CN106588746B - The preparation method of gliclazide side chain and the preparation method of gliclazide - Google Patents
The preparation method of gliclazide side chain and the preparation method of gliclazide Download PDFInfo
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- CN106588746B CN106588746B CN201611055674.7A CN201611055674A CN106588746B CN 106588746 B CN106588746 B CN 106588746B CN 201611055674 A CN201611055674 A CN 201611055674A CN 106588746 B CN106588746 B CN 106588746B
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- ruthenium
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- transition metal
- gliclazide
- azabicyclo
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- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical group C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 229960000346 gliclazide Drugs 0.000 title claims abstract description 28
- 239000003054 catalyst Substances 0.000 claims abstract description 97
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 69
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 67
- 239000002253 acid Substances 0.000 claims abstract description 48
- 150000003949 imides Chemical class 0.000 claims abstract description 43
- 150000003624 transition metals Chemical group 0.000 claims abstract description 38
- FJYWNYLUZBMVKI-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-amine Chemical compound C1CCC2CN(N)CC21 FJYWNYLUZBMVKI-UHFFFAOYSA-N 0.000 claims abstract description 19
- 230000009467 reduction Effects 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 35
- 238000003756 stirring Methods 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 150000003303 ruthenium Chemical class 0.000 claims description 31
- 239000012043 crude product Substances 0.000 claims description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 22
- WPYNXKFLSQEEFE-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-amine;hydrochloride Chemical compound Cl.C1CCC2CN(N)CC21 WPYNXKFLSQEEFE-UHFFFAOYSA-N 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 17
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 16
- 239000002250 absorbent Substances 0.000 claims description 16
- 230000002745 absorbent Effects 0.000 claims description 16
- 239000003610 charcoal Substances 0.000 claims description 16
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 14
- 239000012065 filter cake Substances 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 14
- 239000012046 mixed solvent Substances 0.000 claims description 14
- 229910052750 molybdenum Inorganic materials 0.000 claims description 14
- 230000004044 response Effects 0.000 claims description 14
- 230000006837 decompression Effects 0.000 claims description 13
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 12
- 229910052702 rhenium Inorganic materials 0.000 claims description 12
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 claims description 12
- 229910052721 tungsten Inorganic materials 0.000 claims description 12
- 229910052720 vanadium Inorganic materials 0.000 claims description 12
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 claims description 12
- 230000002378 acidificating effect Effects 0.000 claims description 11
- 238000011084 recovery Methods 0.000 claims description 11
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 claims description 11
- 229910052723 transition metal Inorganic materials 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 239000011733 molybdenum Substances 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 229910017052 cobalt Inorganic materials 0.000 claims description 8
- 239000010941 cobalt Substances 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 239000010937 tungsten Substances 0.000 claims description 7
- 238000010521 absorption reaction Methods 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 5
- 239000012266 salt solution Substances 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 239000002105 nanoparticle Substances 0.000 claims description 4
- 229910021524 transition metal nanoparticle Inorganic materials 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052737 gold Inorganic materials 0.000 claims description 2
- 239000010931 gold Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 230000007704 transition Effects 0.000 claims description 2
- PRZPIHOVOJPUHS-UHFFFAOYSA-N 2-amino-4,5,6,6a-tetrahydro-3aH-cyclopenta[c]pyrrole-1,3-dione Chemical compound C1CCC2C(=O)N(N)C(=O)C21 PRZPIHOVOJPUHS-UHFFFAOYSA-N 0.000 claims 1
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 17
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 4
- 239000002351 wastewater Substances 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- 238000012805 post-processing Methods 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000008367 deionised water Substances 0.000 description 25
- 229910021641 deionized water Inorganic materials 0.000 description 25
- 230000000694 effects Effects 0.000 description 18
- 239000000047 product Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000004817 gas chromatography Methods 0.000 description 11
- 239000013558 reference substance Substances 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 9
- 239000012279 sodium borohydride Substances 0.000 description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 description 9
- 230000004048 modification Effects 0.000 description 8
- 238000012986 modification Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000004064 recycling Methods 0.000 description 6
- 229940058641 actidose Drugs 0.000 description 5
- 238000013019 agitation Methods 0.000 description 5
- 238000000643 oven drying Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- -1 cyclopentane dicarboxylic acid acid anhydride Chemical class 0.000 description 4
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000004280 Sodium formate Substances 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- UFMZWBIQTDUYBN-UHFFFAOYSA-N cobalt dinitrate Chemical compound [Co+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O UFMZWBIQTDUYBN-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 3
- 235000019254 sodium formate Nutrition 0.000 description 3
- QCWDCTDYSDJKTP-UHFFFAOYSA-N 4,5,6,6a-tetrahydro-3ah-cyclopenta[c]pyrrole-1,3-dione Chemical compound C1CCC2C(=O)NC(=O)C21 QCWDCTDYSDJKTP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 229910003206 NH4VO3 Inorganic materials 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 229910003091 WCl6 Inorganic materials 0.000 description 2
- NLMBNVBBHYNBQY-UHFFFAOYSA-N [C].[Ru] Chemical class [C].[Ru] NLMBNVBBHYNBQY-UHFFFAOYSA-N 0.000 description 2
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 2
- 229940010552 ammonium molybdate Drugs 0.000 description 2
- 235000018660 ammonium molybdate Nutrition 0.000 description 2
