CN112679406A - Continuous preparation method of vildagliptin - Google Patents
Continuous preparation method of vildagliptin Download PDFInfo
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- dichloromethane
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- 229960001254 vildagliptin Drugs 0.000 title claims abstract description 34
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 126
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000007788 liquid Substances 0.000 claims abstract description 31
- 239000012074 organic phase Substances 0.000 claims abstract description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000005406 washing Methods 0.000 claims abstract description 22
- 238000001816 cooling Methods 0.000 claims abstract description 19
- ZILVRYHBTINJDJ-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;pyrrolidine-2-carbonitrile Chemical compound N#CC1CCCN1.CC1=CC=C(S(O)(=O)=O)C=C1 ZILVRYHBTINJDJ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 238000010924 continuous production Methods 0.000 claims abstract description 13
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 13
- 238000002425 crystallisation Methods 0.000 claims abstract description 11
- 230000008025 crystallization Effects 0.000 claims abstract description 11
- 239000012071 phase Substances 0.000 claims abstract description 11
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 10
- DWPIPTNBOVJYAD-BQKDNTBBSA-N (5s,7r)-3-aminoadamantan-1-ol Chemical compound C([C@H](C1)C2)[C@@H]3CC2(N)CC1(O)C3 DWPIPTNBOVJYAD-BQKDNTBBSA-N 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 238000010992 reflux Methods 0.000 claims abstract description 7
- 238000001704 evaporation Methods 0.000 claims abstract description 6
- YCWRPKBYQZOLCD-LURJTMIESA-N (2s)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile Chemical compound ClCC(=O)N1CCC[C@H]1C#N YCWRPKBYQZOLCD-LURJTMIESA-N 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 239000008213 purified water Substances 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 10
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 11
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- 238000007670 refining Methods 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 230000000717 retained effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 description 2
- VLLNJDMHDJRNFK-UHFFFAOYSA-N adamantan-1-ol Chemical compound C1C(C2)CC3CC2CC1(O)C3 VLLNJDMHDJRNFK-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- QSJTUXCBPTVKQZ-JEDNCBNOSA-N (2s)-pyrrolidine-2-carbonitrile;hydrochloride Chemical compound Cl.N#C[C@@H]1CCCN1 QSJTUXCBPTVKQZ-JEDNCBNOSA-N 0.000 description 1
- ZILVRYHBTINJDJ-ZSCHJXSPSA-N 4-methylbenzenesulfonic acid;(2s)-pyrrolidine-2-carbonitrile Chemical compound N#C[C@@H]1CCCN1.CC1=CC=C(S(O)(=O)=O)C=C1 ZILVRYHBTINJDJ-ZSCHJXSPSA-N 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- LNBTZMNVDDFNNS-FQEVSTJZSA-N C([ClH]CCCCCCCCCCCCCC)N1[C@@H](CCC1)C#N Chemical compound C([ClH]CCCCCCCCCCCCCC)N1[C@@H](CCC1)C#N LNBTZMNVDDFNNS-FQEVSTJZSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- BVCZEBOGSOYJJT-UHFFFAOYSA-N ammonium carbamate Chemical compound [NH4+].NC([O-])=O BVCZEBOGSOYJJT-UHFFFAOYSA-N 0.000 description 1
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- 150000004283 biguanides Chemical class 0.000 description 1
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- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
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- Pyrrole Compounds (AREA)
Abstract
The invention discloses a continuous preparation method of vildagliptin, which comprises the following steps: firstly, obtaining (S) -1- (2-chloroacetyl) pyrrolidine-2 carbonitrile by using (S) -pyrrolidine-2 carbonitrile p-toluenesulfonate, chloroacetyl chloride, triethylamine and dichloromethane, washing, separating liquid and retaining an organic phase; adding water and 3-amino-1-adamantanol into the organic phase, refluxing, evaporating to remove the organic solvent, heating, and reacting to obtain a feed liquid; thirdly, washing the feed liquid, cooling, adjusting to acidity, and washing to obtain the feed liquid; and fourthly, extracting the water phase, cooling, adjusting to be alkaline, separating the liquid and keeping the organic phase, extracting the water phase again, separating the liquid, combining the organic phase, evaporating the solvent, and adding the crystallization solvent to obtain the vildagliptin with the HPLC purity being equal to or greater than 99.5 percent. The invention provides a method for preparing, storing and feeding the raw material with low water absorption, which is convenient for preparation, storage and feeding; by continuous process operation, the operation steps are reduced, and the overall yield is improved; and finally, water is used as a reaction solvent, so that the production cost is reduced, the environmental pollution pressure is relieved, and the method is suitable for preparing vildagliptin.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a continuous preparation method of vildagliptin.
