CN116675692A - Synthesis method of low-impurity linagliptin - Google Patents
Synthesis method of low-impurity linagliptin Download PDFInfo
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- CN116675692A CN116675692A CN202310639124.3A CN202310639124A CN116675692A CN 116675692 A CN116675692 A CN 116675692A CN 202310639124 A CN202310639124 A CN 202310639124A CN 116675692 A CN116675692 A CN 116675692A
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- linagliptin
- impurity
- methyl
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- dichloromethane
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- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 title claims abstract description 41
- 229960002397 linagliptin Drugs 0.000 title claims abstract description 41
- 239000012535 impurity Substances 0.000 title claims abstract description 26
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- 239000000047 product Substances 0.000 claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 10
- GGPNYXIOFZLNKW-ZJIMSODOSA-N (3r)-piperidin-3-amine;dihydrochloride Chemical compound Cl.Cl.N[C@@H]1CCCNC1 GGPNYXIOFZLNKW-ZJIMSODOSA-N 0.000 claims abstract description 7
- HFZOBQSHTNNKFY-UHFFFAOYSA-N 8-bromo-7-but-2-ynyl-3-methylpurine-2,6-dione Chemical compound CN1C(=O)NC(=O)C2=C1N=C(Br)N2CC#CC HFZOBQSHTNNKFY-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000004537 pulping Methods 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 230000015572 biosynthetic process Effects 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 238000003786 synthesis reaction Methods 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- RCZJXCXNYGHNSR-UHFFFAOYSA-N 8-bromo-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione Chemical compound C1=CC=CC2=NC(CN3C(=O)N(C)C=4N=C(Br)N(C=4C3=O)CC#CC)=NC(C)=C21 RCZJXCXNYGHNSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 238000001179 sorption measurement Methods 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 4
- 238000005406 washing Methods 0.000 abstract description 4
- 239000002351 wastewater Substances 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- KJOZJSGOIJQCGA-UHFFFAOYSA-N dichloromethane;2,2,2-trifluoroacetic acid Chemical compound ClCCl.OC(=O)C(F)(F)F KJOZJSGOIJQCGA-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- 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
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- 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
Abstract
The invention discloses a synthesis method of low-impurity linagliptin, which comprises the following steps: 1) Reacting 8-bromo-7- (2-butynyl) -3-methylxanthine (a) with-chloromethyl-4-methylquinazoline (B) to give intermediate 8-bromo-7- (2-butynyl-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione (C); synthesizing C and (R) -3-aminopiperidine dihydrochloride (H) to obtain a crude linagliptin product F1; linagliptin F1 refined linagliptin F2. The purity of the synthetic method is over 99 percent, the quality of the subsequent finished products is ensured, acid substances such as acetic acid and the like are less used, a large amount of waste water is avoided, the synthetic route is beneficial to environmental protection, the yield of the final product is high, and the pharmaceutically acceptable raw material medicine of the gliptin can be obtained through simple washing and pulping treatment without further purification treatment.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of low-impurity linagliptin.
Background
Linagliptin (linagliptin), trade name of the enzyme "europamine", developed by the company "bologin, germany, approved for marketing by FDA certification in united states in month 5 of 2011, approved for marketing in europe in month 6 of 2011, approved for marketing in china by the national food and drug administration in China in month 4 of 2013, belonging to a new effective selective DDP-4 inhibitor useful for the treatment of type II diabetes.
At present, the linagliptin bulk drug in the market has impurities which affect the output of the API, any single impurity is required to be less than 0.1%, and more manufacturers provide impurities in the market which are about 0.25%, so that the application of the product is seriously affected. Currently, the synthetic supply method of linagliptin is as follows:
the method for removing boc separately uses trifluoroacetic acid to obtain higher impurities, a large amount of alkali is added in the subsequent purification process, a large amount of wastewater is generated, on the other hand, strong acid is required to be distilled in the reaction process, racemization of the product is easy to occur, side reaction is generated by amide fracture, equipment corrosiveness is high, and the impurities are higher.
Disclosure of Invention
In view of the above problems in the background, the present invention is directed to a method for synthesizing linagliptin with low impurity. The method is realized by the following technical scheme:
a synthesis method of low-impurity linagliptin, which comprises the following steps:
1) Synthesis of intermediate C: reacting 8-bromo-7- (2-butynyl) -3-methylxanthine (a) with-chloromethyl-4-methylquinazoline (B) to give intermediate 8-bromo-7- (2-butynyl-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione (C);
2) Synthesis of linagliptin crude product: synthesizing 8-bromo-7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione (C) and (R) -3-aminopiperidine dihydrochloride (H) to obtain a crude linagliptin product F1;
3) Synthesis of linagliptin essence: linagliptin F1 refined linagliptin F2;
the synthetic route is as follows:
further, the reaction solvent in the step 1) is DMAC or DMF, and anhydrous potassium carbonate is added into the reaction solvent to carry out coupling reaction with the reaction raw materials.