- 239000011609 ammonium molybdate Substances 0.000 description 2
- UNTBPXHCXVWYOI-UHFFFAOYSA-O azanium;oxido(dioxo)vanadium Chemical compound [NH4+].[O-][V](=O)=O UNTBPXHCXVWYOI-UHFFFAOYSA-O 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 229910010277 boron hydride Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002910 solid waste Substances 0.000 description 2
- YOUIDGQAIILFBW-UHFFFAOYSA-J tetrachlorotungsten Chemical compound Cl[W](Cl)(Cl)Cl YOUIDGQAIILFBW-UHFFFAOYSA-J 0.000 description 2
- KPGXUAIFQMJJFB-UHFFFAOYSA-H tungsten hexachloride Chemical compound Cl[W](Cl)(Cl)(Cl)(Cl)Cl KPGXUAIFQMJJFB-UHFFFAOYSA-H 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 229910019626 (NH4)6Mo7O24 Inorganic materials 0.000 description 1
- 229910003208 (NH4)6Mo7O24·4H2O Inorganic materials 0.000 description 1
- TUYIHOJSSJJFMO-UHFFFAOYSA-N 2,3,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-3a-amine Chemical compound C1CCC2CNCC21N TUYIHOJSSJJFMO-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- NGIISMJJMXRCCT-UHFFFAOYSA-N [Ru].[N+](=O)(O)[O-] Chemical compound [Ru].[N+](=O)(O)[O-] NGIISMJJMXRCCT-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GHDLZGOOOLEJKI-UHFFFAOYSA-N benzenesulfonylurea Chemical compound NC(=O)NS(=O)(=O)C1=CC=CC=C1 GHDLZGOOOLEJKI-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 229910001981 cobalt nitrate Inorganic materials 0.000 description 1
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- OQUOOEBLAKQCOP-UHFFFAOYSA-N nitric acid;hexahydrate Chemical compound O.O.O.O.O.O.O[N+]([O-])=O OQUOOEBLAKQCOP-UHFFFAOYSA-N 0.000 description 1
- 230000009935 nitrosation Effects 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- DKNJHLHLMWHWOI-UHFFFAOYSA-L ruthenium(2+);sulfate Chemical compound [Ru+2].[O-]S([O-])(=O)=O DKNJHLHLMWHWOI-UHFFFAOYSA-L 0.000 description 1
- OJLCQGGSMYKWEK-UHFFFAOYSA-K ruthenium(3+);triacetate Chemical compound [Ru+3].CC([O-])=O.CC([O-])=O.CC([O-])=O OJLCQGGSMYKWEK-UHFFFAOYSA-K 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a kind of preparation methods of gliclazide side chain N- amino-3-azabicyclo [3.3.0] octane, are obtained with the modified one step hydrogenating reduction N- Aminocyclopentane acid imide of ruthenium C catalyst of transition metal atoms.Modified ruthenium C catalyst catalytic activity used in the present invention is significantly higher than existing business ruthenium C catalyst, and the acid imide hydrogenation reaction being difficult to realize in N- Aminocyclopentane acid imide can be made to go on smoothly.The preparation method of gliclazide side chain of the present invention, safe and efficient, high income, post-processing is simple, and catalyst is recyclable to be applied, and is significantly reduced production cost, has been accomplished green syt substantially, generates without waste water, waste residue, is especially suitable for large-scale industrial production.The invention further relates to a kind of production method of gliclazide, there are the advantages such as short synthetic route, high income, preparation cost be low.
Description
Technical field
The present invention relates to a kind of new preparation process of diabetes medicament gliclazide side chain, and in particular among gliclazide
The new preparation process of body N- amino-3-azabicyclo [3.3.0] octane, the invention further relates to a kind of preparation sides of gliclazide
Method belongs to technical field of organic synthesis.
Background technique
Gliclazide (Gliclazide) is second generation sulfonylurea oral hypoglycemic drug, can be effectively reduced blood glucose and change
Kind coagulation function, especially suitable for the Non-Insulin Dependent Diabetes Mellitus patient of various hypotypes, and side effect is smaller.With me
The increasingly raising of state's living standards of the people, diabetes receive much attention as a kind of rich people's disease, and research antidiabetic drugs have very
Important practical significance.
The synthesis of gliclazide, it is crucial that the synthesis of its side chain N- amino-3-azabicyclo [3.3.0] octane.Mesh
Before, the production technology of gliclazide side chain is outmoded, and pollution is big, and the three wastes are more, higher cost, and gliclazide finished medicines price is caused to occupy
It is high not under.Synthesis gliclazide side chain N- amino-3-azabicyclo [3.3.0] octane is mainly the following route at present:
1. Japan Patent (publication number JP05065270 and JP06041073), disclose it is a kind of use Tetrahydrocyclopenta(c)pyrrole-1,3(2H,3aH)-dione for
Raw material by reduction, nitrosation and zinc powder reduction and etc. obtain target product:
This method is the traditional and classical production method of comparison, domestic at present all to be produced using this method.But the producer
In method, the reduction difficulty of Tetrahydrocyclopenta(c)pyrrole-1,3(2H,3aH)-dione is larger, the prices such as used reducing agent lithium aluminium hydride reduction and alkali metal borohydride
Costly, and explosion is easily caused, all there is biggish danger in transport and use.
2. Chinese patent (publication number CN101235011) mainly uses cyclopentane dicarboxylic acid acid anhydride for raw material, with hydrazine reaction
Synthesize N- Aminocyclopentane acid imide.The patent has been briefly mentioned following route:
But the imido reduction of N- Aminocyclopentane, it is still necessary to it is more high to use the prices such as potassium borohydride and lewis acid
Go back original reagent that is expensive and having certain danger.
3. Chinese patent (publication number CN102584677), synthetic route are as follows:
The route uses N- Aminocyclopentane acid imide for raw material, with zinc-copper catalyst in high temperature (200-250 DEG C), high pressure
Hydrogenation reaction obtains gliclazide side chain under the conditions of (15MPa).However the main defect of this method is severe reaction conditions, to setting
Standby to require height, energy consumption is high, and production risk is bigger, is unfavorable for keeping the safety in production, industrialization difficulty is larger.In addition, in this method
Catalyst cannot effectively recycling and reusing, disposable cost is too high.
Therefore, research and develop a kind of new method for producing gliclazide side chain, reduce production cost, so provide a kind of green,
The gliclazide production method of safety, becomes gliclazide preparation field one of technical problem in the urgent need to address.
Summary of the invention
The object of the present invention is to provide the new methods of a kind of new method for synthesizing gliclazide side chain and synthesis gliclazide.
This method simple process, safety, convenient for operation, high income, low in cost and lossless environment.
