CN105153165A - Preparation method for vildagliptin impurity - Google Patents
Preparation method for vildagliptin impurity Download PDFInfo
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- CN105153165A CN105153165A CN201510457176.4A CN201510457176A CN105153165A CN 105153165 A CN105153165 A CN 105153165A CN 201510457176 A CN201510457176 A CN 201510457176A CN 105153165 A CN105153165 A CN 105153165A
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- vildagliptin
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- 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 40
- 229960001254 vildagliptin Drugs 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000012535 impurity Substances 0.000 title claims abstract description 13
- 229940125782 compound 2 Drugs 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 229940125904 compound 1 Drugs 0.000 claims abstract description 27
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 12
- BLWYXBNNBYXPPL-YFKPBYRVSA-N methyl (2s)-pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1 BLWYXBNNBYXPPL-YFKPBYRVSA-N 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 64
- 239000012074 organic phase Substances 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical compound O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 claims description 24
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 15
- 235000015320 potassium carbonate Nutrition 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 235000007715 potassium iodide Nutrition 0.000 claims description 7
- 229960004839 potassium iodide Drugs 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- KECLYWKKMFOZBI-UHFFFAOYSA-N [Cl].CC(Cl)=O Chemical compound [Cl].CC(Cl)=O KECLYWKKMFOZBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 2
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- PJGSXYOJTGTZAV-UHFFFAOYSA-N pinacolone Chemical compound CC(=O)C(C)(C)C PJGSXYOJTGTZAV-UHFFFAOYSA-N 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 abstract description 7
- 238000012827 research and development Methods 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- DWPIPTNBOVJYAD-UHFFFAOYSA-N 3-aminoadamantan-1-ol Chemical compound C1C(C2)CC3CC1(N)CC2(O)C3 DWPIPTNBOVJYAD-UHFFFAOYSA-N 0.000 abstract 2
- 238000010438 heat treatment Methods 0.000 description 5
- 238000010907 mechanical stirring Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000012912 drug discovery process Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A disclosed preparation method for a vildagliptin impurity comprises the following steps: (1) reacting methyl L-prolinate with chloroacetyl chloride under an alkali condition to generate a compound I; (2) performing condensation reaction on the compound 1 and 3-amino-1-hydroxyadamantane to generate a compound 2; and (3) performing a self condensation reaction on the compound 2 under an alkali condition to obtain vildagliptin related compound 2. According to the vildagliptin related compound 2 synthetic method, methyl L-prolinate is taken as the raw material and is reacted with chloroacetyl chloride under the alkali condition for preparing the compound 1, the compound 1 is condensed with 3-amino-1-hydroxyadamantane for generating the compound 2, and the compound 2 is subjected to the self condensation reaction under the alkali condition for obtaining the vildagliptin related compound 2. The synthetic method is simple, reaction conditions are mild, operationality is high, a product according with quality standard is obtained through simple purification, and research and development cost is effectively reduced.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to the preparation method of Vildagliptin impurity and Vildagliptin diketopiperazine.
Background technology
Vildagliptin is developed by Novartis Co., Ltd, within 2007, obtains European Union's approval listing.Within 2011, CFDA official approval on August 15 Vildagliptin is in Discussion on Chinese Listed.Vildagliptin can treat type II diabetes with biguanides, thiazolidinediones, sulfonylurea drugs drug combination.Vildagliptin has the effect reducing empty stomach and level of postprandial blood sugar, after the meal glucagon secretion and raising β cell function, and the treatment for patients with NIDDM provides new selection.After Vildagliptin listing, sales growth is powerful, within 2011, has reached 6.77 hundred million dollars, and before 2012, the third quarter adds up to sale just close to 6.55 hundred million dollars.
It is below the structure of Vildagliptin diketopiperazine
In drug discovery process, impurity research is an important link, and the foundation of quality standard needs a certain amount of standard substance, so the synthetic method of exploitation impurity is a vital task of drug development.
Vildagliptin diketopiperazine is a specific degradation impurity in Vildagliptin preparation, and the synthetic method of this impurity is so far without bibliographical information, and can only extract from preparation in R&D process and obtain, and from preparation, extract the complex process of this impurity, cost is high.