Background
Vildagliptin (Wildagliptin), chemical name (S) -1- [ [ (3-hydroxy-1-amantadine) amino ] acetyl ] -2-cyanopyrrolidine. Is a DPP-4 inhibitor developed by Nowa, and is approved to be marketed by the European Union in 9 months of 2007. In 2011, 8 months, vildagliptin formally obtains CFDA approval to be listed on the market, and the product is named as 'Jiaweile'. The product is suitable for treating type 2 diabetes, and can be used in combination with biguanides, thiazolidinediones, and sulfonylureas.
The structural formula is as follows:
most of the existing preparation methods of vildagliptin reported in literatures use L-prolinamide or L-proline as a starting material, and the vildagliptin is prepared by obtaining a key intermediate (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile through a series of steps such as acylation, dehydration and the like, and then condensing with adamantanol. Such as original patents W00034241A1, international patents W02006100181, W0201022690 and W020080167479; however, the process has high cost of raw materials, more amide impurities are easily introduced in the reaction process, the purification of the final product needs to be carried out by layer separation, and some of the process also needs dicyclohexylcarbodiimide, so that the water requirement of the system is strict, ammonium carbamate is flammable and has high toxicity, the environment pollution is high, and the industrialization is difficult to realize.
International patent W02014020462a1 discloses a preparation method of vildagliptin: taking L-prolinamide as a raw material, obtaining an intermediate (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile through N protection, amide dehydration and deprotection, finally condensing with adamantanol to obtain a vildagliptin crude product, and then purifying the crude product to obtain the high-purity vildagliptin. The process avoids the generation of a large amount of amide impurities, but has the disadvantages of long route, more complicated operation, lower yield and secondary refining of products.
JP201356872 uses (S) -pyrrolidine-2-carbonitrile hydrochloride as a starting material to prepare a key intermediate with chloroacetyl chloride in a heterogeneous system, but the starting material is very easy to absorb moisture and is inconvenient to prepare, store and feed.
In summary, the following problems still exist in the preparation process of vildagliptin final product: the cost of the initial raw materials is high, or moisture absorption is not easy to store, the yield is low due to long process route, and the final product has more impurities and needs to be refined for the second time to obtain a product with higher purity.
Disclosure of Invention
The invention provides a method for preparing, storing and feeding the raw material with low water absorption, which is convenient for preparation, storage and feeding; through continuous process operation, the crystallization and recrystallization processes of an intermediate are omitted, the operation steps are reduced, and the overall yield is improved; and finally, water is used as a reaction solvent, so that the production cost is reduced, and the environmental pollution pressure is relieved.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a continuous preparation method of vildagliptin comprises the following steps:
step one, adding (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate, chloroacetyl chloride, triethylamine and dichloromethane into a reactor to react to obtain (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile, and reacting with Na2CO3Washing the solution to be neutral, washing the solution with saturated saline solution, separating the solution and retaining an organic phase;
step two, adding purified water and 3-amino-1-adamantanol into the organic phase obtained in the step one, refluxing for 2-6h, completely evaporating the organic solvent, continuously heating, and reacting until the reaction is finished to obtain a first feed liquid;
step three, adding toluene into the first feed liquid at 50-60 ℃ for washing, cooling, adding 10% hydrochloric acid to adjust to acidity, and washing with dichloromethane to obtain a second feed liquid;
step four, adding dichloromethane into the second feed liquid for primary extraction, cooling, and adding Na2CO3Adjusting to be alkaline, separating liquid and keeping an organic phase, adding dichloromethane into a water phase for second extraction and liquid separation, combining the organic phases, evaporating the solvent, and adding a crystallization solvent to obtain the vildagliptin with the HPLC purity of more than or equal to 99.5%.
Further, in the first step, the molar ratio of the (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate salt to chloroacetyl chloride is 1: 1.2-2; the molar ratio of (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate to triethylamine is 1: 1.2-2; the using amount of dichloromethane is 7 to 9 times of the mass of (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate; the volume ratio of the saturated saline solution to the dichloromethane is 1: 2-4.