The present invention provides a kind of preparation sides of gliclazide side chain N- amino-3-azabicyclo [3.3.0] octane (I)
Method, comprising: with the modified ruthenium C catalyst of transition metal atoms, hydrogenating reduction N- Aminocyclopentane acid imide (II) prepares N- ammonia
Base -3- azabicyclo [3.3.0] octane (I)
One according to the present invention specific but non-limiting embodiment, wherein the modified ruthenium carbon of transition metal atoms
Catalyst includes: absorbent charcoal carrier, and ruthenium nano particle and transition metal nanoparticles are loaded on absorbent charcoal carrier.
One according to the present invention specific but non-limiting embodiment, wherein transition metal be molybdenum, tungsten, vanadium, rhenium or
At least one of cobalt.
One according to the present invention specific but non-limiting embodiment, wherein ruthenium atom accounts for the quality hundred of catalyst
Divide than being 3%~10%, the mole of transition metal atoms is the 1/16~1/4 of ruthenium atom mole.
One according to the present invention specific but non-limiting embodiment, which comprises by N- Aminocyclopentane
Acid imide is dissolved in acidic aqueous solution, and the modified ruthenium C catalyst of transition metal atoms is added, Hydrogen Vapor Pressure be 6~
9MPa is restored 16~20 hours under conditions of temperature is 90~140 DEG C, generates N- amino-3-azabicyclo [3.3.0] octane.
One according to the present invention specific but non-limiting embodiment, the method further includes: reaction is completed
Afterwards, it is cooled to room temperature, pressure release, filtering, filter cake ruthenium C catalyst set is for reaction next time, filtrate decompression concentration, recovery acid water jacket
For lower secondary response, it is concentrated to get N- amino-3-azabicyclo [3.3.0] octane crude product, crude product HCl treatment passes through first
Benzene-alcohol mixed solvent recrystallization, is filtered, and drying obtains N- amino-3-azabicyclo [3.3.0] octane hydrochloride.
One according to the present invention specific but non-limiting embodiment, wherein catalysis acid is acetic acid, phosphoric acid, sulfuric acid
Or at least one of methanesulfonic acid.
One according to the present invention specific but non-limiting embodiment, wherein sour mole is N- amino cyclopentyl
1~3 times of alkane acid imide mole.
One according to the present invention specific but non-limiting embodiment, wherein Hydrogen Vapor Pressure is 8~9Mpa, reduction
Temperature is 120~130 DEG C.
One according to the present invention specific but non-limiting embodiment, wherein the quality of catalyst is N- amino ring
The 10~30% of pentane acid imide quality.
One according to the present invention specific but non-limiting embodiment, wherein the modified ruthenium carbon of transition metal atoms
The preparation of catalyst the following steps are included:
By absorbent charcoal carrier and ruthenium solution mixing and absorption；
A certain amount of transition metal salt solution is added, continues stirring and adsorbing 1~3 hour；
Reducing agent solution is added to restore 1~3 hour；
After reaction, it filters, washs, it is dry, obtain the modified ruthenium C catalyst of transition metal atoms.
The present invention also provides a kind of preparation methods of gliclazide, comprising: prepares gliclazide side chain in aforementioned manners
N- amino-3-azabicyclo [3.3.0] octane (I), by N- amino-3-azabicyclo [3.3.0] octane (I) obtained and to first
Benzene sulfonylurea reaction, prepares gliclazide.
The beneficial effects are mainly reflected as follows:
1. the present invention using N- Aminocyclopentane acid imide as raw material, is catalyzed with the modified high activity ruthenium carbon of transition metal atoms
One step of agent adds hydrogen to obtain gliclazide side chain N- amino-3-azabicyclo [3.3.0] octane.Modified ruthenium carbon used in the present invention
Catalyst activity is significantly higher than existing business ruthenium C catalyst, can make the acyl being difficult to realize in N- Aminocyclopentane acid imide
Imines hydrogenation reaction is gone on smoothly.
2. the production method of gliclazide side chain of the invention, hydrogenation reaction temperature is low, and Hydrogen Vapor Pressure is low, safe and efficient；
Process route is short, and yield is up to 90% or so；Post-processing is simple, and catalyst can apply (recyclings) 20 times or more, sour water steaming
After evaporating be recycled apply, accomplished green syt substantially, without waste water,
Waste residue generates, and avoids in existing production method and is generated largely using reduction such as boron hydride, lithium aluminium hydride reduction, zinc powders
Solid waste and waste water are suitble to large-scale industrial production.
3. the production method of gliclazide of the invention, synthetic route is short, high income, significantly reduces preparation cost, system
The gliclazide drug obtained has more price advantage.
Specific embodiment
Provided hereinafter specific embodiments to further illustrate the present invention, but the present invention is not limited only to implementation below
Mode.
To achieve the above object, inventor is by constantly the study found that using Green Kai Mo company's independent research manufacture
The modified special ruthenium C catalyst of transition metal atoms, can make the acid imide being difficult to realize in N- Aminocyclopentane acid imide add hydrogen
Reaction is gone on smoothly, and adds hydrogen to produce gliclazide side chain by one step of N- Aminocyclopentane acid imide to realize, and obtain
90% or so high yield.This method is not only avoided in existing production method and is urged using boron hydride, lithium aluminium hydride reduction, zinc powder etc.
Agent reduction leads to the problem of a large amount of solid wastes and waste water, and catalyst can significantly reduce production cost with recycling and reusing.
Gliclazide is produced with this method, not only synthetic route is short, high income, post-processes simply, but also production cost is low, more price
Advantage efficiently solves the problems of the prior art.
