, δ 23.196, 21.438 δ, δ 2.969; wherein δ 81.029, δ 73.681 are olefin carbon signals; the number of other carbon signals positioned in the high field area is 6; and target molecule C25H28N8O2And (5) the consistency is achieved.
FIG. 3 HRMs of linagliptin obtained in an embodiment of the present invention.
Wherein, the molecular formula is C as can be seen from the high-resolution mass spectrogram25H28N8O2Consistent with the target molecule, molecular ion peak 473.24 is [ M + H]+Consistent with the target molecule linagliptin.
Detailed Description
The following examples further illustrate the embodiments of the present invention in detail.
The embodiment provides a preparation method of linagliptin, which comprises the following specific steps:
adding 240mL of acetonitrile and 24mL of purified water into a 500mL reaction bottle, stirring uniformly, adding 6.4g of sodium hydroxide (0.16mol), 20.2g (0.105mol) of raw material I and 29.7g (0.10mol) of raw material II, heating to 70 ℃, keeping the temperature, stirring, reacting for 5 hours, detecting by thin-layer chromatography (TLC), stopping the reaction after the reaction of the raw material II is finished. The pH of the solution after the reaction was adjusted to 8 with 5% hydrochloric acid, and the mixed solution was concentrated under reduced pressure at 60 ℃ using a rotary evaporator to distill off acetonitrile. To the residue was added 200mL of purified water, and the mixture was extracted 2 times with 200mL of methylene chloride and dried overnight with 20g of anhydrous sodium sulfate. Suction filtration was carried out, the filter cake was washed with a small amount of dichloromethane and the filtrate was concentrated to give intermediate III as a pale yellow solid 43.0g (0.095mol) in 94.9% yield (based on the charge of starting material II).
A1000 mL reaction flask was charged with 430mL acetonitrile, 43mL purified water, and 41.4g (0.30mol) potassium carbonate, and after stirring well, 18.1g (0.105mol) of raw material IV and 43.0g (0.095mol) of intermediate III were added, and the mixture was stirred at 75 ℃ for 7 hours, and then the reaction was stopped after completion of the reaction of intermediate III as detected by Thin Layer Chromatography (TLC). The pH of the solution after the reaction was adjusted to 8 with 5% hydrochloric acid, and the mixed solution was concentrated under reduced pressure at 60 ℃ using a rotary evaporator to distill off acetonitrile. To the residue was added 200mL of purified water, and the mixture was extracted 2 times with 200mL of dichloromethane, dried overnight with 20g of anhydrous sodium sulfate, filtered, the filter cake was washed with a small amount of dichloromethane, and the filtrate was concentrated to give an off-white solid. Then 200mL of isopropyl ether is added into the obtained off-white solid, the mixture is stirred for 1h, after suction filtration, a filter cake is washed by a small amount of isopropyl ether, and then the filter cake is dried for more than 12h under the vacuum condition of 50 ℃, so that an off-white solid product V33.1 g (0.070mol), the yield is 73.7% (calculated by the input amount of the intermediate III) and the purity is 99.6% (calculated by an HPLC area normalization method) is obtained.
And (3) carrying out hydrogen spectrum, carbon spectrum and mass spectrum analysis on the product V, and proving that the obtained product V is linagliptin (shown in figures 1-3).
The second preparation method of linagliptin comprises the following specific steps:
adding 250mL of acetone and 30mL of purified water into a 500mL reaction bottle, stirring uniformly, adding 41.4g of potassium carbonate (0.30mol), adding 21.2g (0.11mol) of raw material I and 29.7g (0.10mol) of raw material II, heating to 70 ℃, keeping the temperature, stirring, reacting for 6 hours, detecting by thin-layer chromatography (TLC), stopping the reaction after the reaction of the raw material II is finished. The pH of the solution after the reaction was adjusted to 8 with a 5% hydrochloric acid solution, and the mixed solution was concentrated under reduced pressure using a rotary evaporator at 60 ℃. To the residue was added 200mL of purified water, and the mixture was extracted 2 times with 200mL of methylene chloride and dried overnight with 20g of anhydrous sodium sulfate. Suction filtration was carried out, the filter cake was washed with a small amount of dichloromethane and the filtrate was concentrated to give intermediate III as a pale yellow solid 39.6g (0.087mol) in 87.4% yield (based on the charge of starting material II).
A 1000mL reaction flask was charged with 400mL of acetone, 40mL of purified water, and 55.2g (0.4mol) of potassium carbonate, and after stirring uniformly, 18.1g (0.105mol) of raw material IV and 39.6g (0.087mol) of intermediate III were added, and the mixture was stirred at 75 ℃ for 8 hours, followed by Thin Layer Chromatography (TLC), and after completion of the reaction of intermediate III, the reaction was stopped, and the pH of the solution after the reaction was adjusted to 8 with 5% hydrochloric acid, and then the mixed solution was concentrated under reduced pressure by a rotary evaporator at 60 ℃ to distill off acetone. To the residue was added 200mL of purified water, and the mixture was extracted 2 times with 200mL of dichloromethane, dried overnight with 20g of anhydrous sodium sulfate, filtered, the filter cake was washed with a small amount of dichloromethane, and the filtrate was concentrated to give an off-white solid. Then 200mL of isopropyl ether is added into the obtained off-white solid, the mixture is stirred for 1h, after suction filtration, a filter cake is washed by a small amount of isopropyl ether, and then the filter cake is dried for more than 12h under the vacuum condition of 50 ℃ to obtain 28.1g (0.059mol) of off-white solid linagliptin, the yield is 67.8% (calculated by the feeding amount of the raw material II), and the purity is 99.4% (calculated by an HPLC area normalization method).