Summary of the invention
The object of the invention is the synthetic method studying Vildagliptin diketopiperazine, obtain this impurity by the means of controlled syntheses, for drug research and development provides reliable standard substance, and effectively reduce R&D costs.
The technical scheme that the present invention takes is:
A preparation method for Vildagliptin impurity, comprises the following steps:
(1) L-PROLINE methyl esters and chloroacetyl chloride reacting generating compound 1 in the basic conditions;
(2) compound 1 and the condensation reaction of 3-amino-1-adamantane alcohol generate compound 2;
(3) there is self-condensation in the basic conditions and be obtained by reacting Vildagliptin diketopiperazine in compound 2.
A preparation method for Vildagliptin impurity, preferred version is: comprise the following steps:
(1) chloroacetyl chloride is added in solvent, by L-PROLINE methyl esters, triethylamine or/and n-Butyl Amine 99 is or/and pyridine reagent adds in solvent, drop in the solvent of dissolved chlorine Acetyl Chloride 98Min., stirring reaction, add water extracting and demixing, and then wash organic phase with water, and organic phase is dry, obtain compound 1; Described solvent is that methylene dichloride is or/and THF is or/and ethyl acetate is or/and butylacetate is or/and 1,2-ethylene dichloride;
(2) compound 1 is added acetone or/and 2-butanone is or/and in methyl tertbutyl ketone, make the solution of compound 1, by 3-amino-1-adamantane alcohol, salt of wormwood or/and sodium carbonate, potassiumiodide are or/and sodium iodide adds in acetone, reflux, and instill the solution of compound 1, stirring reaction, filtered while hot, filtrate is spin-dried for, add water dissolution, then add dichloromethane extraction, organic phase is added water washing, organic phase drying is spin-dried for, obtains compound 2;
(3) add in reaction solvent by compound 2 and alkali, temperature of reaction is 30 ~ 100 DEG C, stirring reaction, filters, add water and methylene dichloride, volume ratio is 3:2, and extracting and demixing, by organic phase washed with water, layering, is spin-dried for organic phase drying, obtains Vildagliptin diketopiperazine.
The reaction solvent that the compound 2 of step (3) prepares Vildagliptin diketopiperazine is one or more in methyl alcohol, ethanol, DMF, DMA, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, methylene dichloride, chloroform, dioxane.
The alkali that step (3) uses is triethylamine, one or more in salt of wormwood, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH, sodium amide.
The compound 2 of step (3) is 1:1 to 1:10 with the mol ratio of alkali.
Step (1) is preferably:
Chloroacetyl chloride is added in methylene dichloride, then L-PROLINE methyl esters and triethylamine are dissolved in methylene dichloride, drop in the methylene dichloride of dissolved chlorine Acetyl Chloride 98Min., stirring reaction 1 hour, add water extracting and demixing, and then wash organic phase with water, organic phase is dry, obtain compound 1, wherein chloroacetyl chloride: L-PROLINE methyl esters: the mol ratio of triethylamine is 1.5:1:1.
Step (2) is preferably:
Compound 1 is added in acetone, make the solution of compound 1,3-amino-1-adamantane alcohol, salt of wormwood, potassiumiodide are added in acetone, reflux, and instill the solution of compound 1, stirring reaction 1 hour, filtered while hot, is spin-dried for filtrate, adds water dissolution, add dichloromethane extraction again, organic phase is added water washing, organic phase drying decompression is spin-dried for, obtains compound 2, wherein, compound 1:3-amino-1-adamantane alcohol: salt of wormwood: the mol ratio of potassiumiodide is: 1:1.5:1:0.05.
Step (3) is preferably:
Be that compound 2 and the salt of wormwood of 1:1 adds in DMF by mol ratio, 50 DEG C of stirring reactions 3 hours, filter, add water and methylene dichloride, volume ratio is 3:2, and extracting and demixing, by organic phase washed with water, layering, is spin-dried for organic phase drying, obtains Vildagliptin diketopiperazine.
Step (3) can be:
Be that compound 2 and the salt of wormwood of 1:1 adds in tetrahydrofuran (THF) by mol ratio, 60 DEG C of stirring reactions 3 hours, filter, add water and methylene dichloride, volume ratio is 3:2, and extracting and demixing, by organic phase washed with water, layering, is spin-dried for organic phase drying, obtains Vildagliptin diketopiperazine.
