CN102267999B - Flumazenil compound and preparation method thereof - Google Patents
Flumazenil compound and preparation method thereof Download PDFInfo
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- CN102267999B CN102267999B CN 201110198315 CN201110198315A CN102267999B CN 102267999 B CN102267999 B CN 102267999B CN 201110198315 CN201110198315 CN 201110198315 CN 201110198315 A CN201110198315 A CN 201110198315A CN 102267999 B CN102267999 B CN 102267999B
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- 229960004381 flumazenil Drugs 0.000 title claims abstract description 56
- -1 Flumazenil compound Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title abstract description 10
- OFBIFZUFASYYRE-UHFFFAOYSA-N flumazenil Chemical compound C1N(C)C(=O)C2=CC(F)=CC=C2N2C=NC(C(=O)OCC)=C21 OFBIFZUFASYYRE-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 18
- 238000004821 distillation Methods 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical group Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 8
- 238000005261 decarburization Methods 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 8
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 7
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 7
- 229960003280 cupric chloride Drugs 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 3
- 238000000638 solvent extraction Methods 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 18
- 229940049706 benzodiazepine Drugs 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- 239000005557 antagonist Substances 0.000 abstract description 3
- 238000005886 esterification reaction Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000002243 precursor Substances 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 abstract 1
- 238000001179 sorption measurement Methods 0.000 abstract 1
- 150000001557 benzodiazepines Chemical class 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CRDNMYFJWFXOCH-BUHFOSPRSA-N Couroupitine B Natural products N\1C2=CC=CC=C2C(=O)C/1=C1/C2=CC=CC=C2NC1=O CRDNMYFJWFXOCH-BUHFOSPRSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 102000003946 Prolactin Human genes 0.000 description 2
- 108010057464 Prolactin Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 229940097325 prolactin Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MZHUTGQZAZLFKW-UHFFFAOYSA-N 1H-1,2-benzodiazepine-3-carboxylic acid Chemical compound C1=CC(C(=O)O)=NNC2=CC=CC=C21 MZHUTGQZAZLFKW-UHFFFAOYSA-N 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- MPCRDALPQLDDFX-UHFFFAOYSA-L Magnesium perchlorate Chemical compound [Mg+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O MPCRDALPQLDDFX-UHFFFAOYSA-L 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 description 1
- 229910000360 iron(III) sulfate Inorganic materials 0.000 description 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a preparation method of a flumazenil compound, and the preparation method comprises the following steps of: carrying out hydrolysis reaction to obtain a flumazenil precursor intermediate, purifying the flumazenil precursor intermediate by activated carbon adsorption, and then carrying out esterification reaction to obtain flumazenil. The preparation method provided by the invention has the advantages of simple reaction steps, high product yield, high product purity and low cost, and is suitable for industrial mass production; and the quality of a preparation product prepared by the method is improved, and the toxic and side effects of the flumazenil compound used as benzodiazepine selective antagonist drugs can be reduced.
Description
Technical field
The present invention relates to a kind of flumazenil compound and method for making thereof, belong to medical technical field.
Background technology
Flumazenil (Flumazenil), chemical name is: 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazoles (1,5-α) (Isosorbide-5-Nitrae) benzodiazepine-3-carboxylic acid, ethyl ester, molecular formula: C
15H
14FN
3O
3, molecular weight: 303.29, structural formula is:
Flumazenil is benzodiazepines (BDZ) selective antagonist, can act on brain BDZ acceptor, retardance acceptor and the effect that do not produce the BDZ medicine.Pharmacological evaluation shows, flumazenil can reverse the BDZ class and central nervous system BDZ acceptor is had the effect of the non-BDZ class medicine of affinity, anticonvulsant action that also can the antagonism Sodium Valproate.Antipsychotic drug often can increase the level of prolactin in the body, and BDZ class tranquilizer can make it to reduce, and this kind of flumazenil energy antagonism reduces the effect of prolactin, proves from another point of view this product tool BDZ antagonistic action.
The Main Function of flumazenil has: after (1) is used for anesthesia: the inpatient induce with the BDZ class and keep general anesthesia after available this product stop its effect; After outpatient service and inpatient carry out the diagnosis or treatment operation of short period of time, can stop the sedative effect of BDZ.(2) be used for first aid: as the diagnostic medicine of BDZ class poisoning, or get rid of BDZ and poison; As agnogenic unconscious diagnosis medicine, poison or brain injury in order to differentiate BDZ, other drug.
Flumazenil is first disclosed as among US4316839 and the EP27214, its thick product needs to make through ethyl alcohol recrystallization, Peng Zhenyun etc. were " Chinese Journal of Pharmaceuticals " 1994, reported the synthetic of flumazenil in 25 (1), it is take the 5-fluoro indigo red as starting raw material, generate 6-fluoro indigo red acid anhydrides through peroxidation, hydroxide, react to get the benzodiazepine diketone with sarkosine again, last and isocyano acid B ester condensation makes flumazenil.This route productive rate is about 40%, and cost is high, and the product purity that obtains is relatively poor.
