CN107033054A - A kind of synthetic method of vildagliptin - Google Patents
A kind of synthetic method of vildagliptin Download PDFInfo
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- CN107033054A CN107033054A CN201710464334.8A CN201710464334A CN107033054A CN 107033054 A CN107033054 A CN 107033054A CN 201710464334 A CN201710464334 A CN 201710464334A CN 107033054 A CN107033054 A CN 107033054A
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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 54
- 229960001254 vildagliptin Drugs 0.000 title claims abstract description 53
- 238000010189 synthetic method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 88
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000003368 amide group Chemical group 0.000 claims abstract description 10
- 238000009833 condensation Methods 0.000 claims abstract description 10
- 230000005494 condensation Effects 0.000 claims abstract description 10
- 125000001841 imino group Chemical group [H]N=* 0.000 claims abstract description 10
- 230000000977 initiatory effect Effects 0.000 claims abstract description 9
- 239000000463 material Substances 0.000 claims abstract description 9
- 238000005917 acylation reaction Methods 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 141
- 150000001875 compounds Chemical class 0.000 claims description 95
- 239000000243 solution Substances 0.000 claims description 62
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 22
- 235000019441 ethanol Nutrition 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical class NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 238000012545 processing Methods 0.000 claims description 16
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical class C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 238000013517 stratification Methods 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 10
- 150000008065 acid anhydrides Chemical class 0.000 claims description 9
- 239000011230 binding agent Substances 0.000 claims description 9
- 230000018044 dehydration Effects 0.000 claims description 9
- 238000006297 dehydration reaction Methods 0.000 claims description 9
- 238000010511 deprotection reaction Methods 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 238000009413 insulation Methods 0.000 claims description 7
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- 239000010446 mirabilite Substances 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 238000012544 monitoring process Methods 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 4
- 238000005292 vacuum distillation Methods 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- 239000012267 brine Substances 0.000 claims description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 2
- 150000003235 pyrrolidines Chemical class 0.000 claims description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims 6
- 230000006837 decompression Effects 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000013067 intermediate product Substances 0.000 abstract description 3
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- -1 ethyl (3 dimethylaminopropyl) Chemical group 0.000 abstract description 2
- VLLNJDMHDJRNFK-UHFFFAOYSA-N adamantan-1-ol Chemical compound C1C(C2)CC3CC2CC1(O)C3 VLLNJDMHDJRNFK-UHFFFAOYSA-N 0.000 abstract 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 abstract 2
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 description 19
- 239000001257 hydrogen Substances 0.000 description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 16
- 239000012071 phase Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 9
- 239000007791 liquid phase Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000005100 correlation spectroscopy Methods 0.000 description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 244000061458 Solanum melongena Species 0.000 description 2
- 150000001721 carbon Chemical class 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000004519 grease Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229960005382 phenolphthalein Drugs 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 1
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical compound CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 description 1
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-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
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
The present invention relates to technical field of medicine synthesis, a kind of synthetic method of vildagliptin is specifically provided.The synthetic method through imino group including using L prolineamides as initiation material, being protected, amide groups is dehydrated, is deprotected into salt using p-methyl benzenesulfonic acid obtains（S）The toluenesulfonate of 2 Cyanopyrolidines；The adamantanol of 3 amino 1 is substituted, hydrolyzes and obtains the adamantanol of 3 acetimidic acid base 1；By the adamantanol of 3 acetimidic acid base 1 with（S）Condensation acylation reaction occurs under the effect of 1 ethyl (3 dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and obtains vildagliptin for 2 Cyanopyrolidines.Reaction condition of the present invention is gentle, and intermediate product is nonhygroscopic, easy to maintain, and the vildagliptin purity of synthesis is high >=99.50%, it is maximum it is single it is miscellaneous≤0.10%.
Description
Technical field
It is to be related to a kind of synthetic method of vildagliptin more specifically the invention belongs to technical field of medicine synthesis.
Background technology
Vildagliptin chemistry is entitled：1- [[(3- hydroxy-l-adamantyls) amino] acetyl group] -2- cyano group-(S)-tetrahydrochysene
Pyrrolidines, is a kind of dipeptidyl peptidase-4 (DPP-4) inhibitor for treating diabetes B researched and developed by Switzerland's Novartis.In
September in 2007 obtains EU Committee's approval listing on the 28th.China is preferred dimension in the approval of import on the 15th of August in 2011, trade name
Pleasure/GALVUS.Vildagliptin structural formula is under：
The synthetic method of document report vildagliptin is passed through mainly using L-PROLINE or L- prolineamides as initiation material
Series reaction obtains (S) -1- chloracetyl -2- Cyanopyrolidines and then obtains target with the reaction of 3- amino-1-adamantane alcohols
Product.
The synthesis technique using L- prolineamides as initiation material of document report mainly has following several：
, Weir Hao Er etc. in 2004[1]First reported the synthetic method of this route, the route with L- prolineamides and
Chloracetyl chloride is initiation material, is substituted and obtains key intermediate (S) -1- chloracetyl -2- Cyanopyrolidines with dehydration
(5)；Again target product vildagliptin (1) is obtained with the reaction of 3- aminoadamantans alcohol.
The advantage of this method is：Route is short, and raw material is easy to get；Shortcoming is：In the step of synthesizing end-product during normal-temperature reaction
Between it is long, finished product needs chromatogram purification to be unfavorable for industrialized production.