The present invention provides a kind of preparation method of gliclazide side chain N- amino-3-azabicyclo [3.3.0] octane (I),
With N- Aminocyclopentane acid imide (II) for raw material, hydrogen is added to obtain with modified one step of high activity ruthenium C catalyst of transition metal atoms
To gliclazide side chain (I), it is specific the preparation method is as follows:
N- Aminocyclopentane acid imide (II) is dissolved in acidic aqueous solution, it is living that the modified height of transition metal atoms is added
Property ruthenium C catalyst, Hydrogen Vapor Pressure be 6~9MPa, temperature be 90~140 DEG C under conditions of, restore 16~20 hours, generate
N- amino-3-azabicyclo [3.3.0] octane (I).It is cooled to room temperature later, pressure release is filtered, and filter cake ruthenium C catalyst can be applied
(recycling) in lower secondary response, filtrate decompression concentration, sour water recycles usually after distilling can cover for reaction next time, be concentrated to give
To gliclazide side chain crude product, crude product HCl treatment is recrystallized by toluene-ethano mixed solvent, is filtered, and drying obtains
N- amino-3-azabicyclo [3.3.0] octane hydrochloride.
Wherein, catalysis acid can be acetic acid, phosphoric acid, sulfuric acid or methanesulfonic acid etc., preferably acetic acid.It is catalyzed in acid condition,
Acid can allow ruthenium to keep activity, be not passivated by nitrogenous compound.The mole of acid can be N- Aminocyclopentane acid imide mole
1~3 times of amount.
Use water as solvent, the quality of water can be imido 2~4 times of N- Aminocyclopentane.
Preferably, Hydrogen Vapor Pressure is 8~9Mpa, reduction temperature is 120~130 DEG C.
The quality of catalyst can be the 10~30% of N- Aminocyclopentane acid imide quality.
Ruthenium C catalyst used in the present invention is the high activity ruthenium carbon catalysis by Green Kai Mo company's independent research manufacture
Agent, comprising: absorbent charcoal carrier loads ruthenium nano particle and transition metal nanoparticles on absorbent charcoal carrier.Wherein, transition gold
Belong at least one of preferred molybdenum, tungsten, vanadium, rhenium or cobalt.The mass percent that ruthenium atom accounts for catalyst is 3wt%~10wt%.
The mole of transition metal atoms can be the 1/16~1/4 of ruthenium atom mole.The high activity ruthenium C catalyst of the modification is
The defending party to the application applies for a patent, application number: 201611030379.6, a kind of denomination of invention: high activity that transition metal atoms are modified
Ruthenium C catalyst and preparation method thereof, is cited in full text herein.
The high activity ruthenium C catalyst of the modification can be prepared by following methods:
(1) by absorbent charcoal carrier and ruthenium solution mixing and absorption；
(2) a certain amount of transition metal salt solution is added, continues stirring and adsorbing 1~3 hour；
(3) reducing agent solution is added to restore 1~3 hour；
(4) after reaction, it filters, is washed with deionized to weakly acidic pH, it is dry, obtain what transition metal atoms were modified
Ruthenium C catalyst.
Wherein, in step (1), ruthenium solution is soluble ruthenium solution, such as ruthenic chloride, ruthenium sulfate, three nitric acid Ruthenium nitrosyls
Or ruthenium acetate solution etc..The mass percent that catalyst is accounted for according to ruthenium atom is 3wt%~10wt%, and the ruthenium for preparing corresponding amount is molten
Liquid.
In step (2), transition metal salt solution is preferably the soluble-salt of at least one of molybdenum, tungsten, vanadium, rhenium or cobalt metal
Solution, such as ammonium molybdate solution ((NH4)6Mo7O24), tungsten chloride solution (WCl6), Ammonium Vanadate Solution (NH4VO3), ammonium perrhenate solution
(NH4ReO4) or cobalt nitrate solution (Co (NO3)2) etc..The mole of transition metal atoms can be the 1/16 of ruthenium atom mole
~1/4.Reducing agent can be sodium borohydride or sodium formate.Reducing agent should be suitably excessive, and ruthenium solution and transition metal salt is molten
Liquid restores completely to be advisable.
The high activity ruthenium C catalyst of the modification enables its catalytic activity substantially to mention by the way that transition metal atoms are added
It rises, has broken the activity limitation bottleneck of traditional ruthenium C catalyst, shown the catalytic activity more much higher than business ruthenium C catalyst.
The modified reason for effectively improving ruthenium C catalyst activity of transition metal atoms may be: after transition metal atoms incorporation, on the one hand
Reaction substrate is increased in the absorption on its surface, is on the other hand that transition metal atoms and ruthenium atom generate synergistic effect, changes
The electronic structure of ruthenium atom is conducive to activate hydrogen.By a large amount of experimental study, inventor found out molybdenum, tungsten, vanadium,
Rhenium or cobalt are several very effective modified metal atoms and above-mentioned method of modifying.
One step hydrogenation synthesis gliclazide side chain N- of N- Aminocyclopentane acid imide is catalyzed with the ruthenium C catalyst of the modification
Amino-3-azabicyclo [3.3.0] octane, is not only achieved the acid imide hydrogenation reaction being difficult to realize, obtains 90%
The high-purity of the high yield and 99% of left and right or more, and catalyst can be applied 20 times or more, also be recycled set after sour water distillation
With, be truly realized green, safety synthesis.
N- amino-3-azabicyclo [3.3.0] octane (I) made from the above method is further anti-with tolylsulfonylurea
It answers, synthesizes gliclazide, specific reaction is as follows:
N- amino-3-azabicyclo [3.3.0] octane hydrochloride made from the above method and tolylsulfonylurea are massaged
You are added in toluene than 1:1~1.5, are heated to reflux to fully reacting；It depressurizes rotary evaporation and removes toluene, water, room temperature analysis is added
Crystalline substance filters, and solid is washed with water, re-crystallizing in ethyl acetate, and 70~90 DEG C of vacuum drying obtain gliclazide product.
The present invention is using N- Aminocyclopentane acid imide as raw material, with the modified high activity ruthenium C catalyst of transition metal atoms
One step adds hydrogen to obtain gliclazide side chain N- amino-3-azabicyclo [3.3.0] octane, and life is then reacted with tolylsulfonylurea
At the route of gliclazide, have short synthetic route, high income, post-processing simple, the advantages such as preparation cost is low are especially suitable for big
Technical scale metaplasia produces.
The present invention is further elaborated combined with specific embodiments below, but the present invention is not limited to following embodiments.
Above and experimental method used in following embodiments is conventional method unless otherwise specified.