Brave generals Lee etc. are at " Chinese Pharmaceutical Affairs " 2010, reported in 24 (4) that the HPLC method checks the related substance of flumazenil, the related substance that flumazenil may exist intermediate, by product and degraded product is disclosed, and disclose and increased by 2 recrystallizations to the process for purification of flumazenil, obtained single impurity＜0.2%, total impurities＜0.5%.
In fact, above-mentioned synthetic and process for purification, yield is low, and is difficult to obtain highly purified flumazenil compound.In addition, deposit improper or shelf-time when long at compound, can cause the active constituents of medicine content, color and luster is strengthened, and its related substances raises.In some cases, because controlling of production process is improper, cause pharmaceutical purity also undesirable.In order to improve drug quality, reduce adverse drug reaction, need more highly purified flumazenil compound.
The applicant is on the basis of a large amount of existing documents, experiment by a large amount of screenings, find that above-mentioned document and general method for purifying and separating such as the methods such as crystallization are difficult to obtain the flumazenil compound of high purity high yield, the inventor is through long-term conscientious research, be surprisingly found out that a kind of preparation method of flumazenil compound, thereby finished the present invention.
Summary of the invention
The object of the present invention is to provide a kind of method for making of flumazenil compound, the flumazenil precursor intermediate that it obtains by hydrolysis reaction, by the charcoal absorption purifying, to carry out again esterification and obtain flumazenil, reactions steps is simple, productive rate is high, cost is low, and product purity is high, has improved the formulation products quality, reduce toxic side effect, be suitable for industrialized production.
The applicant is on the basis of a large amount of existing documents, by a large amount of experiments, organic solvent, catalyzer, solid drier have been screened and with the kind of aqua, optimized reaction conditions, the unexpected discovery take intermediate (II) as raw material, hexanaphthene is catalyzer for being with aqua and strong acid salt, has obtained the highly purified flumazenil of high yield.
Present method can be used for the last handling process of the preparation of prior art flumazenil, also can be used for the purifying of the underproof product of purity.
The technical scheme that the present invention solves comprises:
The purification process of the flumazenil compound shown in a kind of formula (I),
Step comprises:
(1) the flumazenil crude product is scattered in the water, the adding mass percent is about 6% sodium hydroxide solution as catalyzer, is heated to 45-60 ℃, stirring reaction 2-3 hour, with acid for adjusting pH to 5.5～6.5, use organic solvent extraction, dry through solid drier, filter, add the gac of total liquid volume 0.1-0.5% (g/ml), be incubated 40-50 ℃ of whip attachment 30 minutes, filter decarburization, organic solvent is removed in underpressure distillation, gets intermediate (II);
(2) in intermediate (II), add excessive ethanol, add strong acid salt as catalyzer, cyclohexane give is the band aqua again, stirs lower reflux, stopped reaction during anhydrous telling to the water trap, filtering insolubles, filtrate use solid drier dry again, and underpressure distillation is to doing, 50-60 ℃ of vacuum-drying 4～6 hours makes flumazenil.
Further, as preferably, organic solvent is selected from one or more in chloroform, methylene dichloride, ether, sherwood oil, hexanaphthene and the pentane in the aforesaid method, is preferably ether.
Further, as preferably, the strong acid salt catalyzer is selected from iron(ic) chloride (FeCl in the aforesaid method
36H
2O), cupric chloride (CuCl
22H
2O), ferric sulfate (Fe
2(SO
4)
39H
2O), copper sulfate (CuSO
45H
2O) a kind of in is preferably cupric chloride (CuCl
22H
2O).
Further, as preferably, solid drier is selected from a kind of in anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate or the activated alumina in the aforesaid method, is preferably activated alumina.
Further, the usage quantity that it is suitable that the present invention confirms gac is the 0.1-0.5% (g/ml) of overall solution volume, is preferably 0.2-0.4% (g/ml).
Further, as preferably, intermediate (II) is about 1: 1.2 with the mol ratio of ethanol～and 1.5.The mol ratio of intermediate (II) and catalyzer strong acid salt is about 1: 0.05～and 0.1, intermediate (II) is about 1: 0.8 with the mol ratio of hexanaphthene～and 1.
As embodiment of the present invention, the flumazenil compound purity of method preparation of the present invention is all greater than 99.8%.
As embodiment of the present invention, the flumazenil compound of the method for the invention preparation is at the medicine that can be used for preparing the benzodiazepines selective antagonist.