Venkal Raman etc.[2], it was recently reported that this route, protect the active hydrogen in compound (2) on N to obtain with Boc acid anhydrides
Boc prolineamides (3), then by dehydration, substitution reaction generation (S) -1- chloracetyl -2- Cyanopyrolidines (7), afterwards and 3-
Aminoadamantan alcohol generation target product (1).
The advantage of this method is that reaction condition is gentle, and the condition such as no high temperature requirement, product purity is high, document report 99% with
On.Shortcoming is the easy moisture absorption of mesylate of (5) that are generated when compound (4) is deprotected with methanesulfonic acid, it is difficult to deposited, after influence
Continuous reaction.
Manne etc.[3]This route of report, 3- ammonia -1- adamantanols are obtained with bromoethyl acetate by substitution reaction
(3) compound (4) then, is obtained in alkaline solution reclaimed water solution, then is obtained with 2- Cyanopyrolidines using DCC/DMAP as dehydrating agent
To target product 1.
The advantage of this method is：Reactions steps are short, and reaction condition is gentle.Shortcoming is：The expensive difficulty of 2- Cyanopyrolidines
To obtain；(4) the condensation reagent DCC used when being condensed with (5) accessory substance is insoluble, is difficult to separate with product.
Graziano etc.[4]Report this route, using L- prolineamides and monoxone as initiation material, after using DCC as condensation
Agent obtains intermediate (4) by condensation reaction, and (4) occur substitution reaction with (5) and obtain intermediate (6), and (6) are through POCl3
Dehydration obtains vildagliptin.
The advantage of this method is：Reaction scheme is short；Shortcoming is：DCC accessory substance is insoluble, and intermediate (4) is difficult to purify, most
Latter step POCl3 dehydration yield is low, and only 60.1%, do not meet Atom economy.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of vildagliptin, it is intended to solves existing vildagliptin synthesis side
Intermediate product present in method is not easy to maintain, final product is difficult to separating-purifying and the problems such as not high purity.
To achieve the above object, the technical solution adopted by the present invention is：
L- prolineamides are subjected to imino group protection reaction treatment, obtain comprising structural formula as shown in Formula II compound the
One reaction solution；
Compound shown in the Formula II is subjected to amide groups dehydration processing, structural formula is obtained and changes as shown in formula III
Compound；
Compound shown in the formula III and p-methyl benzenesulfonic acid are subjected to deprotection salt-forming reaction processing, structural formula is obtained
Compound as shown in formula IV；
3- aminoadamantans alcohol is subjected to substitution reaction processing, the compound of structural formula shown as a formula V is obtained；
Reaction treatment is hydrolyzed in the compound of structural formula shown as a formula V, chemical combination of the structural formula as shown in Formula IV is obtained
Thing；
Compound of the structural formula as shown in formula IV and sodium hydroxide solution are subjected to reaction treatment, is handled through split-phase and obtains 2-
The dichloromethane solution of Cyanopyrolidine；
The temperature of dichloromethane solution of the 2- Cyanopyrolidines is controlled at 0~15 DEG C, structural formula such as Formula IV institute is added
Compound, 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, catalyst and the acid binding agent shown be condensed instead
It should handle, obtain the vildagliptin of structural formula shown in formula I；
Wherein, the compound difference shown in the Formulas I~VI is as follows：
A kind of beneficial effect of the synthetic method for vildagliptin that the present invention is provided is：
Compared with prior art, the present invention is deprotected into salt using p-methyl benzenesulfonic acid, obtains structural formula such as formula IV
(S) toluenesulfonate of -2- Cyanopyrolidines, the compound IV is nonhygroscopic, it is easy to preserve；With 1- ethyls-(3- diformazans
Base aminopropyl) phosphinylidyne diimmonium salt hydrochlorate is as the dehydrated reagent in condensation reaction, and obtained final product can be easily separated, dimension
Ge Lieting purity >=99.50%, it is maximum single it is miscellaneous≤0.10%.Reaction condition of the present invention is gentle, and intermediate product is easy to maintain, synthesis
Vildagliptin purity is high, and impurity content is low.
Brief description of the drawings
Accompanying drawing 1 is the high-efficient liquid phase chromatogram for the compound III that the embodiment of the present invention 1 is provided；
Accompanying drawing 2 is the high-efficient liquid phase chromatogram for the vildagliptin that the embodiment of the present invention 1 is provided；
Accompanying drawing 3 is the high resolution mass spec figure for the vildagliptin that the embodiment of the present invention 1 is provided；
Accompanying drawing 4 is the hydrogen spectrogram for the vildagliptin that the embodiment of the present invention 1 is provided；
Accompanying drawing 5 is the high-efficient liquid phase chromatogram for the vildagliptin that the present embodiment 2 is provided.
Embodiment
In order that technical problems, technical solutions and advantages to be solved are more clearly understood, tie below
Drawings and Examples are closed, the present invention will be described in further detail.It should be appreciated that specific embodiment described herein is only
To explain the present invention, it is not intended to limit the present invention.