Further, the reaction temperature in the step 1) is 70-80 ℃ and the reaction time is 3-10h.
And further, recrystallizing the reaction product in the step 1) in a dichloromethane and methanol solution, adding activated carbon for adsorption and dehydration, and crystallizing and drying to obtain an intermediate.
Further, the reaction solvent in the step 2) is DMF or ethanol, and sodium bicarbonate, an intermediate and (R) -3-aminopiperidine dihydrochloride (H) are added into the reaction solvent for coupling reaction.
Further, after the reaction temperature is raised to 90 ℃, stirring and reacting for 8 hours, cooling to room temperature, decompressing and distilling DMF, adding dichloromethane, stirring and filtering, washing a filter cake with dichloromethane and isopropanol to obtain filtrate, concentrating, washing an aqueous phase with 200ml of 10% sodium bicarbonate to pH8-8.5, extracting with dichloromethane, decompressing and concentrating to obtain crude product F1.
Further, the volume ratio of dichloromethane to isopropanol is 15-20:1.
further, the refining process is to dissolve the obtained F1 crude product in dichloromethane, add 10% of active carbon, reflux for 1h under heating, filter and remove active carbon while hot, distill solvent, and subsequently use dichloromethane: petroleum ether 1: stirring and pulping the mixed solvent of 15-20 for 1h, filtering, eluting with ethanol, and drying the obtained filter cake at 45 ℃ to obtain white solid F2.
Compared with the prior art, the invention has the following advantages:
1) The synthesis method of the intermediate C has the purity of over 99 percent after purification, and ensures the quality of the subsequent finished products;
2) The synthesis method is greatly improved, the generation of impurities is reduced by adopting a step-by-step mode, and meanwhile, acidic substances such as acetic acid and the like are reduced, so that a large amount of wastewater is avoided, and the method is beneficial to environmental protection;
3) In the invention, the intermediate for replacing the Boc protecting group is reacted under normal pressure, a common ethanol system is used for replacing trifluoroacetic acid-DCM to carry out the reaction, the post-treatment is simpler, the post-treatment is directly carried out in the process, the generated impurities are fewer, the post-treatment process is simplified, and the generation of impurities due to the fracture of the intermediate amide is avoided;
4) The synthesis route of the invention has high yield of the final product, and can obtain the pharmaceutically acceptable raw material medicine of the gliptin through simple washing and pulping treatment without further purification treatment.
Detailed Description
The invention is further described below in connection with specific examples to provide a better understanding of the present technical solution.
In the present invention, wt% means mass fraction.
Example 1
1) Synthesis of intermediate C: 8-bromo-7- (2-butynyl) -3-methylxanthine (A) is reacted with-chloromethyl-4-methylquinazoline (B) to give intermediate C.
The operation steps are as follows: to a 1L reaction flask, 20g of A, 300ml of DMAC, 18.6g of anhydrous potassium carbonate and B (13 g) were added, the temperature was raised to 75℃and the mixture was stirred for 5 hours, cooled to room temperature, 200ml of water was added to precipitate a solid, the solid was washed with 20ml of methanol, recrystallized in methylene chloride and methanol solution (1:6wt%) and 1.2g of activated carbon was added to decolorize, and the product was dried after crystallization to obtain 29.7g of a product with a purity of 99% and a yield of 90%.
2) Synthesis of linagliptin crude product: 8-bromo-7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione (C) and (R) -3-aminopiperidine dihydrochloride (H) are synthesized to obtain a crude linagliptin product F1.
The operation steps are as follows: in a 1L reaction flask, 300ml of DMF, 18g of sodium bicarbonate, 30g of C and 13g of H were added, the temperature was raised to 90 degrees and the mixture was stirred for 8 hours, cooled to room temperature, DMF was distilled under reduced pressure, 100ml of dichloromethane was added, the mixture was stirred for 0.5 hour, filtration was carried out, the filter cake was washed with 50ml of dichloromethane to isopropanol ratio (15:1), the filtrate was obtained and concentrated, the aqueous phase was washed with 200ml of 10% sodium bicarbonate to pH8, extracted with dichloromethane and concentrated under reduced pressure to obtain crude F1.
3) Synthesis of linagliptin essence: linagliptin F1 refined linagliptin F2.
The operation steps are as follows: dissolving the obtained F1 crude product in dichloromethane, adding 10% of active carbon, heating and refluxing for 1h, filtering while hot to remove the active carbon, distilling the solvent, and subsequently using dichloromethane: petroleum ether 1:15, stirring and pulping the mixed solvent for 1h, filtering, eluting with ethanol (1:1.5), and drying the obtained filter cake at 45 degrees to obtain white solid F2 with the yield of 70%. 0.04% of unknown impurities and meets the requirement of 0.1% of unknown impurities.
Example 2
1) Synthesis of intermediate C. 8-bromo-7- (2-butynyl) -3-methylxanthine (A) is reacted with-chloromethyl-4-methylquinazoline (B) to give intermediate C.