Step (3) can also be:
Be that compound 2 and the sodium hydride of 1:1 adds in tetrahydrofuran (THF) by mol ratio, 50 DEG C of stirring reactions 4 hours, filter, add water and methylene dichloride, volume ratio is 3:2, and extracting and demixing, by organic phase washed with water, layering, is spin-dried for organic phase drying, obtains Vildagliptin diketopiperazine.
The invention has the beneficial effects as follows:
The synthetic method of Vildagliptin diketopiperazine of the present invention, with L-PROLINE methyl esters for raw material prepares compound 1 with chloroacetyl chloride in the basic conditions, compound 1 and the condensation of 3-amino-1-adamantane alcohol generate compound 2; There is self-condensation in the basic conditions and be obtained by reacting Vildagliptin diketopiperazine in compound 2.This synthetic method is simple, reaction conditions is gentle, workable, can obtain through simple purification the product meeting quality standard, effectively reduce R&D costs.
Embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this.
The preparation of embodiment 1 compound 1
The chloroacetyl chloride of 16.9g (0.15mol) is added in the 1000ml four-hole bottle that mechanical stirring, prolong, thermometer, heating unit be housed, add 70ml methylene dichloride again, then 12.9g (0.1mol) L-PROLINE methyl esters and 10.1g (0.1mol) triethylamine are dissolved in 200ml methylene dichloride and slowly drop in reaction flask, stirring reaction 1 hour, add 200ml water extracting and demixing, and then by 200ml water washing organic phase, organic phase drying is spin-dried for, obtains compound 1.
The preparation of embodiment 2 compound 2
25g (0.15mol) 3-amino-1-adamantane alcohol, 13.8g (0.1mol) salt of wormwood, 0.85g potassiumiodide and 200ml acetone is added in the 1000ml four-hole bottle that mechanical stirring, prolong, thermometer, heating unit be housed, reflux, 20.5g (0.1mol) compound 1 is dissolved in 200ml acetone and slowly drops in reaction flask, stirring reaction 1 hour, filtered while hot, filtrate is spin-dried for, add 200ml water dissolution, add 200ml dichloromethane extraction again, organic phase is added 200ml water washing, organic phase drying is spin-dried for, obtains compound 2.
The preparation of embodiment 3 Vildagliptin diketopiperazine
33.6g (0.1mol) compound 2 is added in the 1000ml four-hole bottle that mechanical stirring, prolong, thermometer, heating unit be housed, add 13.8g (0.1mol) salt of wormwood and 200mlDMF again, 50 DEG C of stirring reactions 3 hours, filter, add 300ml water and the layering of 200ml dichloromethane extraction, organic phase is used 200ml water washing, layering, organic phase drying is spin-dried for, obtains Vildagliptin diketopiperazine, yield 80%.
The preparation of embodiment 4 Vildagliptin diketopiperazine
33.6g (0.1mol) compound 2 is added in the 1000ml four-hole bottle that mechanical stirring, prolong, thermometer, heating unit be housed, add 13.8g (0.1mol) salt of wormwood and 200m tetrahydrofuran (THF) again, 50 DEG C of stirring reactions 3 hours, filter, add 300ml water and the layering of 200ml dichloromethane extraction, organic phase is used 200ml water washing, layering, organic phase drying is spin-dried for, obtains Vildagliptin diketopiperazine, yield 60%.
The preparation of embodiment 5 Vildagliptin diketopiperazine
33.6g (0.1mol) compound 2 is added in the 1000ml four-hole bottle that mechanical stirring, prolong, thermometer, heating unit be housed, add 2.4g (0.1mol) sodium hydride and 200m tetrahydrofuran (THF) again, 50 DEG C of stirring reactions 3 hours, filter, add 300ml water and the layering of 200ml dichloromethane extraction, organic phase is used 200ml water washing, layering, organic phase drying is spin-dried for, obtains Vildagliptin diketopiperazine, yield 70%.