L- prolineamides are subjected to imino group protection reaction treatment, obtain comprising structural formula as shown in Formula II compound the
One reaction solution；
Compound shown in the Formula II is subjected to amide groups dehydration processing, structural formula is obtained and changes as shown in formula III
Compound；
Compound shown in the formula III and p-methyl benzenesulfonic acid are subjected to deprotection salt-forming reaction processing, structural formula is obtained
Compound as shown in formula IV；
3- aminoadamantans alcohol is subjected to substitution reaction processing, the compound of structural formula shown as a formula V is obtained；
Reaction treatment is hydrolyzed in the compound of structural formula shown as a formula V, chemical combination of the structural formula as shown in Formula IV is obtained
Thing；
Compound of the structural formula as shown in formula IV and sodium hydroxide solution are subjected to reaction treatment, is handled through split-phase and obtains 2-
The dichloromethane solution of Cyanopyrolidine；
The temperature of dichloromethane solution of the 2- Cyanopyrolidines is controlled at 0~15 DEG C, structural formula such as Formula IV institute is added
Compound, 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, catalyst and the acid binding agent shown be condensed instead
It should handle, obtain the vildagliptin of structural formula shown in formula I；
Wherein, the compound difference shown in the Formulas I~VI is as follows：
Detailed explanation is done to above-mentioned building-up process below.
Specifically, the imino group protection reaction treatment is：Using L- prolineamides as initiation material, dichloromethane is molten
Agent, the mass ratio 4 of the dichloromethane and the L- prolineamides:1-6:1, addition be with the L- prolineamides mol ratio
1.2-1.6:1 triethylamine, at -15~5 DEG C, it is 1.1-1.3 to be added dropwise with the L- prolineamides mol ratio:1 Boc acid anhydrides
Dichloromethane solution, the mass concentration of the Boc acid anhydrides is 40%-60%, after time for adding is 1-2h, completion of dropping, is protected
Temperature reacts 5-10h, and holding temperature is -16~-14 DEG C, is monitored using TLC to reaction and terminates to obtain comprising compound shown in Formula II
The first reaction solution.
Preferably, the amide groups dehydration processing comprises the following steps：
Step 1：First reacting liquid temperature is reduced to less than -15.0 DEG C, triethylamine, the triethylamine and institute is added
State the mol ratio 1.2-1.6 of compound shown in Formula II:1, the dichloromethane solution of TFAA, the TFAA is added dropwise
With compound mole ratio 1.5 shown in the Formula II:1-2.0:1, the mass concentration of the TFAA is 40%-60%, drop
It is that insulation reaction 1-2h, holding temperature is -16~-14 DEG C after 2-3h, completion of dropping between added-time, using TLC monitoring display reactions
Finish；
Step 2：Purified water, washing layering are added in the solution obtained to step 1 reaction treatment；PH is adjusted with 1M hydrochloric acid
Save as 1-3, control temperature is less than 0 DEG C, stirring 30-45min, stratification；
Step 3：The brine It split-phase for being 5%-10% with mass concentration；Organic layer is dried with glauber salt, filtering, is subtracted
Pressure removes dichloromethane, obtains the compound as shown in formula III.
Preferably, the deprotection salt-forming reaction comprises the following steps：
Step 1：Compound shown in the formula III is dissolved in acetonitrile, the acetonitrile and compound shown in the formula III
Mass ratio is 3-5：1, maintain the temperature at 0-10 DEG C, add p-methyl benzenesulfonic acid, react 10-12h, monitored using TLC to anti-
It should finish；
Step 2：After completion of the reaction, -5~0 DEG C is reduced the temperature to, 2-3h is incubated, filtered, is dried, filter cake is such as formula IV
Shown compound.
Wherein, it is the p-methyl benzenesulfonic acid according to mol ratio in the reaction of the step 1：Change shown in the formula III
Compound=1.8-2.2:1.
Preferably, the 3- aminoadamantans alcohol substitution reaction comprises the following steps：
Step 1：Using 3- aminoadamantans alcohol as initiation material, dichloromethane, potassium carbonate, the dichloromethane and institute are added
The mass ratio for stating 3- aminoadamantan alcohol is 9-12：1, the mol ratio 1.0 of the potassium carbonate and the 3- aminoadamantans alcohol:1-
1.4:1, control temperature is added dropwise at -10~-5 DEG C, under stirring and the mol ratio of the 3- aminoadamantans alcohol is 1.2:
1-1.4:1 ethyl chloroacetate, time for adding is 1-2h, is monitored to reaction and finished using TLC；
Step 2：Mixed solution and dripping and the ethyl chloroacetate mass ratio 2-4 into step 1：1 water, stirring
10-15min, stratification；The saturated sodium bicarbonate solution with water homogenous quantities is added, 15-25min, stratification is stirred；
Step 3：Clean, the dry methylene chloride phase by moisture, vacuum distillation is to dry；Add the isopropyl acetate of 2-5 times of volume
Ester, rising temperature for dissolving, cooling crystallization produces the compound shown in the Formula V.
Preferably, the compound shown in the Formula V is dissolved in absolute ethyl alcohol, is warming up to 60-65 DEG C, KOH solution is added dropwise,
The mol ratio of the KOH and the compound shown in the Formula V is 1.5:1-3:1, treat that hydrolysis is finished, adjusted pH with 1M hydrochloric acid
For 4.8-5.0, suction filtration, drying, compound shown in Formula IV is obtained.