Above and the materials, reagents and the like used in the following examples, be commercially available unless otherwise specified or
It is prepared with known conventional method.
Embodiment 1
(1) preparation of the modified ruthenium C catalyst of molybdenum atom
47.26kg active carbon powder is weighed to be scattered in 200L deionized water；Tri- chloride hydrate ruthenium of 6.723kg is weighed, it is molten
Solution is in 100L deionized water；Under agitation, the two is mixed, is adsorbed 1 hour；Weigh 1.911kg ammonium molybdate solid
((NH4)6Mo7O24·4H2O), it is dissolved in 50L deionized water, is gradually added under stirring condition in above-mentioned Actidose；It stirs
After mixing absorption 1 hour, it is gradually added into sodium borohydride aqueous solution (1.2kg sodium borohydride is dissolved in 100L deionized water), at room temperature
After reaction 1 hour, filter, clean 5 times to weakly acidic pH with deionized water, 80 DEG C oven drying 12 hours, obtain molybdenum atom modification
Ruthenium C catalyst, wherein the mass percentage of ruthenium is 5wt%, and the mass percentage of molybdenum is that 2wt% (presses the total matter of catalyst
Meter).It can be seen that, the particle that about 5 nanometers of size is uniformly distributed on absorbent charcoal carrier from TEM electron microscope.
(2) preparation of gliclazide side chain
In 20L there-necked flask, N- Aminocyclopentane acid imide 4kg, acetic acid 3L, water 10L, stirring and dissolving, in addition is added
State modified ruthenium C catalyst (ruthenium content: 5wt%, molybdenum content: 2wt%) 600g of molybdenum atom of preparation.Under stirring, vacuum suck
In 20L autoclave.It is that 8MPa reacts 20 hours under conditions of temperature is 130 DEG C in Hydrogen Vapor Pressure.It is cooled to room temperature, pressure release,
Filtering.Filter cake ruthenium C catalyst set is for reaction next time.Filtrate decompression concentration, recovery of acetic acid water jacket are used for lower secondary response.Concentration
Obtain gliclazide side chain crude product about 4.2kg.Crude product HCl treatment is recrystallized by toluene-ethano mixed solvent, filtering,
Drying, obtains N- amino-3-azabicyclo [3.3.0] octane hydrochloride 3.8kg, purity 99.6% (GC), yield: 89%.Institute
It is consistent with reference substance (GC analysis) to obtain product.
(3) catalyst is applied
In 20L there-necked flask, N- Aminocyclopentane acid imide 4kg, acetic acid 3L, water 10L is added, stirring and dissolving is added back
600g (has been recycled 6 times) in the modified ruthenium C catalyst of the molybdenum atom of receipts under the same reaction conditions.Under stirring, vacuum is inhaled
Enter in 20L autoclave.It is that 8MPa reacts 16 hours under conditions of temperature is 140 DEG C in Hydrogen Vapor Pressure.It is cooled to room temperature, is let out
Pressure, filtering.Filter cake ruthenium C catalyst set is for reaction next time.Filtrate decompression concentration, recovery of acetic acid water jacket are used for lower secondary response.It is dense
Contracting obtains gliclazide side chain crude product about 4.1kg.Crude product HCl treatment is recrystallized, mistake by toluene-ethano mixed solvent
Filter, drying, obtains N- amino-3-azabicyclo [3.3.0] octane hydrochloride 3.9kg, purity 99.7% (GC), yield: 91%.
Products obtained therefrom is consistent with reference substance (GC analysis).
As it can be seen that catalyst still keeps very high activity after applying repeatedly.
Embodiment 2
In 500L autoclave, N- Aminocyclopentane acid imide 100kg, acetic acid 70L, water 250L is added, stirring and dissolving adds
Enter modified ruthenium C catalyst (ruthenium content: 5wt%, molybdenum content: 2wt%) 15kg of molybdenum atom of embodiment 1 (1) preparation.Control hydrogen
Atmospheric pressure is that 8MPa reacts 20 hours under conditions of temperature is 135 DEG C.It is cooled to room temperature, pressure release, filtering.The catalysis of filter cake ruthenium carbon
Agent set is for reaction next time.Filtrate is transferred to concentration kettle reduced pressure, and recovery of acetic acid water jacket is used for lower secondary response.It is concentrated to get lattice
Lie Qite side chain crude product about 114kg.HCl treatment is added, toluene-ethano mixed solvent recrystallization is then added, centrifuge is got rid of
Material, drying, obtains N- amino-3-azabicyclo [3.3.0] octane hydrochloride 97.7kg, purity 99.7% (GC), yield:
92%.Products obtained therefrom is consistent with reference substance (GC analysis).
Embodiment 3
(1) preparation of the modified ruthenium C catalyst of tungsten atom
47.26kg active carbon powder is weighed to be scattered in 200L deionized water；Tri- chloride hydrate ruthenium of 6.723kg is weighed, it is molten
Solution is in 100L deionized water；Under agitation, the two is mixed, is adsorbed 1 hour；Weigh 1kg tungsten chloride solid (WCl6),
It is dissolved in 50L deionized water, is gradually added under stirring condition in above-mentioned Actidose；After stirring and adsorbing 1 hour, gradually plus
Enter aqueous sodium formate solution (2kg sodium formate is dissolved in 100L deionized water), after being reacted 1 hour at 80 DEG C, filters, use deionized water
Cleaning 5 times to weakly acidic pH, 80 DEG C oven drying 12 hours, obtain the modified ruthenium C catalyst of tungsten atom, wherein the quality hundred of ruthenium
Dividing content is 5wt%, and the mass percentage of tungsten is 0.9wt% (based on catalyst gross mass).It can from TEM electron microscope
It arrives, the particle that about 8 nanometers of size is uniformly distributed on absorbent charcoal carrier.