Further, the amount of the purified water in the second step is 7-9 times of the mass of the (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate; the dosage of the 3-amino-1-adamantanol is 1.7eq of (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate; and in the second step, the temperature is continuously increased to 50-80 ℃.
Further, when the toluene is washed in the third step, the volume ratio of the toluene to the purified water is 0.2-0.3: 1; cooling to 25-30 deg.C; the pH value of the acid solution in the third step is adjusted to 4.0-4.5.
Further, the volume ratio of the dichloromethane to the purified water is 0.2-0.3:1 when the dichloromethane is washed in the third step.
Further, in the first extraction of the dichloromethane in the fourth step, the volume ratio of the dichloromethane to the purified water is 0.5-0.7: 1, cooling to 0-5 ℃ in the fourth step; in the fourth step, the pH value of the alkali is adjusted to 10.0-10.5.
Further, when the dichloromethane is extracted for the second time in the fourth step, the volume ratio of the dichloromethane to the purified water is 0.2-0.3:1, and the extraction times are 3 times.
Further, the dosage of the crystallization solvent in the step four is 2 to 4 times of the mass of the (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate; and in the fourth step, the crystallization solvent is a mixed solvent of ethanol and ethyl acetate.
Further, the volume ratio of the ethanol to the ethyl acetate is 1: 3-6.
Further, the volume ratio of the ethanol to the ethyl acetate is 1: 4.
As the invention adopts the invention, compared with the prior art, the invention has the technical progress that:
(1) the invention adopts a continuous process, does not separate the intermediate (S) -1- (2-chloracetyl) pyrrolidine-2-carbonitrile in the reaction process, directly and simply carries out phase inversion and subsequent reaction, simplifies the process, avoids solid aggregation caused by directly distilling off dichloromethane, ensures the reaction effect, does not need crystallization, simultaneously can ensure the product purity, and is beneficial to industrial production.
(2) In the post-treatment process, the pH value is accurately controlled at different temperatures, and different solvents are used for washing and extracting, so that the process impurities in the two steps can be removed at one time, and the final purity of the product is ensured.
(3) The crystallization process of the invention can ensure thorough treatment of all trace impurities by using the mixed solvent, secondary refining or recrystallization is not needed, the product yield can reach 76.5 percent, and the HPLC purity is as high as 99.9 percent.
In conclusion, the invention provides the preparation method which has low water absorption of raw materials and is convenient to prepare, store and feed; through continuous process operation, the crystallization and recrystallization processes of an intermediate are omitted, the operation steps are reduced, and the overall yield is improved; and finally, water is used as a reaction solvent, so that the production cost is reduced, the environmental pollution pressure is relieved, and the method is suitable for preparing vildagliptin.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention.
In the drawings:
fig. 1 is an HPLC profile of vildagliptin as a final product in example 1 of the present invention.
Detailed Description
The following description is given in conjunction with preferred embodiments of the present invention. It should be understood that the preferred embodiments described herein are for purposes of illustration and explanation only and are not intended to limit the present invention.
Example 1
(1) Adding 20g of (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate, 11.87g of chloroacetyl chloride, 9.19g of triethylamine and 160ml of dichloromethane into a reaction bottle, cooling to 0-5 ℃, stirring for 2 hours, monitoring by HPLC, and stopping the reaction after the raw materials are completely converted; the feed liquid was treated with 30ml of Na2CO3After washing, 50ml of saturated saline (50ml × 2) (50ml × 2 represents washing 2 times with 50ml of saturated saline), the organic phase was separated and retained; then directly to itAdding 160ml of water and 20g of 3-amino-1-adamantanol, refluxing for 4h, continuously heating to 50 ℃ after the organic solvent is completely distilled off, and finishing the reaction after 6h to obtain the product liquid.
(2) Adding 30ml of toluene into the feed liquid at 50-60 ℃ to wash for 2 times; then reducing the temperature to 25-30 ℃, adjusting the pH to 4.3 by using 10% hydrochloric acid, and adding 30ml of dichloromethane for washing for 2 times; adding 100ml dichloromethane into the water phase, cooling to 0-5 deg.C, and adding Na2CO3Adjusting the pH value of the solution to 10.2, and keeping an organic phase; then the aqueous phase was further extracted 3 times with 50ml of dichloromethane (50 ml. times.3), separated, the organic phases were combined and the solvent was distilled off; and finally, 60ml of ethanol and ethyl acetate are added for refining, the volume ratio of the ethanol to the ethyl acetate is 1:4, 9.82g of vildagliptin is obtained, the total yield is 76.5%, and the HPLC purity is 99.9%.