Preferably, the condensation acylation reaction comprises the following steps：
Step 1：Compound shown in the formula IV is dissolved in dichloromethane, the compound shown in the formula IV with it is described
The mass ratio of dichloromethane is 6:1-9:1,10wt% NaOH solution, drop is added dropwise at 0~15 DEG C in the temperature of control system reaction
Continue to stir 15-45min after 0.5-1h between added-time, completion of dropping, stand, split-phase；
Step 2：Handled to split-phase and anhydrous sodium sulfate drying is added in obtained dichloromethane phase to moisture 0.2wt%
Hereinafter, the dichloromethane solution of 2- Cyanopyrolidines is obtained；
Step 3：The temperature of reaction system is controlled at 0~15 DEG C, into the dichloromethane solution of the 2- Cyanopyrolidines
Add the compound shown in the Formula IV, 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, catalyst and tie up
Sour agent, reacts 1-2h, and reaction terminates rear suction filtration, dries, produces the vildagliptin of structural formula shown in formula I.
Wherein, in the reaction of the step 3, according to mol ratio, the compound shown in the formula IV：Chemical combination shown in Formula IV
Thing=1-1.2：1.In the reaction of the step 3, it is according to mol ratio, the 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne
Diimmonium salt hydrochlorate：Compound=1-1.2 shown in Formula IV:1, the catalyst：Compound=1 shown in Formula IV:10-20,
The acid binding agent：Compound=1-1.2 shown in Formula IV:1；
Wherein, the catalyst is I-hydroxybenzotriazole；The acid binding agent is triethylamine.
Condensing agent is done using 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (EDCHCL), this contracting
The advantage of mixture is that the accessory substance urea of its reaction generation of EDCHCL is water miscible, it is easy to be washed with water；With N- hydroxy benzenes
And triazole (HOBT) does acylation catalyst, the yield of condensation is improved, and HOBT is also water miscible, processing to reaction and pure
Change also relatively easy.Reaction mechanism is as follows：
For the technical scheme of the synthetic method that is better understood from a kind of vildagliptin of the invention, further below by many
Individual example is illustrated.
Embodiment 1
Concrete technology synthetic route is as follows：
Imino group protection processing reaction
Into the four-hole bottle of clean dried, L- prolineamides 22.3g (0.195mol), dichloromethane 90mL, three second are added
Amine 30.0g (0.297mol), is cooled to -15 DEG C of stirring reactions；The dichloromethane solution of Boc acid anhydrides is added dropwise into above-mentioned solution,
The Boc acid anhydrides is 0.234mol, and time for adding is 2h, insulation reaction 10h, and TLC, which is monitored to reaction, to be terminated, and obtains being included
First reaction solution of structural formula compound as shown in Formula II.
Amide groups dewater treatment comprises the following steps：
Step 1：- 15.0 DEG C will be cooled to comprising structural formula first reaction solution of compound as shown in Formula II, add three second
Amine 30.0g, is added dropwise the dichloromethane solution containing 0.357mol TFAAs (TFAA), time for adding is 2h, completion of dropping
Afterwards, insulation reaction 1h, holding temperature is -15.0 DEG C, and TLC monitorings show that reaction is finished；
Step 2：Purified water 100mL, washing layering are added in solution into step 1；PH is adjusted to 1M hydrochloric acid
1, control temperature stirs 30-45min, stratification below 0 DEG C；
Step 3：The dilute saline solution 100mL for being 5%-10% with mass concentration washs split-phase；Organic layer is dried with glauber salt,
Filtering, is removed under reduced pressure dichloromethane, obtains grease 55.0g (0.280mol), i.e. structural formula compound as shown in formula III.Will
Compound III does efficient liquid phase chromatographic analysis, and chromatogram is as shown in Figure 1.In Fig. 1, retention time is 12.403min for chemical combination
Thing III, remaining is impurity peaks, and the peak height at all peaks and peak area data list is as follows.
The compound III of table 1 efficient liquid phase chromatographic analysis
As shown in table 1, prepared compound III HPLC purity >=95.0%.
Deprotection salt-forming reaction comprises the following steps：
Step 1：By structural formula, the compound 55.0g (0.280mol) as shown in formula III is placed in the four-hole bottle of clean dried,
Using acetonitrile as solvent, add acetonitrile 150mL and dissolve compound III, maintain the temperature at less than 10 DEG C, add p-methyl benzenesulfonic acid
(P-TsOH) 106.4g (0.560mol), reacts 10h, and TLC is monitored to reaction and finished；
Step 2：After completion of the reaction, there is solid precipitation, reduce the temperature to -5 DEG C, be incubated 2h, filter, dry, filter cake is
Compound 44.9g (0.168mol) as shown in formula IV.
Imino group protection reaction, amide groups dewater treatment, deprotection salt-forming reaction three step total recovery are 86.0%, and titration contains
Amount >=98.0%, moisture≤0.50 saves backup compound IV.
Titration method is：Accurate Weigh Compound IV sample 0.2904g, are placed in 250mL triangular flasks, add water 20mL, phenol
Phthalein indicator solution 2 drips, and is titrated with 0.09496mol/L NaOH solution, is in aubergine to solution, and be corrected with blank.