HPLC(99.2％)
ESI(m/z):305.3[M+1]
1HNMR(CDCl3，600M)1.53(d,1H,J＝12Hz)，1.59(d,1H,J＝12Hz),1.70(t,4H,J＝12Hz)，1.86-1.94(m,1H),1.97-2.21(m,9H),2.29-2.35(m,3H),3.51-3.61(m,2H),3.88(d,1H,J＝16Hz),4.02(t,1H,J＝6Hz)，4.11(d,1H,J＝16Hz)。
13CNMR(CDCl3，150M)22.9，28.8，30.9，31.0，34.7，38.4(2)，43.8(2)，44.9，47.3，47.9，60.5，61.5，69.4，164.1，168.6。
Claims (10)
1. a preparation method for Vildagliptin impurity, is characterized in that: comprise the following steps:
(1) L-PROLINE methyl esters and chloroacetyl chloride reacting generating compound 1 in the basic conditions;
(2) compound 1 and the condensation reaction of 3-amino-1-adamantane alcohol generate compound 2;
(3) there is self-condensation in the basic conditions and be obtained by reacting Vildagliptin diketopiperazine in compound 2;
2. preparation method as claimed in claim 1, is characterized in that:
(1) chloroacetyl chloride is added in solvent, by L-PROLINE methyl esters, triethylamine or/and n-Butyl Amine 99 is or/and pyridine reagent adds in solvent, drop in the solvent of dissolved chlorine Acetyl Chloride 98Min., stirring reaction, add water extracting and demixing, and then wash organic phase with water, and organic phase is dry, obtain compound 1; Described solvent is that methylene dichloride is or/and THF is or/and ethyl acetate is or/and butylacetate is or/and 1,2-ethylene dichloride;
(2) compound 1 is added acetone or/and 2-butanone is or/and in methyl tertbutyl ketone, make the solution of compound 1, by 3-amino-1-adamantane alcohol, salt of wormwood or/and sodium carbonate, potassiumiodide are or/and sodium iodide adds in acetone, reflux, and instill the solution of compound 1, stirring reaction, filtered while hot, filtrate is spin-dried for, add water dissolution, then add dichloromethane extraction, organic phase is added water washing, organic phase drying is spin-dried for, obtains compound 2;
(3) add in reaction solvent by compound 2 and alkali, temperature of reaction is 30 ~ 100 DEG C, stirring reaction, filters, add water and methylene dichloride, volume ratio is 3:2, and extracting and demixing, by organic phase washed with water, layering, is spin-dried for organic phase drying, obtains Vildagliptin diketopiperazine.
3. preparation method as claimed in claim 2, is characterized in that: the reaction solvent that the compound 2 of described step (3) prepares Vildagliptin diketopiperazine is one or more in methyl alcohol, ethanol, DMF, DMA, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, methylene dichloride, chloroform, dioxane.
4. preparation method as claimed in claim 2, it is characterized in that: described step (3), the alkali of use be triethylamine, one or more in salt of wormwood, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH, sodium amide.
5. the preparation method as described in as arbitrary in Claims 1-4, is characterized in that: the compound 2 of described step (3) is 1:1 to 1:10 with the mol ratio of alkali.
6. preparation method as claimed in claim 5, is characterized in that: described step (1) is:
Chloroacetyl chloride is added in methylene dichloride, then L-PROLINE methyl esters and triethylamine are dissolved in methylene dichloride, drop in the methylene dichloride of dissolved chlorine Acetyl Chloride 98Min., stirring reaction 1 hour, add water extracting and demixing, and then wash organic phase with water, organic phase is dry, obtain compound 1, wherein chloroacetyl chloride: L-PROLINE methyl esters: the mol ratio of triethylamine is 1.5:1:1.
7. preparation method as claimed in claim 5, is characterized in that: described step (2) is:
Compound 1 is added in acetone, make the solution of compound 1,3-amino-1-adamantane alcohol, salt of wormwood, potassiumiodide are added in acetone, reflux, and instill the solution of compound 1, stirring reaction 1 hour, filtered while hot, is spin-dried for filtrate, adds water dissolution, add dichloromethane extraction again, organic phase is added water washing, organic phase drying decompression is spin-dried for, obtains compound 2, wherein, compound 1:3-amino-1-adamantane alcohol: salt of wormwood: the mol ratio of potassiumiodide is: 1:1.5:1.:0.05.