As the present invention's one preferred embodiment, the purification step of described flumazenil compound comprises:
(1) the flumazenil crude product is scattered in the water, the adding mass percent is about 6% sodium hydroxide solution as catalyzer, is heated to 45-60 ℃, stirring reaction 2-3 hour, with acid for adjusting pH to 5.5～6.5, use ether extraction, dry through solid drier, filter, add the gac of total liquid volume 0.1-0.5% (g/ml), be incubated 40-50 ℃ of whip attachment 30 minutes, filter decarburization, organic solvent is removed in underpressure distillation, gets intermediate (II);
(2) be the ethanol of 1.2～1.5 molar ratios to the middle relative intermediate of adding of intermediate (II) (II), add again strong acid salt as catalyzer, cyclohexane give is the band aqua, stir lower reflux, stopped reaction during anhydrous telling to the water trap, filtering insolubles, filtrate uses solid drier dry again, underpressure distillation is to doing, and 50-60 ℃ of vacuum-drying 4～6 hours makes flumazenil.
Advantage of the present invention shows: the present invention makes highly purified flumazenil compound by hydrolysis reaction and esterification, and reactions steps is simple, and productive rate is high, and cost is low, has improved the quality product of preparation, has reduced toxic side effect.In addition, the present invention selects the strong acid salt catalyzer, and the reaction times is short, and yield is high, and cost is low, is a kind of desirable good catalyzer; The hexanaphthene that the present invention selects is good band aqua.
Embodiment
Further explain and describe by the following examples content of the present invention, but these embodiment are not to be construed as limiting the scope of the invention.
The purifying of embodiment 1 flumazenil
(1) the flumazenil crude product with 100g purity 98.24% is scattered in the 500ml water, and the adding mass percent is about 6% sodium hydroxide solution 200ml as catalyzer, is heated to 45 ℃, stirring reaction 2 hours, with acid for adjusting pH to 5.5, extract with ether 500ml, dry through solid drier, filter, add the gac of 0.5g, be incubated 40 ℃ of whip attachment 30 minutes, filter decarburization, ether is removed in underpressure distillation, gets intermediate (II) 83.15g;
(2) in intermediate (II), add 16.8g ethanol, add again 2.6g cupric chloride (CuCl
22H
2O) as catalyzer, the 26ml cyclohexane give is the band aqua, stirs lower reflux, stopped reaction during anhydrous telling to the water trap, filtering insolubles, filtrate use activated alumina dry again, and ether is removed in underpressure distillation, 60 ℃ of vacuum-drying 4 hours, obtain flumazenil 92.30g, yield 93.95%, purity 99.88% (HPLC, retention time is consistent with standard substance), mp:202～203 ℃.
The purifying of embodiment 2 flumazenils
(1) the flumazenil crude product with 100g purity 98.24% is scattered in the 500ml water, and the adding mass percent is about 6% sodium hydroxide solution 200ml as catalyzer, is heated to 55 ℃, stirring reaction 2 hours, with acid for adjusting pH to 6.0, extract with ether 500ml, dry through solid drier, filter, add the gac of 2.5g, be incubated 45 ℃ of whip attachment 30 minutes, filter decarburization, ether is removed in underpressure distillation, gets 83.24g intermediate (II);
(2) in intermediate (II), add 18.8g ethanol, add again 3.9g cupric chloride (CuCl
22H
2O) as catalyzer, the 29ml cyclohexane give is the band aqua, stirs lower reflux, stopped reaction during anhydrous telling to the water trap, the filtering insolubles, filtrate uses activated alumina dry again, and ether is removed in underpressure distillation, 50 ℃ of vacuum-drying 6 hours, obtain flumazenil 91.38g, yield 93.02%, purity 99.85%, mp:202～203 ℃.
The purifying of embodiment 3 flumazenils
(1) the flumazenil crude product with 100g purity 98.24% is scattered in the 500ml water, and the adding mass percent is about 6% sodium hydroxide solution 200ml as catalyzer, is heated to 60 ℃, stirring reaction 2.5 hours, with acid for adjusting pH to 6.5, extract with ether 500ml, dry through solid drier, filter, add the gac of 1g, be incubated 50 ℃ of whip attachment 30 minutes, filter decarburization, organic solvent is removed in underpressure distillation, gets 81.68g intermediate (II);
(2) in intermediate (II), add 20.5g ethanol, add again 5.1g cupric chloride (CuCl
22H
2O) as catalyzer, the 32ml cyclohexane give is the band aqua, stirs lower reflux, stopped reaction during anhydrous telling to the water trap, the filtering insolubles, filtrate uses activated alumina dry again, and ether is removed in underpressure distillation, 55 ℃ of vacuum-drying 5 hours, obtain flumazenil 90.64g, yield 92.26%, purity 99.89%, 202～203 ℃ of mp.