The 3- aminoadamantans alcohol substitution reaction comprises the following steps：
Step 1：3- aminoadamantan alcohol 33.5g (0.200mol) are added into the four-hole bottle of clean dried, dichloro is added
Ethyl chloroacetate 29.4g is added dropwise in methane 250mL, potassium carbonate 33.2g (0.240mol), control temperature under -5 DEG C, stirring
(0.240mol), time for adding is 2h, and TLC is monitored to reaction and finished；
Step 2：Mixed solution and dripping water 100mL into step 1, stirs 15min, stratification；Add saturated carbon
Sour hydrogen sodium solution 100mL, stirs 15min, stratification；
Step 3：Clean, the dry methylene chloride phase by moisture, vacuum distillation is to dry；Add isopropyl acetate 75mL, heating
Dissolving, cooling crystallization produces compound 43.0g (0.170mol) shown as a formula V, and yield is 85.0%.
Hydrolysis：The compound V 43.0g (0.170mol) are placed in the four-hole bottle of clean dried, added anhydrous
Ethanol 400mL dissolves, and it is 2.35 to be warming up to 65 DEG C of mol ratios that KOH solution 75mL, the KOH and compound V is added dropwise:1,
Treat that hydrolysis is finished, pH is adjusted to 5.0 with 1M hydrochloric acid, suction filtration, drying, obtain compound 37.0g as shown in Formula IV
(0.165mol), yield is 97.4%.
The condensation acylation reaction comprises the following steps：
Step 1：Compound IV 45.0g (0.168mol) are placed in the four-hole bottle of clean dried, 300mL dichloros are added
Methane stirring mixing, system temperature is controlled at 0 DEG C, is added dropwise after 10wt% NaOH solution 75mL, time for adding 1h, completion of dropping
Continue to stir 30min, stand, split-phase；
Step 2：Anhydrous sodium sulfate drying is added to moisture to through the undue dichloromethane obtained to processing
Below 0.2wt%, obtains the dichloromethane solution of 2- Cyanopyrolidines；
Step 3：Temperature control system temperature adds the compound at 0 DEG C into the dichloromethane solution of 2- Cyanopyrolidines
VI 35.0g (0.155mol), dehydrated reagent 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (EDC
HCl) 32.2g (0.168mol), catalyst I-hydroxybenzotriazole (HOBT) 1.35g (0.01mol), acid binding agent TEA 17.0g
(0.168mol), reacts 1-2h, and reaction terminates rear suction filtration, dries, and produces such as structural formula I vildagliptin 45.80g, and yield is
90.0%.
Fig. 2 is the high-efficient liquid phase chromatogram of prepared vildagliptin, and wherein retention time is 5.230min to be made
Standby vildagliptin, remaining is impurity peaks.The peak height at all peaks in high-efficient liquid phase chromatogram and peak area data list is as follows.
The high performance liquid chromatography of the vildagliptin of table 2
As known from Table 2, prepared vildagliptin purity >=99.50%, it is maximum single it is miscellaneous≤0.10%.Compound IV is with changing
Compound VI does condensation reagent accessory substance using EDCHCl when being condensed and is dissolved in solvent, and product is separated out, and obtained product purity is high,
The problem of end-product is difficult to separation in solution.
The vildagliptin of above-mentioned preparation is done into high resolution mass spec analysis, as a result as shown in figure 3, mass-spectrometry analysis result
As shown in table 3.
The high resolution mass spec figure test result analysis of table 3
As known from Table 1, vildagliptin m/z measured values be 304.2018, calculated value 304.2020, error for-
0.6575ppm；Its element is constituted：C17H25N3O2, it is consistent with vildagliptin.
The vildagliptin of above-mentioned preparation is done into hydrogen spectrum to be analyzed, as shown in figure 4, hydrogen analysis of spectrum result is as shown in table 4.
The hydrogen spectrum test result of the vildagliptin of table 4
Hydrogen nuclear magnetic resonance (1H-NMR in) composing, in addition to solvent water peak (δ=4.79ppm), the integral area of each group spectral peak is total
Be shown as 23, show to have 23 protons, because-the OH in molecular formula ,-NH belong to ripple hydrogen living, they and D2Quick hand over occurs for O
Change, therefore they do not show in hydrogen spectrum, so the integrated value of hydrogen spectrum and the proton number of vildagliptin molecule coincide.Due to molecule
Various hydrogen is mutually overlapping in formula, and the peak type of each Hydrogen Proton can not be it is clear that the ownership and parsing composed to hydrogen increase difficulty
Degree, so according to1The chemical displacement value and two-dimensional spectrum integration analysis ownership of H-NMR spectrums are as follows：
Two-dimentional COSY spectrum in, δ 2.264-2.299 are related to δ 2.144-2.158, δ 2.144-2.158 and with δ 3.505-
3.669 is related, and it is Hydrogen Proton adjacent to each other to illustrate them, because they compared with low field, are meeting containing the pentacyclic Hydrogen Protons of N
Displacement study, therefore they are attributed to that 3-H is related to 4-H's and correlation of 4-H and 5-H, i.e., be 3-H, 4-H and 5-H successively.δ
4.755-4.778 has COSY related to 3-H again, and in most low field, therefore hydrogen ownership 2-H.δ 3.422-3.474 are connected with N,
Should be and related without COSY compared with low field, therefore hydrogen ownership 7-H.With reference to two-dimentional HSQC and DEPT spectral technologies, show δ 2.264-
2.299 be methine protons, therefore is attributed to 12-H and 14-H, and two hydrogen are overlapping because of magnetic eqivalence.The overlap peak respectively with δ 1.647-
1.665 have COSY related to δ 1.523, show that this overlap peak is adjacent with them respectively, are then attributed to 11-H and 13-H respectively.Hydrogen
Spectrum also shows that 11-H is overlapping with 17-H, and 12-H is overlapping with 14-H.Similarly reasoning, δ 1.523 has COSY related to 14-H, therefore the hydrogen
15-H is attributed to, hydrogen spectrum also shows that 15-H is overlapping with 16-H.δ 1.596 is related without COSY, then is attributed to 9-H.