(2) preparation of gliclazide side chain
In 20L there-necked flask, N- Aminocyclopentane acid imide 4kg, acetic acid 4L, water 15L, stirring and dissolving, in addition is added
State modified ruthenium C catalyst (ruthenium content: 5wt%, W content: 0.9wt%) 700g of tungsten atom of preparation.Under stirring, vacuum suck
In 20L autoclave.It is that 9MPa reacts 17 hours under conditions of temperature is 130 DEG C in Hydrogen Vapor Pressure.It is cooled to room temperature, pressure release,
Filtering.Filter cake ruthenium C catalyst set is for reaction next time.Filtrate decompression concentration, recovery of acetic acid water jacket are used for lower secondary response.Concentration
Obtain gliclazide side chain crude product about 4.7kg.Crude product HCl treatment is recrystallized by toluene-ethano mixed solvent, filtering,
Drying, obtains N- amino-3-azabicyclo [3.3.0] octane hydrochloride 4kg, purity 99.5% (GC), yield: 94%.Gained
Product is consistent with reference substance (GC analysis).
(3) catalyst is applied
In 20L there-necked flask, N- Aminocyclopentane acid imide 4kg, acetic acid 4L, water 15L is added, stirring and dissolving is added back
700g (has been recycled 6 times) in the modified ruthenium C catalyst of the tungsten atom of receipts under the same reaction conditions.Under stirring, vacuum is inhaled
Enter in 20L autoclave.It is that 9MPa reacts 16 hours under conditions of temperature is 140 DEG C in Hydrogen Vapor Pressure.It is cooled to room temperature, is let out
Pressure, filtering.Filter cake ruthenium C catalyst set is for reaction next time.Filtrate decompression concentration, recovery of acetic acid water jacket are used for lower secondary response.It is dense
Contracting obtains gliclazide side chain crude product about 4.8kg.Crude product HCl treatment is recrystallized, mistake by toluene-ethano mixed solvent
Filter, drying, obtains N- amino-3-azabicyclo [3.3.0] octane hydrochloride 4.1kg, purity 99.4% (GC), yield: 96%.
Products obtained therefrom is consistent with reference substance (GC analysis).
As it can be seen that catalyst still keeps very high activity after applying repeatedly.
Embodiment 4
(1) preparation of the modified ruthenium C catalyst of vanadium atom
47.5kg active carbon powder is weighed to be scattered in 200L deionized water；Tri- chloride hydrate ruthenium of 6.47kg is weighed, is dissolved
In 100L deionized water；Under agitation, the two is mixed, is adsorbed 1 hour；Weigh 0.3kg ammonium vanadate solid
(NH4VO3), it is dissolved in 50L deionized water, is gradually added under stirring condition in above-mentioned Actidose；Stirring and adsorbing 1 hour
Afterwards, it is gradually added into sodium borohydride aqueous solution (1.2kg sodium borohydride is dissolved in 100L deionized water), after reacting 1 hour at room temperature,
Filter, clean 5 times to weakly acidic pH with deionized water, 80 DEG C oven drying 12 hours, obtain the ruthenium C catalyst of vanadium atom modification,
Wherein the mass percentage of ruthenium is 5wt%, and the mass percentage of vanadium is 0.26wt% (based on catalyst gross mass).From
It can be seen that, the particle that about 10 nanometers of size is uniformly distributed on absorbent charcoal carrier in TEM electron microscope.
(2) preparation of gliclazide side chain
In 20L there-necked flask, N- Aminocyclopentane acid imide 4kg, methanesulfonic acid 5L, water 8L, stirring and dissolving, in addition is added
State modified ruthenium C catalyst (ruthenium content: 5wt%, content of vanadium: 0.26wt%) 650g of vanadium atom of preparation.Under stirring, vacuum is inhaled
Enter in 20L autoclave.It is that 6MPa reacts 20 hours under conditions of temperature is 130 DEG C in Hydrogen Vapor Pressure.It is cooled to room temperature, is let out
Pressure, filtering.Filter cake ruthenium C catalyst set is for reaction next time.Filtrate decompression concentration, recycling methanesulfonic acid water jacket are used for lower secondary response.
It is concentrated to get gliclazide side chain crude product about 4.1kg.Crude product HCl treatment is recrystallized, mistake by toluene-ethano mixed solvent
Filter, drying, obtains N- amino-3-azabicyclo [3.3.0] octane hydrochloride 3.9kg, purity 99.4% (GC), yield: 92%.
Products obtained therefrom is consistent with reference substance (GC analysis).
(3) catalyst is applied
In 20L there-necked flask, N- Aminocyclopentane acid imide 4kg, methanesulfonic acid 5L, water 8L is added, stirring and dissolving is added back
650g (has been recycled 6 times) in the modified ruthenium C catalyst of the vanadium atom of receipts under the same reaction conditions.Under stirring, vacuum is inhaled
Enter in 20L autoclave.It is that 7MPa reacts 19 hours under conditions of temperature is 130 DEG C in Hydrogen Vapor Pressure.It is cooled to room temperature, is let out
Pressure, filtering.Filter cake ruthenium C catalyst set is for reaction next time.Filtrate decompression concentration, recycling methanesulfonic acid water jacket are used for lower secondary response.
It is concentrated to get gliclazide side chain crude product about 4.3kg.Crude product HCl treatment is recrystallized, mistake by toluene-ethano mixed solvent
Filter, drying, obtains N- amino-3-azabicyclo [3.3.0] octane hydrochloride 4kg, purity 99.2% (GC), yield: 94%.Institute
It is consistent with reference substance (GC analysis) to obtain product.
As it can be seen that catalyst still keeps very high activity after applying repeatedly.
Embodiment 5
(1) preparation of the modified ruthenium C catalyst of rhenium atom
47.5kg active carbon powder is weighed to be scattered in 200L deionized water；Tri- chloride hydrate ruthenium of 6.47kg is weighed, is dissolved
In 100L deionized water；Under agitation, the two is mixed, is adsorbed 1 hour；Weigh 0.66kg ammonium perrhenate solid
(NH4ReO4), it is dissolved in 50L deionized water, is gradually added under stirring condition in above-mentioned Actidose；Stirring and adsorbing 1 hour
Afterwards, it is gradually added into sodium borohydride aqueous solution (1.2kg sodium borohydride is dissolved in 100L deionized water), after reacting 1 hour at room temperature,
Filter, clean 5 times to weakly acidic pH with deionized water, 80 DEG C oven drying 12 hours, obtain the ruthenium C catalyst of rhenium atom modification,
Wherein the mass percentage of ruthenium is 5wt%, and the mass percentage of rhenium is 0.9wt% (based on catalyst gross mass).