| Name (R) | Retention time | Area of | % area | Height | |
| 1 | Impurity 1 | 9.848 | 12292 | 0.07 | 1237 |
| 2 | Vildagliptin | 15.475 | 17016137 | 99.93 | 1175961 |
Example 2
(1) Adding 20g of (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate, 11.87g of chloroacetyl chloride, 9.19g of triethylamine and 160ml of dichloromethane into a reaction bottle, cooling to 0-5 ℃, stirring for 2 hours, monitoring by HPLC, and stopping the reaction after the raw materials are completely converted; the feed liquid was treated with 30ml of Na2CO3After washing, 50ml of saturated saline (50ml × 2) (50ml × 2 represents washing 2 times with 50ml of saturated saline), the organic phase was separated and retained; and then, directly adding 160ml of water and 20g of 3-amino-1-adamantanol into the mixture, refluxing for 4 hours, continuously heating to 60 ℃ after the organic solvent is completely distilled off, and finishing the reaction after 7 hours to obtain the product feed liquid.
(2) Adding 40ml of toluene into the feed liquid at 50-60 ℃ to wash for 2 times; then reducing the temperature to 25-30 ℃, adjusting the pH to 4.3 by using 10% hydrochloric acid, and adding 40ml of dichloromethane for washing for 2 times; adding 100ml dichloromethane into the water phase, cooling to 0-5 deg.C, and adding Na2CO3Adjusting the pH value of the solution to 10.2, and keeping an organic phase; then the aqueous phase was further extracted 3 times with 50ml of dichloromethane (50 ml. times.3), separated, the organic phases were combined and the solvent was distilled off; and finally, 60ml of ethanol and ethyl acetate are added for refining, the volume of the ethanol and the ethyl acetate is 1:5, 9.8g of vildagliptin is obtained, the total yield is 76.3%, and the HPLC purity is 99.5%.
Example 3
(1) Adding 20g of (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate, 11.87g of chloroacetyl chloride, 9.19g of triethylamine and 160ml of dichloromethane into a reaction bottle, cooling to 0-5 ℃, stirring for 2 hours, monitoring by HPLC, and stopping the reaction after the raw materials are completely converted; the feed liquid was treated with 30ml of Na2aCO350ml of a saturated saline solution (50 ml. about.2) was washed, and then (50ml of the solution was added thereto)ml × 2 represents washing 2 times with 50ml of saturated saline), and the organic phase is retained by liquid separation; and then, directly adding 160ml of water and 20g of 3-amino-1-adamantanol into the mixture, refluxing for 4 hours, continuously heating to 70 ℃ after the organic solvent is completely distilled off, and finishing the reaction after 5 hours to obtain the product feed liquid.
(2) Adding 50ml toluene into the feed liquid at 50-60 deg.C, extracting for 2 times, and discarding the organic phase; continuously adding 50ml of dichloromethane into the water tank, reducing the temperature to 25 ℃, adjusting the pH value to 4.5 by using 10% hydrochloric acid, extracting, and then removing an organic phase; adding 100ml dichloromethane into the water phase, cooling to 0 deg.C, and adding Na2CO3Adjusting the pH value of the solution to 10.5, and reserving an organic phase; then the aqueous phase was further extracted 3 times with 50ml of dichloromethane (50 ml. times.3), separated, the organic phases were combined and the solvent was distilled off; and finally, adding 60ml of ethanol and ethyl acetate for refining, wherein the volume ratio of the ethanol to the ethyl acetate is 1:3, so that 9.75g of vildagliptin is obtained, the total yield is 76%, and the HPLC purity is 99.6%.
Example 4
(1) Adding 20g of (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate, 11.87g of chloroacetyl chloride, 9.19ga of triethylamine and 160ml of dichloromethane into a reaction bottle, cooling to 0-5 ℃, stirring for 2 hours, monitoring by HPLC, and stopping the reaction after the raw materials are completely converted; the feed liquid is respectively mixed with 30mNA2CO3After 50ml of saturated saline (50 ml. times.2) washing, (50 ml. times.2 represents washing with 50ml of saturated saline 2 times), the organic phase was separated and retained; and then, directly adding 160ml of water and 20g of 3-amino-1-adamantanol into the mixture, refluxing for 4 hours, continuously heating to 80 ℃ after the organic solvent is completely distilled off, and finishing the reaction after 4 hours to obtain the product feed liquid.