Embodiment 2
Concrete technology synthetic route is as follows：
Imino group protection processing reaction
Into the four-hole bottle of clean dried, L- prolineamides 22.3g (0.195mol), dichloromethane 120mL, three second are added
Amine 31.5g, is cooled to -15 DEG C of stirring reactions；The dichloromethane solution of Boc acid anhydrides, the Boc acid anhydrides are added dropwise into above-mentioned solution
For 0.293mol, time for adding is 2h, insulation reaction 10h, and TLC, which is monitored to reaction, to be terminated, and obtains obtaining comprising structural formula such as formula
First reaction solution of compound shown in II.
Amide groups dewater treatment comprises the following steps：
Step 1：- 15.0 DEG C will be cooled to comprising structural formula first reaction solution of compound as shown in Formula II, add three second
Amine 31.5g, is added dropwise the dichloromethane solution containing 0.390mol TFAAs (TFAA), time for adding is 2h, completion of dropping
Afterwards, insulation reaction 1h, holding temperature is -15.0 DEG C, and TLC monitorings show that reaction is finished；
Step 2：Purified water 120mL, washing layering are added in solution into step 1；PH is adjusted to 1M hydrochloric acid
1, control temperature stirs 30-45min, stratification below 0 DEG C；
Step 3：The dilute saline solution 120mL for being 5%-10% with mass concentration washs split-phase；Organic layer is dried with glauber salt,
Filtering, is removed under reduced pressure dichloromethane, obtains grease 56.2g, i.e. the structural formula compound as shown in formula III.
Deprotection salt-forming reaction comprises the following steps：
Step 1：By structural formula, the compound 56.2g (0.287mol) as shown in formula III is placed in the four-hole bottle of clean dried,
Using acetonitrile as solvent, add acetonitrile 200mL and dissolve compound III, maintain the temperature at less than 10 DEG C, add p-methyl benzenesulfonic acid
(P-TsOH) 119.9g (0.631mol), reacts 10h, and TLC is monitored to reaction and finished；
Step 2：After completion of the reaction, there is solid precipitation, reduce the temperature to -5 DEG C, be incubated 2h, filter, dry, filter cake is
Compound 45.4g (0.169mol) as shown in formula IV.
Imino group protection reaction, amide groups dewater treatment, deprotection salt-forming reaction three step total recovery are 86.8%, and titration contains
Amount >=98.0%, moisture≤0.50% saves backup compound IV.
Titration method is：Accurate Weigh Compound IV sample 0.2904g, are placed in 250mL triangular flasks, add water 20mL, phenol
Phthalein indicator solution 2 drips, and is titrated with 0.09496mol/L NaOH solution, is in aubergine to solution, and be corrected with blank.
The 3- aminoadamantans alcohol substitution reaction comprises the following steps：
Step 1：3- aminoadamantan alcohol 33.5g (0.200mol) are added into the four-hole bottle of clean dried, dichloro is added
Ethyl chloroacetate 31.9g is added dropwise in methane 250mL, potassium carbonate 35.9g (0.260mol), control temperature under -5 DEG C, stirring
(0.260mol), time for adding is 2h, and TLC is monitored to reaction and finished；
Step 2：Mixed solution and dripping water 120mL into step 1, stirs 15min, stratification；Add saturated carbon
Sour hydrogen sodium solution 120mL, stirs 15min, stratification；
Step 3：Clean, the dry methylene chloride phase by moisture, vacuum distillation is to dry；Add isopropyl acetate 90mL, heating
Dissolving, cooling crystallization produces compound 43.5g (0.172mol) shown as a formula V, and yield is 86.0%.
Hydrolysis：The compound V 43.0g (0.170mol) are placed in the four-hole bottle of clean dried, added anhydrous
Ethanol 450mL dissolves, and it is 2.50 to be warming up to 65 DEG C of mol ratios that KOH solution 75mL, the KOH and compound V is added dropwise:1,
Treat that hydrolysis is finished, pH is adjusted to 4.8 with 1M hydrochloric acid, suction filtration, drying, obtain compound 37.5g as shown in Formula IV
(0.167mol), yield is 98.6%.