The purifying of Comparative Examples 1 flumazenil
(1) the flumazenil crude product with 100g purity 98.24% is scattered in the 500ml water, and the adding mass percent is about 6% sodium hydroxide solution 200ml as catalyzer, is heated to 45 ℃, stirring reaction 2 hours, with acid for adjusting pH to 5.5, extract with ether 500ml, dry through solid drier, filter, add the gac of 0.5g, be incubated 40 ℃ of whip attachment 30 minutes, filter decarburization, ether is removed in underpressure distillation, gets intermediate (II) 83.15g;
(2) add 16.8g ethanol in intermediate (II), add the 4.2g magnesium perchlorate as catalyzer again, the 26ml cyclohexane give is the band aqua, stir lower reflux, stopped reaction during anhydrous telling to the water trap, the filtering insolubles, filtrate uses activated alumina dry again, ether is removed in underpressure distillation, 60 ℃ of vacuum-drying 4 hours obtains flumazenil 87.52g, yield 89.09%, purity 99.03%, 201～203 ℃ of mp.
The purifying of Comparative Examples 2 flumazenils
(1) the flumazenil crude product with 1.5g purity 98.24% is scattered in the 100ml water, adds 1mol/L potassium hydroxide solution 100ml, and By Hydrolysis At Room Temperature 2 hours reacts complete dropping concentrated hydrochloric acid and regulates pH to 5～6.Use ethyl acetate extraction, successively water and saturated brine washing, anhydrous sodium sulfate drying.Filter, solvent evaporated obtains intermediate (II);
(2) in intermediate (II), add ethanol 100ml, vitriol oil 2ml, about 4 hours of heating reflux reaction, be cooled to room temperature, add 20% sodium bicarbonate to the reaction solution alkalize, pressure reducing and steaming ethanol, use dichloromethane extraction, successively water and saturated brine washing, anhydrous sodium sulfate drying.Filter, solvent evaporated obtains flumazenil 0.75g, yield 50.90%, purity 99.14%, 202～203 ℃ of mp.
The purifying of comparative example's 3 flumazenils
(1) the flumazenil crude product with 100g purity 98.24% is scattered in the 500ml water, adds 6% sodium hydroxide solution 20ml as catalyzer, is heated to 60 ℃, stirring reaction 2.5 hours, with acid for adjusting pH to 6.5, extract with ether 500ml, dry through solid drier, filter, add the gac of 1g, be incubated 50 ℃ of whip attachment 30 minutes, filter decarburization, organic solvent is removed in underpressure distillation, gets 81.68g intermediate (II);
(2) in intermediate (II), add 20.5g ethanol, add again 5.1g cupric chloride (CuCl
22H
2O) as catalyzer, 36ml toluene stirs lower reflux as the band aqua, stopped reaction during anhydrous telling to the water trap, the filtering insolubles, filtrate uses activated alumina dry again, and ether is removed in underpressure distillation, 55 ℃ of vacuum-drying 5 hours, obtain flumazenil 80.60g, yield 82.04%, purity 99.26%, 201～203 ℃ of mp.
Compare by above-described embodiment and the used parameter of comparative example and result, can find out, the process for purification of the flumazenil compound that provides in the scope of the invention, the purifying product yield that makes is high, and purity is good; And the product that the parameter beyond the scope of the invention or method obtain, purity is low, and yield is also low.The effect that has proved absolutely the inventive method is excellent, unexpected.Each reference that the application quotes, which is hereby incorporated by reference.
Claims (1)
1. the purification process of the flumazenil compound shown in the formula (I), its step comprises:
(1) the flumazenil crude product is scattered in the water, adds mass percent and be 6% sodium hydroxide solution as catalyzer, be heated to 45-60 ℃, stirring reaction 2-3 hour, with acid for adjusting pH to 5.5～6.5, use organic solvent extraction, dry through solid drier, filter, add the gac of total liquid volume 0.2-0.4%g/ml, be incubated 40-50 ℃ of whip attachment 30 minutes, filter decarburization, organic solvent is removed in underpressure distillation, gets intermediate (II);
(2) in intermediate (II), add excessive ethanol, add strong acid salt as catalyzer, cyclohexane give is the band aqua again, stirs lower reflux, stopped reaction during anhydrous telling to the water trap, filtering insolubles, filtrate use solid drier dry again, and underpressure distillation is to doing, 50-60 ℃ of vacuum-drying 4～6 hours makes purity greater than 99.8% flumazenil;
And wherein said organic solvent is ether, and described strong acid salt catalyzer is cupric chloride CuCl
22H
2O, described solid drier are activated alumina;
And wherein said intermediate (II) is 1: 1.2～1.5 with the mol ratio of ethanol, and intermediate (II) is 1: 0.05～0.1 with the mol ratio of catalyzer strong acid salt, and intermediate (II) is 1: 0.8～1 with the mol ratio of hexanaphthene.
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