Claims (7)
1. The preparation method of the linagliptin is characterized in that a raw material I and a raw material II are mixed with an inorganic base A, a solvent A and water to prepare an intermediate III, and the intermediate III and the raw material IV are mixed with an inorganic base B, a solvent B and water to prepare a product V; the reaction scheme is as follows:
the product V is linagliptin, and the chemical names of the raw material I, the raw material II, the intermediate III and the raw material IV are respectively as follows:
raw material I: 2-chloromethyl-4-methyl quinazoline;
raw material II: 8-bromo-7- (2-butynyl) -3-methyl-1H-purine-2, 6(3H,7H) -dione;
intermediate III: 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1- [ (4-methylquinazolin-2-yl) -methyl ] -1H-purine-2, 6-dione;
raw material IV: (R) -3-aminopiperidine hydrochloride.
2. The method for preparing linagliptin according to claim 1, wherein the inorganic base A and the inorganic base B are both acid-binding agents, and the acid-binding agents are any one or a mixture of two or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
3. The method for preparing linagliptin according to claim 1, wherein the solvent A and the solvent B are both polar organic solvents, and the polar organic solvent is any one of acetonitrile, acetone, methanol, ethanol, isopropanol and tetrahydrofuran or a mixture of two or more of the above.
4. The method for preparing linagliptin according to claim 1, wherein, in the reaction process for preparing the intermediate III from the raw material I and the raw material II, the molar ratio of the raw material I to the raw material II is 1.05-1.2: 1, the molar ratio of the inorganic base A to the raw material II is 1.5-3.0: 1, the volume-to-mass ratio (mL/g) of the solvent A to the raw material II is 8-15: 1; the volume ratio of water to the solvent A is 0.05-0.3: 1; the reaction temperature is 70-80 ℃, and the reaction time is 5-6 h.
5. The method for preparing linagliptin according to claim 1, wherein in the reaction process for preparing the product V linagliptin from the raw material IV and the intermediate III, the molar ratio of the raw material IV to the intermediate III is 1.3-1.1: 1, the molar ratio of the inorganic base B to the intermediate III is 3.5-5.0: 1, the volume-to-mass ratio (mL/g) of the solvent B to the intermediate III is 8-15: 1; the volume ratio of the water to the solvent B is 0.05-0.30: 1; the reaction temperature is 70-80 ℃, and the reaction time is 7-8 h.
6. The preparation method of linagliptin as claimed in claim 1, characterized in that after the reaction of the raw material I and the raw material II for preparing the intermediate III is finished, hydrochloric acid is used for adjusting the pH value of the solution to 8, the organic solvent is evaporated out by concentration under reduced pressure at 60 ℃, water is added into the residue, dichloromethane is used for extraction for 2 times, anhydrous sodium sulfate is added for drying overnight, the filtration is carried out, dichloromethane is used for washing the filter cake, and the filtrate is concentrated to obtain the intermediate III.
7. The preparation method of linagliptin as claimed in claim 1, characterized in that after the reaction of preparing the product V linagliptin from the raw material IV and the intermediate III is finished, the pH of the solution is adjusted to 8 by hydrochloric acid, the organic solvent is evaporated by vacuum concentration at 60 ℃, water is added into the residue, the residue is extracted by dichloromethane for 2 times, anhydrous sodium sulfate is added for drying overnight, the filtration is carried out, the filter cake is washed by dichloromethane, and the filtrate is concentrated to obtain a white-like solid; adding isopropyl ether into the obtained white-like solid, stirring for 1h, carrying out suction filtration, washing a filter cake with isopropyl ether, and drying for more than 12h at 50 ℃ under a vacuum condition to obtain the product V linagliptin.
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Citations (6)
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| WO2013098775A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Improved process for preparation of pure linagliptin |
| WO2014009970A2 (en) * | 2012-07-09 | 2014-01-16 | Hetero Research Foundation | Linagliptin solid dispersion |
| CN104387315A (en) * | 2013-11-12 | 2015-03-04 | 药源药物化学（上海）有限公司 | Compound I and (R)-3-aminopiperidine hydrochloride II, preparation method and application in Linagliptin synthesis |
| CN105440034A (en) * | 2015-11-16 | 2016-03-30 | 山东罗欣药业集团股份有限公司 | Preparation method of linagliptin and intermediate thereof |
| CN109761983A (en) * | 2019-02-11 | 2019-05-17 | 深圳市第二人民医院 | A kind of preparation method of Li Gelieting |
| CN112209929A (en) * | 2020-11-15 | 2021-01-12 | 山东永丞制药有限公司 | Novel preparation process of linagliptin |
-
2021
- 2021-03-16 CN CN202110280677.5A patent/CN112961155A/en active Pending
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| WO2013098775A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Improved process for preparation of pure linagliptin |
| US20140357863A1 (en) * | 2011-12-28 | 2014-12-04 | Dr. Reddy's Laboratories Limited | Process for preparation of pure linagliptin |
| WO2014009970A2 (en) * | 2012-07-09 | 2014-01-16 | Hetero Research Foundation | Linagliptin solid dispersion |
| CN104387315A (en) * | 2013-11-12 | 2015-03-04 | 药源药物化学（上海）有限公司 | Compound I and (R)-3-aminopiperidine hydrochloride II, preparation method and application in Linagliptin synthesis |
| CN105440034A (en) * | 2015-11-16 | 2016-03-30 | 山东罗欣药业集团股份有限公司 | Preparation method of linagliptin and intermediate thereof |
| CN109761983A (en) * | 2019-02-11 | 2019-05-17 | 深圳市第二人民医院 | A kind of preparation method of Li Gelieting |
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Application publication date: 20210615 |