The condensation acylation reaction comprises the following steps：
Step 1：Compound IV 45.4g (0.169mol) are placed in the four-hole bottle of clean dried, 300mL dichloros are added
Methane stirring mixing, system temperature is controlled at 0 DEG C, is added dropwise after 10wt% NaOH solution 80mL, time for adding 1h, completion of dropping
Continue to stir 30min, stand, split-phase；
Step 2：Anhydrous sodium sulfate drying is added to moisture to through the undue dichloromethane obtained to processing
Below 0.2wt%, obtains the dichloromethane solution of 2- Cyanopyrolidines；
Step 3：Temperature control system temperature adds the compound at 0 DEG C into the dichloromethane solution of 2- Cyanopyrolidines
VI 36.0g (0.159mol), dehydrated reagent 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (EDC
HCl) 40.2g (0.191mol), catalyst I-hydroxybenzotriazole (HOBT) 1.50g (0.011mol), acid binding agent TEA 19.3g
(0.191mol), reacts 1-2h, and reaction terminates rear suction filtration, dries, and produces such as structural formula I vildagliptin 46.20g, and yield is
90.8%.Purity >=99.50%, it is maximum single it is miscellaneous≤0.10%.
The high-efficient liquid phase chromatogram for the vildagliptin that Fig. 5 provides for the present embodiment, wherein retention time are 5.230min's
It is for prepared vildagliptin, the peak height of vildagliptin in high-efficient liquid phase chromatogram and peak area data list is as follows.
The high performance liquid chromatography of the vildagliptin of table 5
As known from Table 5, prepared vildagliptin purity is 100%.Compound IV and compound VI is used when being condensed
EDCHCl does condensation reagent accessory substance and is dissolved in solvent, and product is separated out, and obtained product purity is high, and end-product is difficult in solution
The problem of separation.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
Any modifications, equivalent substitutions and improvements made within refreshing and principle etc., should be included in the scope of the protection.
Claims (10)
1. a kind of synthetic method of vildagliptin, it is characterised in that at least comprise the following steps：
L- prolineamides are subjected to imino group protection reaction treatment, obtain comprising structural formula as shown in Formula II compound it is first anti-
Answer liquid；
Compound shown in the Formula II is subjected to amide groups dehydration processing, structural formula compound as shown in formula III is obtained；
Compound shown in the formula III and p-methyl benzenesulfonic acid are subjected to deprotection salt-forming reaction processing, structural formula such as formula is obtained
Compound shown in IV；
3- aminoadamantans alcohol is subjected to substitution reaction processing, the compound of structural formula shown as a formula V is obtained；
Reaction treatment is hydrolyzed in the compound of structural formula shown as a formula V, compound of the structural formula as shown in Formula IV is obtained；
Compound of the structural formula as shown in formula IV and sodium hydroxide solution are subjected to reaction treatment, is handled through split-phase and obtains 2- cyano group
The dichloromethane solution of pyrrolidines；
The temperature of dichloromethane solution of the 2- Cyanopyrolidines is controlled at 0~15 DEG C, structural formula is added as shown in Formula IV
Compound, 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, catalyst and acid binding agent are carried out at condensation reaction
Reason, obtains the vildagliptin of structural formula shown in formula I；
Wherein, the compound difference shown in the Formulas I~VI is as follows：
2. a kind of synthetic method of vildagliptin according to claim 1, it is characterised in that：The deprotection salt-forming reaction
Comprise the following steps：
Step 1：Compound shown in the formula III is dissolved in acetonitrile, the acetonitrile and the quality of compound shown in the formula III
Than for 3-5：1, maintain the temperature at 0-10 DEG C, add p-methyl benzenesulfonic acid, react 10-12h, monitored using TLC to having reacted
Finish；
Step 2：After completion of the reaction, -5~0 DEG C is reduced the temperature to, 2-3h is incubated, filtered, is dried, filter cake is shown in formula IV
Compound.
3. a kind of synthetic method of vildagliptin according to claim 2, it is characterised in that：In the reaction of the step 1,
It is the p-methyl benzenesulfonic acid according to mol ratio：Compound=1.8-2.2 shown in the formula III:1.
4. a kind of synthetic method of vildagliptin according to claim 1, it is characterised in that：The condensation acylation reaction bag
Include following steps：
Step 1：Compound shown in the formula IV is dissolved in dichloromethane, the compound shown in the formula IV and the dichloro
The mass ratio of methane is 6:1-9:1, at 0~15 DEG C 10wt% NaOH solution is added dropwise, during dropwise addition in the temperature of control system reaction
Between 0.5-1h, continue after completion of dropping to stir 15-45min, stand, split-phase；
Step 2：Handled to split-phase added in obtained dichloromethane phase anhydrous sodium sulfate drying to moisture 0.2wt% with
Under, obtain the dichloromethane solution of 2- Cyanopyrolidines；
Step 3：Control the temperature of reaction system at 0~15 DEG C, added into the dichloromethane solution of the 2- Cyanopyrolidines
Compound, 1- ethyls shown in the Formula IV-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, catalyst and tie up acid
Agent, reacts 1-2h, and reaction terminates rear suction filtration, dries, produces the vildagliptin of structural formula shown in formula I.
5. a kind of synthetic method of vildagliptin according to claim 4, it is characterised in that：In the reaction of the step 3,
According to mol ratio, the compound shown in the formula IV：Compound=1-1.2 shown in Formula IV：1.
6. a kind of synthetic method of vildagliptin according to claim 4, it is characterised in that：In the reaction of the step 3,
It is according to mol ratio, the 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate：Compound shown in Formula IV=
1-1.2:1, the catalyst：Compound=1 shown in Formula IV:10-20, the acid binding agent：Compound=1- shown in Formula IV
1.2:1；
Wherein, the catalyst is I-hydroxybenzotriazole；The acid binding agent is triethylamine.