The operation steps are as follows: to a 1L reaction flask were added 20g of A, 300ml of DMF, 18.6g of anhydrous potassium carbonate and B (13 g), the temperature was raised to 80℃and the mixture was stirred for 4 hours, cooled to room temperature, 200ml of water was added, the solid was precipitated, washed with 20ml of methanol, recrystallized in methylene chloride and methanol solution (1:10 wt%), 1.8 (9%) g of activated carbon was added to decolorize, and the product was dried after crystallization to give 30g of a product with a purity of 99.2% and a yield of 91%.
2) Synthesis of crude linagliptin, synthesis of 8-bromo-7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione (C) and (R) -3-aminopiperidine dihydrochloride (H) to obtain crude linagliptin F1.
The operation steps are as follows: to a 1L reaction flask, 300ml of ethanol, 18g of sodium bicarbonate, 30g of C and 13g of H were added, the mixture was warmed to 90℃and stirred for reaction for 8 hours, cooled to room temperature, DMF was distilled under reduced pressure, 100ml of dichloromethane was added, stirred for 0.5 hour, filtration was performed, the cake was washed with 50ml of dichloromethane to isopropanol (20:1) to give a filtrate, the aqueous phase was washed with 200ml of 10% sodium bicarbonate to pH8.5, extraction was performed with dichloromethane, and concentration was performed under reduced pressure to give crude F1.
3) Synthesis of linagliptin essence linagliptin F1 refined linagliptin F2
The operation steps are as follows: dissolving the obtained F1 crude product in dichloromethane, adding 10% of active carbon, heating and refluxing for 1h, filtering while hot to remove the active carbon, distilling the solvent, and subsequently using dichloromethane: petroleum ether 1: the 20 mixed solvent is stirred and pulped for 1h, filtered, and then rinsed with ethanol (1:2), and the obtained filter cake is dried at 50 ℃ to obtain white solid F2 with the yield of 68%. 0.06% of unknown impurities and meets the requirement of 0.1% of unknown impurities.
Claims (8)
1. A synthesis method of low-impurity linagliptin, which is characterized by comprising the following steps:
1) Synthesis of intermediate C: reacting 8-bromo-7- (2-butynyl) -3-methylxanthine (a) with-chloromethyl-4-methylquinazoline (B) to give intermediate 8-bromo-7- (2-butynyl-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione (C);
2) Synthesis of linagliptin crude product: synthesizing 8-bromo-7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione (C) and (R) -3-aminopiperidine dihydrochloride (H) to obtain a crude linagliptin product F1;
3) Synthesis of linagliptin essence: linagliptin F1 refined linagliptin F2;
the synthetic route is as follows:
2. the method for synthesizing low-impurity linagliptin according to claim 1, wherein the reaction solvent in the step 1) is DMAC or DMF, and anhydrous potassium carbonate is added into the reaction solvent to perform a coupling reaction with the reaction raw materials.
3. The method for synthesizing low-impurity linagliptin according to claim 1, wherein the reaction temperature in the step 1) is 70-80 ℃ and the reaction time is 3-10h.
4. The method for synthesizing low-impurity linagliptin according to claim 1, wherein the reaction product in the step 1) is recrystallized in a solution of dichloromethane and methanol, activated carbon is added for adsorption and dehydration, and an intermediate is obtained after crystallization and drying.
5. The method for synthesizing low-impurity linagliptin according to claim 1, wherein the reaction solvent in the step 2) is DMF or ethanol, and sodium bicarbonate is added into the reaction solvent to perform coupling reaction with the intermediate and (R) -3-aminopiperidine dihydrochloride (H).
6. The process for synthesizing low-impurity linagliptin according to claim 5, wherein the reaction is carried out for 8 hours under stirring after the temperature is raised to 90 ℃, after cooling to room temperature, DMF is distilled under reduced pressure, dichloromethane is added, stirring and filtering are carried out, filter cakes are washed with dichloromethane and isopropanol, filtrate is concentrated, aqueous phase is washed with 200ml of 10% sodium bicarbonate until the pH is 8-8.5, extraction is carried out with dichloromethane, and concentration is carried out under reduced pressure, thus obtaining crude product F1.
7. The method for synthesizing low-impurity linagliptin according to claim 6, wherein the volume ratio of dichloromethane to isopropanol is 15-20:1.
8. the synthesis method of low-impurity linagliptin according to claim 1, wherein in the refining process in the step 3), the obtained crude product of F1 is dissolved in dichloromethane, 10% of active carbon is added, heating reflux is carried out for 1h, the active carbon is removed by filtering while hot, the solvent is distilled, and dichloromethane is used subsequently: petroleum ether 1: stirring and pulping the mixed solvent of 15-20 for 1h, filtering, eluting with ethanol, and drying the obtained filter cake at 45 degrees to obtain white solid F2.
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