8. preparation method as claimed in claim 5, is characterized in that: described step (3) is:
Be that compound 2 and the salt of wormwood of 1:1 adds in DMF by mol ratio, 50 DEG C of stirring reactions 3 hours, filter, add water and methylene dichloride, volume ratio is 3:2, and extracting and demixing, by organic phase washed with water, layering, is spin-dried for organic phase drying, obtains Vildagliptin diketopiperazine.
9. preparation method as claimed in claim 5, is characterized in that: described step (3) is:
Be that compound 2 and the salt of wormwood of 1:1 adds in tetrahydrofuran (THF) by mol ratio, 60 DEG C of stirring reactions 3 hours, filter, add water and methylene dichloride, volume ratio is 3:2, and extracting and demixing, by organic phase washed with water, layering, is spin-dried for organic phase drying, obtains Vildagliptin diketopiperazine.
10. preparation method as claimed in claim 5, is characterized in that: described step (3) is:
Be that compound 2 and the sodium hydride of 1:1 adds in tetrahydrofuran (THF) by mol ratio, 50 DEG C of stirring reactions 4 hours, filter, add water and methylene dichloride, volume ratio is 3:2, and extracting and demixing, by organic phase washed with water, layering, is spin-dried for organic phase drying, obtains Vildagliptin diketopiperazine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108329322A (en) * | 2018-05-10 | 2018-07-27 | 上海医药集团青岛国风药业股份有限公司 | A kind of preparation method of vildagliptin ring amidine impurity |
| CN113527309A (en) * | 2021-07-20 | 2021-10-22 | 重庆医科大学附属大学城医院 | Vildagliptin diketopiperazine and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101143852A (en) * | 2006-09-13 | 2008-03-19 | 深圳市翰宇生物工程有限公司 | Method for preparing cyclodipeptide cyclo(L-Asp-L-Pro) |
| WO2010022690A2 (en) * | 2008-08-26 | 2010-03-04 | Zentiva, K.S. | A method of preparation of highly pure vildagliptin |
| CN103787944A (en) * | 2012-11-01 | 2014-05-14 | 天津药物研究院 | Preparation method of 1-(2-chloroacetyl)-2-(S)-nitrile pyrrolidine |
| CN104311467A (en) * | 2014-09-11 | 2015-01-28 | 青岛国风药业股份有限公司 | Method and device for continuous preparation of Vildagliptin by tubular reaction |
| CN104672243A (en) * | 2015-02-10 | 2015-06-03 | 华润赛科药业有限责任公司 | Method for preparing vildagliptin degraded impurities |
-
2015
- 2015-07-30 CN CN201510457176.4A patent/CN105153165B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101143852A (en) * | 2006-09-13 | 2008-03-19 | 深圳市翰宇生物工程有限公司 | Method for preparing cyclodipeptide cyclo(L-Asp-L-Pro) |
| WO2010022690A2 (en) * | 2008-08-26 | 2010-03-04 | Zentiva, K.S. | A method of preparation of highly pure vildagliptin |
| CN103787944A (en) * | 2012-11-01 | 2014-05-14 | 天津药物研究院 | Preparation method of 1-(2-chloroacetyl)-2-(S)-nitrile pyrrolidine |
| CN104311467A (en) * | 2014-09-11 | 2015-01-28 | 青岛国风药业股份有限公司 | Method and device for continuous preparation of Vildagliptin by tubular reaction |
| CN104672243A (en) * | 2015-02-10 | 2015-06-03 | 华润赛科药业有限责任公司 | Method for preparing vildagliptin degraded impurities |
Non-Patent Citations (1)
| Title |
|---|
| EDWIN B. VILLHAUER等，: ""1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: A Potent,Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties"", 《J. MED. CHEM.》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108329322A (en) * | 2018-05-10 | 2018-07-27 | 上海医药集团青岛国风药业股份有限公司 | A kind of preparation method of vildagliptin ring amidine impurity |
| CN108329322B (en) * | 2018-05-10 | 2020-02-21 | 上海医药集团青岛国风药业股份有限公司 | Preparation method of vildagliptin cyclic amidine impurity |
| CN113527309A (en) * | 2021-07-20 | 2021-10-22 | 重庆医科大学附属大学城医院 | Vildagliptin diketopiperazine and preparation method thereof |
| CN113527309B (en) * | 2021-07-20 | 2024-05-31 | 重庆医科大学附属大学城医院 | Vildagliptin diketopiperazine and preparation method thereof |
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