7. a kind of synthetic method of vildagliptin according to claim 1, it is characterised in that：The imino group protection reaction
It is processed as：Using L- prolineamides as initiation material, dichloromethane is solvent, the matter of the dichloromethane and the L- prolineamides
Amount compares 4:1-6:1, it is 1.2-1.6 to add with the L- prolineamides mol ratio:1 triethylamine, at -15~5 DEG C, be added dropwise with
The L- prolineamides mol ratio is 1.1-1.3:The dichloromethane solution of 1 Boc acid anhydrides, the mass concentration of the Boc acid anhydrides
For 40%-60%, after time for adding is 1-2h, completion of dropping, insulation reaction 5-10h, holding temperature is -16~-14 DEG C, is used
TLC monitors to reaction the first reaction solution for terminating to obtain and including compound shown in Formula II.
8. a kind of synthetic method of vildagliptin according to claim 1, it is characterised in that：The amide groups dehydration
Processing comprises the following steps：
Step 1：First reacting liquid temperature is reduced to less than -15.0 DEG C, triethylamine, the triethylamine and the formula is added
The mol ratio 1.2-1.6 of compound shown in II:1, the dichloromethane solution of TFAA, the TFAA and institute is added dropwise
State compound mole ratio 1.5 shown in Formula II:1-2.0:1, the mass concentration of the TFAA is 40%-60%, during dropwise addition
Between be 2-3h, after completion of dropping, insulation reaction 1-2h, holding temperature is -16~-14 DEG C, has been reacted using TLC monitoring displays
Finish；
Step 2：Purified water, washing layering are added in the solution obtained to step 1 reaction treatment；PH is adjusted to 1M hydrochloric acid
1-3, control temperature stirs 30-45min, stratification below 0 DEG C；
Step 3：The brine It split-phase for being 5%-10% with mass concentration；Organic layer is dried with glauber salt, and filtering, decompression is removed
Dichloromethane is removed, the compound as shown in formula III is obtained.
9. a kind of synthetic method of vildagliptin according to claim 1, it is characterised in that：The 3- aminoadamantans alcohol
Substitution reaction comprises the following steps：
Step 1：Using 3- aminoadamantans alcohol as initiation material, dichloromethane, potassium carbonate, the dichloromethane and the 3- are added
The mass ratio of aminoadamantan alcohol is 9-12：1, the mol ratio 1.0 of the potassium carbonate and the 3- aminoadamantans alcohol:1-1.4:
1, control temperature is added dropwise at -10~-5 DEG C, under stirring and the mol ratio of the 3- aminoadamantans alcohol is 1.2:1-
1.4:1 ethyl chloroacetate, time for adding is 1-2h, is monitored to reaction and finished using TLC；
Step 2：Mixed solution and dripping and the ethyl chloroacetate mass ratio 2-4 into step 1：1 water, stirs 10-
15min, stratification；The saturated sodium bicarbonate solution with water homogenous quantities is added, 15-25min, stratification is stirred；
Step 3：Clean, the dry methylene chloride phase by moisture, vacuum distillation is to dry；The isopropyl acetate of 2-5 times of volume is added, is risen
Temperature dissolving, cooling crystallization produces the compound shown in the Formula V.
10. a kind of synthetic method of vildagliptin according to claim 1, it is characterised in that：The hydrolysis：By institute
State the compound shown in Formula V to be dissolved in absolute ethyl alcohol, be warming up to 60-65 DEG C, KOH solution, the KOH and the Formula V institute is added dropwise
The mol ratio for the compound shown is 1.5:1-3:1, treat that hydrolysis is finished, pH is adjusted to 4.8-5.0 with 1M hydrochloric acid, it is suction filtration, dry
It is dry, obtain compound shown in Formula IV.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369779A (en) * | 2018-12-21 | 2019-02-22 | 江苏诺泰澳赛诺生物制药股份有限公司 | A kind of synthetic method of Taltirelin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011101861A1 (en) * | 2010-01-29 | 2011-08-25 | Msn Laboratories Limited | Process for preparation of dpp-iv inhibitors |
| CN106029635A (en) * | 2014-02-28 | 2016-10-12 | 海蔻有限公司 | Novel economic process for vildagliptin |
-
2017
- 2017-06-19 CN CN201710464334.8A patent/CN107033054A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011101861A1 (en) * | 2010-01-29 | 2011-08-25 | Msn Laboratories Limited | Process for preparation of dpp-iv inhibitors |
| CN106029635A (en) * | 2014-02-28 | 2016-10-12 | 海蔻有限公司 | Novel economic process for vildagliptin |
Non-Patent Citations (3)
| Title |
|---|
| JIANG WANG ER AL.: "Synthesis and biological evaluation of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives as dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| XUN JI ET AL.: "Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 杨金路等: "维格列汀的合成路线改进", 《中国新药杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369779A (en) * | 2018-12-21 | 2019-02-22 | 江苏诺泰澳赛诺生物制药股份有限公司 | A kind of synthetic method of Taltirelin |
| CN109369779B (en) * | 2018-12-21 | 2021-12-10 | 江苏诺泰澳赛诺生物制药股份有限公司 | Synthetic method of taltirelin |
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