(2) preparation of gliclazide side chain
In 20L there-necked flask, N- Aminocyclopentane acid imide 4kg, acetic acid 2L, water 10L, stirring and dissolving, in addition is added
State modified ruthenium C catalyst (ruthenium content: 5wt%, rhenium content: 0.9wt%) 550g of rhenium atom of preparation.Under stirring, vacuum suck
In 20L autoclave.It is that 6MPa reacts 20 hours under conditions of temperature is 130 DEG C in Hydrogen Vapor Pressure.It is cooled to room temperature, pressure release,
Filtering.Filter cake ruthenium C catalyst set is for reaction next time.Filtrate decompression concentration, recovery of acetic acid water jacket are used for lower secondary response.Concentration
Obtain gliclazide side chain crude product about 4.3kg.Crude product HCl treatment is recrystallized by toluene-ethano mixed solvent, filtering,
Drying, obtains N- amino-3-azabicyclo [3.3.0] octane hydrochloride 4kg, purity 99.7% (GC), yield: 94%.Gained
Product is consistent with reference substance (GC analysis).
(3) catalyst is applied
In 20L there-necked flask, N- Aminocyclopentane acid imide 4kg, acetic acid 2L, water 10L is added, stirring and dissolving is added back
550g (has been recycled 6 times) in the modified ruthenium C catalyst of the rhenium atom of receipts under the same reaction conditions.Under stirring, vacuum is inhaled
Enter in 20L autoclave.It is that 8MPa reacts 18 hours under conditions of temperature is 120 DEG C in Hydrogen Vapor Pressure.It is cooled to room temperature, is let out
Pressure, filtering.Filter cake ruthenium C catalyst set is for reaction next time.Filtrate decompression concentration, recovery of acetic acid water jacket are used for lower secondary response.It is dense
Contracting obtains gliclazide side chain crude product about 4.2kg.Crude product HCl treatment is recrystallized, mistake by toluene-ethano mixed solvent
Filter, drying, obtains N- amino-3-azabicyclo [3.3.0] octane hydrochloride 3.9kg, purity 99.7% (GC), yield: 92%.
Products obtained therefrom is consistent with reference substance (GC analysis).
As it can be seen that catalyst still keeps very high activity after applying repeatedly.
Embodiment 6
(1) preparation of the modified ruthenium C catalyst of cobalt atom
47.5kg active carbon powder is weighed to be scattered in 200L deionized water；Tri- chloride hydrate ruthenium of 6.47kg is weighed, is dissolved
In 100L deionized water；Under agitation, the two is mixed, is adsorbed 1 hour；Weigh 0.69kg cabaltous nitrate hexahydrate solid
(Co(NO3)2·6H2O), it is dissolved in 50L deionized water, is gradually added under stirring condition in above-mentioned Actidose；Stirring is inhaled
After attached 1 hour, it is gradually added into sodium borohydride aqueous solution (1.2kg sodium borohydride is dissolved in 100L deionized water), reacts 1 at room temperature
After hour, filter, clean 5 times to weakly acidic pH with deionized water, 80 DEG C oven drying 12 hours, obtain the ruthenium carbon of cobalt atom modification
Catalyst, wherein the mass percentage of ruthenium is 5wt%, and the mass percentage of cobalt is that 0.3wt% (presses catalyst gross mass
Meter).It can be seen that, the particle that about 5 nanometers of size is uniformly distributed on absorbent charcoal carrier from TEM electron microscope.
(2) preparation of gliclazide side chain
In 20L there-necked flask, N- Aminocyclopentane acid imide 4kg, acetic acid 3L, water 15L, stirring and dissolving, in addition is added
State modified ruthenium C catalyst (ruthenium content: 5wt%, cobalt content: 0.3wt%) 800g of cobalt atom of preparation.Under stirring, vacuum suck
In 20L autoclave.It is that 9MPa reacts 17 hours under conditions of temperature is 100 DEG C in Hydrogen Vapor Pressure.It is cooled to room temperature, pressure release,
Filtering.Filter cake ruthenium C catalyst set is for reaction next time.Filtrate decompression concentration, recovery of acetic acid water jacket are used for lower secondary response.Concentration
Obtain gliclazide side chain crude product about 4.4kg.Crude product HCl treatment is recrystallized by toluene-ethano mixed solvent, filtering,
Drying, obtains N- amino-3-azabicyclo [3.3.0] octane hydrochloride 4.1kg, purity 99.2% (GC), yield: 96%.Institute
It is consistent with reference substance (GC analysis) to obtain product.
(3) catalyst is applied
In 20L there-necked flask, N- Aminocyclopentane acid imide 4kg, acetic acid 3L, water 15L is added, stirring and dissolving is added back
800g (has been recycled 6 times) in the modified ruthenium C catalyst of the cobalt atom of receipts under the same reaction conditions.Under stirring, vacuum is inhaled
Enter in 20L autoclave.It is that 8MPa reacts 16 hours under conditions of temperature is 120 DEG C in Hydrogen Vapor Pressure.It is cooled to room temperature, is let out
Pressure, filtering.Filter cake ruthenium C catalyst set is for reaction next time.Filtrate decompression concentration, recovery of acetic acid water jacket are used for lower secondary response.It is dense
Contracting obtains gliclazide side chain crude product about 4.3kg.Crude product HCl treatment is recrystallized, mistake by toluene-ethano mixed solvent
Filter, drying, obtains N- amino-3-azabicyclo [3.3.0] octane hydrochloride 4kg, purity 99.3% (GC), yield: 94%.Institute
It is consistent with reference substance (GC analysis) to obtain product.
As it can be seen that catalyst still keeps very high activity after applying repeatedly.