(2) Adding 30ml toluene into the feed liquid at 50-60 deg.C, extracting for 2 times, and discarding the organic phase; adding 30ml of dichloromethane into the water phase, cooling to 25 ℃, adjusting the pH value to 4.0 by using 10% hydrochloric acid, extracting, and then removing the organic phase; adding 100ml dichloromethane into the water phase, cooling to 0 deg.C, and adding Na2CO3Adjusting the pH value of the solution to 10.0, and reserving an organic phase; then the aqueous phase was further extracted 3 times with dichloromethane (50 ml. times.3), the phases were separated, the organic phases were combined and the solvent was evaporated off; finally adding 60ml ethanol and ethyl acetate for refiningThe volume ratio of the ethyl ester is 1:6, so that the vildagliptin is 9.87, the total yield is 76.9%, and the HPLC purity is 99.6%.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the claims of the present invention.
Claims (10)
1. A continuous preparation method of vildagliptin is characterized by comprising the following steps: the method comprises the following steps:
step one, adding (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate, chloroacetyl chloride, triethylamine and dichloromethane into a reactor to react to obtain (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile, and reacting with Na2CO3Washing the solution to be neutral, washing the solution with saturated saline solution, separating the solution and retaining an organic phase;
step two, adding purified water and 3-amino-1-adamantanol into the organic phase obtained in the step one, refluxing for 2-6h, completely evaporating the organic solvent, continuously heating, and reacting until the reaction is finished to obtain a first feed liquid;
step three, adding toluene into the first feed liquid at 50-60 ℃ for washing, cooling, adding 10% hydrochloric acid to adjust to acidity, and washing with dichloromethane to obtain a second feed liquid;
step four, adding dichloromethane into the second feed liquid for primary extraction, cooling, and adding Na2CO3Adjusting to be alkaline, separating liquid and keeping an organic phase, adding dichloromethane into a water phase for second extraction and liquid separation, combining the organic phases, evaporating the solvent, and adding a crystallization solvent to obtain the vildagliptin with the HPLC purity of more than or equal to 99.5%.
2. The continuous production method of vildagliptin according to claim 1, characterized in that: in the first step, the molar ratio of (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate to chloroacetyl chloride is 1: 1.2-2; the molar ratio of (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate to triethylamine is 1: 1.2-2; the using amount of dichloromethane is 7 to 9 times of the mass of (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate; the volume ratio of the saturated saline solution to the dichloromethane is 1: 2-4.
3. The continuous production method of vildagliptin according to claim 1, characterized in that: in the second step, the amount of the purified water is 7-9 times of the mass of the (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate; the dosage of the 3-amino-1-adamantanol is 1.7eq of (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate; and in the second step, the temperature is continuously increased to 50-80 ℃.
4. The continuous production method of vildagliptin according to claim 1, characterized in that: when the toluene is washed in the third step, the volume ratio of the toluene to the purified water is 0.2-0.3: 1; cooling to 25-30 deg.C; the pH value of the acid solution in the third step is adjusted to 4.0-4.5.
5. The continuous production method of vildagliptin according to claim 1, characterized in that: when washing with dichloromethane in the third step, the volume ratio of dichloromethane to purified water is 0.2-0.3: 1.
6. The continuous production method of vildagliptin according to claim 1, characterized in that: in the fourth step, when the dichloromethane is extracted for the first time, the volume ratio of the dichloromethane to the purified water is 0.5-0.7: 1, cooling to 0-5 ℃ in the fourth step; in the fourth step, the pH value of the alkali is adjusted to 10.0-10.5.
7. The continuous production method of vildagliptin according to claim 1, characterized in that: in the fourth step, when the dichloromethane is extracted for the second time, the volume ratio of the dichloromethane to the purified water is 0.2-0.3:1, and the extraction times are 3 times.
8. The continuous production method of vildagliptin according to claim 1, characterized in that: in the fourth step, the dosage of the crystallization solvent is 2-4 times of the mass of the (S) -pyrrolidine-2-carbonitrile p-toluenesulfonate; and in the fourth step, the crystallization solvent is a mixed solvent of ethanol and ethyl acetate.
9. The continuous production method of vildagliptin according to claim 8, characterized in that: the volume ratio of the ethanol to the ethyl acetate is 1: 3-6.
10. The continuous production method of vildagliptin according to claim 9, characterized in that: the volume ratio of the ethanol to the ethyl acetate is 1: 4.
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