Embodiment 7
The preparation of gliclazide
N- amino-3-azabicyclo [3.3.0] octane hydrochloride of embodiment 6 (2) preparation is added in 250mL there-necked flask
20g, tolylsulfonylurea 30g, toluene 100ml are heated to reflux, and are reacted 3 hours, after reaction, are removed toluene under reduced pressure, are added
Crystallization is stirred at room temperature 12 hours in 100ml water, filter, wash solid, re-crystallizing in ethyl acetate, 80 DEG C vacuum drying 15h hours,
Obtain product 37g, yield 86%.
The above is only specific application examples of the invention, are not limited in any way to protection scope of the present invention.All uses
Equivalent transformation or equivalent replacement and the technical solution formed, all fall within rights protection scope of the present invention.
Claims (16)
1. a kind of preparation method of gliclazide side chain N- amino-3-azabicyclo [3.3.0] octane (I), comprising: by N- amino
Tetrahydrocyclopenta(c)pyrrole-1,3(2H,3aH)-dione (II) is dissolved in acidic aqueous solution, and the modified ruthenium C catalyst of transition metal atoms, hydrogenating reduction is added
N- Aminocyclopentane acid imide (II) prepares N- amino-3-azabicyclo [3.3.0] octane (I)；
Wherein, the modified ruthenium C catalyst of transition metal atoms are as follows: absorbent charcoal carrier loads ruthenium nanoparticle on absorbent charcoal carrier
Son and transition metal nanoparticles, transition metal are at least one of molybdenum, tungsten, vanadium, rhenium or cobalt
2. the method according to claim 1, wherein the mass percent that ruthenium atom accounts for catalyst is 3%~10%, transition metal
The mole of atom is the 1/16~1/4 of ruthenium atom mole.
3. method according to claim 1 or 2, comprising: N- Aminocyclopentane acid imide is dissolved in acidic aqueous solution, is added
The modified ruthenium C catalyst of transition metal atoms is 6~9MPa in Hydrogen Vapor Pressure, under conditions of temperature is 90~140 DEG C, reduction
16~20 hours, generate N- amino-3-azabicyclo [3.3.0] octane.
4. according to the method in claim 3, wherein catalysis acid is at least one of acetic acid, phosphoric acid, sulfuric acid or methanesulfonic acid.
5. according to the method in claim 3, wherein sour mole is 1~3 times of N- Aminocyclopentane acid imide mole.
6. according to the method in claim 3, wherein Hydrogen Vapor Pressure is 8~9MPa, and reduction temperature is 120~130 DEG C.
7. according to the method in claim 3, wherein the quality of catalyst be N- Aminocyclopentane acid imide quality 10~
30%.
8. according to claim 1-2, method of any one of 4-7, wherein the system of the modified ruthenium C catalyst of transition metal atoms
It is standby the following steps are included:
By absorbent charcoal carrier and ruthenium solution mixing and absorption；
A certain amount of transition metal salt solution is added, continues stirring and adsorbing 1~3 hour；
Reducing agent solution is added to restore 1~3 hour；
After reaction, it filters, washs, it is dry, obtain the modified ruthenium C catalyst of transition metal atoms.
9. a kind of preparation method of gliclazide side chain N- amino-3-azabicyclo [3.3.0] octane hydrochloride, comprising: by N-
Aminocyclopentane acid imide is dissolved in acidic aqueous solution, the modified ruthenium C catalyst of transition metal atoms is added, in hydrogen pressure
Power is that 6~9MPa is restored 16~20 hours under conditions of temperature is 90~140 DEG C, after the reaction was completed, is cooled to room temperature, lets out
Pressure, filtering, filter cake ruthenium C catalyst set are used for lower secondary response, concentration for reaction next time, filtrate decompression concentration, recovery acid water jacket
N- amino-3-azabicyclo [3.3.0] octane crude product is obtained, crude product HCl treatment is tied again by toluene-ethano mixed solvent
Crystalline substance filters, and drying obtains N- amino-3-azabicyclo [3.3.0] octane hydrochloride；
Wherein, the modified ruthenium C catalyst of transition metal atoms are as follows: absorbent charcoal carrier loads ruthenium nanoparticle on absorbent charcoal carrier
Son and transition metal nanoparticles, transition metal are at least one of molybdenum, tungsten, vanadium, rhenium or cobalt.
10. method according to claim 9, wherein the mass percent that ruthenium atom accounts for catalyst is 3%~10%, transition gold
The mole for belonging to atom is the 1/16~1/4 of ruthenium atom mole.
11. method according to claim 9, wherein catalysis acid is at least one of acetic acid, phosphoric acid, sulfuric acid or methanesulfonic acid.
12. method according to claim 9, wherein sour mole is 1~3 times of N- Aminocyclopentane acid imide mole.
13. method according to claim 9, wherein Hydrogen Vapor Pressure is 8~9MPa, and reduction temperature is 120~130 DEG C.
14. method according to claim 9, wherein the quality of catalyst be N- Aminocyclopentane acid imide quality 10~
30%.
15. method according to claim 9, wherein the preparation of the modified ruthenium C catalyst of transition metal atoms includes following step
It is rapid:
By absorbent charcoal carrier and ruthenium solution mixing and absorption；
A certain amount of transition metal salt solution is added, continues stirring and adsorbing 1~3 hour；
Reducing agent solution is added to restore 1~3 hour；
After reaction, it filters, washs, it is dry, obtain the modified ruthenium C catalyst of transition metal atoms.
16. a kind of preparation method of gliclazide, comprising: prepare gliclazide side chain N- ammonia with claim 1-8 either method
Base -3- azabicyclo [3.3.0] octane (I), by N- amino-3-azabicyclo [3.3.0] octane (I) obtained and to toluene sulphur
Uride reaction, prepares gliclazide.
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Denomination of invention: Preparation method of gliclazide side chain and preparation method of gliclazide Effective date of registration: 20220525 Granted publication date: 20190813 Pledgee: Panjin financing guarantee Group Co.,Ltd. Pledgor: GREENCHEM PANJIN SCIENCE AND TECHNOLOGY CO.,LTD. Registration number: Y2022210000051 |