CN116023342A - Preparation method of high-purity clonazepam - Google Patents
Preparation method of high-purity clonazepam Download PDFInfo
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- CN116023342A CN116023342A CN202111250598.6A CN202111250598A CN116023342A CN 116023342 A CN116023342 A CN 116023342A CN 202111250598 A CN202111250598 A CN 202111250598A CN 116023342 A CN116023342 A CN 116023342A
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- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 title claims abstract description 95
- 229960003120 clonazepam Drugs 0.000 title claims abstract description 94
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 102
- 239000002904 solvent Substances 0.000 claims abstract description 62
- 238000000746 purification Methods 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 239000012043 crude product Substances 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 229910017053 inorganic salt Inorganic materials 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 8
- 239000007858 starting material Substances 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 32
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 25
- 238000010992 reflux Methods 0.000 claims description 22
- 238000001914 filtration Methods 0.000 claims description 20
- 239000000047 product Substances 0.000 claims description 19
- 239000004312 hexamethylene tetramine Substances 0.000 claims description 16
- 235000010299 hexamethylene tetramine Nutrition 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 15
- 239000005456 alcohol based solvent Substances 0.000 claims description 15
- 150000003863 ammonium salts Chemical class 0.000 claims description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims description 9
- 150000007522 mineralic acids Chemical class 0.000 claims description 9
- 238000004821 distillation Methods 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 235000019270 ammonium chloride Nutrition 0.000 claims description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 229910017604 nitric acid Inorganic materials 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 150000008282 halocarbons Chemical class 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- BIGPRXCJEDHCLP-UHFFFAOYSA-N ammonium bisulfate Chemical compound [NH4+].OS([O-])(=O)=O BIGPRXCJEDHCLP-UHFFFAOYSA-N 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims 2
- 239000000523 sample Substances 0.000 claims 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims 1
- 239000000758 substrate Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 235000019441 ethanol Nutrition 0.000 description 30
- 239000012535 impurity Substances 0.000 description 21
- 229910021642 ultra pure water Inorganic materials 0.000 description 16
- 239000012498 ultrapure water Substances 0.000 description 16
- 239000012467 final product Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- YBAJRIMWOFPRTG-UHFFFAOYSA-N 2-chloro-n-[2-(2-chlorobenzoyl)-4-nitrophenyl]acetamide Chemical compound [O-][N+](=O)C1=CC=C(NC(=O)CCl)C(C(=O)C=2C(=CC=CC=2)Cl)=C1 YBAJRIMWOFPRTG-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 2
- 229960004782 chlordiazepoxide Drugs 0.000 description 2
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- XSTMFEOLMKEEMU-UHFFFAOYSA-N 2-bromo-n-[2-(2-chlorobenzoyl)-4-nitrophenyl]acetamide Chemical group [O-][N+](=O)C1=CC=C(NC(=O)CBr)C(C(=O)C=2C(=CC=CC=2)Cl)=C1 XSTMFEOLMKEEMU-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- DUEPRVBVGDRKAG-UHFFFAOYSA-N carbofuran Chemical compound CNC(=O)OC1=CC=CC2=C1OC(C)(C)C2 DUEPRVBVGDRKAG-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- 229960001454 nitrazepam Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Images
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of high-purity clonazepam, which takes 2- (2-haloacetamido) -5-nitro-2' -chlorobenzophenone as a starting material and prepares clonazepam by reaction in the presence of a cyclization agent. In the purification process, the crude product is converted into the clonazepam inorganic salt, and the alcohol solvent is used as the purification solvent, so that the purification effect is effectively improved, and the high-quality clonazepam is obtained.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of high-purity clonazepam.
Background
Clonazepam (Clonazepam), also known as chlordiazepoxide or chlordiazepoxide, is known by the chemical name 1, 3-dihydro-7-nitro-5- (2-chlorophenyl) -2H-1, 4-benzodiazepine
-2-one. Clonazepam is a benzodiazepine +.>
Sedatives are used for the treatment of epilepsy and convulsions, have 5-fold stronger anticonvulsant action than diazepam and nitrazepam, are rapid in action, have anxiolytic, hypnotic and central muscle relaxant actions, and were approved by the FDA in the united states in 1975.
At present, the synthesis method of clonazepam mainly comprises the following steps:
the synthetic preparation of clonazepam was reported by mcdonugh, j.a et al on Organic Process Research & Development in the last 90 th century, but this method produced higher levels of dimeric impurities during the synthesis of intermediates.
Chinese patent CN112898203A discloses a preparation method of continuous flow synthesis of clonazepam, which takes 2- (2-chloroacetamido) -5-nitro-2' -chlorobenzophenone as a starting material, exchanges with KI in a pipeline reactor to obtain an iodo-compound, continuously reacts under the action of ammonia gas, and the reaction liquid is distilled to recover a solvent, and the residue is refined to obtain a finished product. The method has the advantages that the reaction can realize continuous production; although the content of dimer is reduced in the synthesis process, the purity of the final product is still poor, the maximum is only 99.8%, and the content of dimer impurity is still high, about 0.08%. In addition, the solubility of the clonazepam in most solvents is poor, and impurities in the clonazepam cannot be effectively removed by a solvent refining method, so that the purity of the clonazepam is difficult to reach more than 99.9%.
Based on the above problems, the purity of the prepared clonazepam is not high, so a new preparation method of clonazepam needs to be provided to obtain a high-purity product, and the preparation method is easy to amplify and operate, so that mass production is realized.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of high-purity clonazepam, which takes 2- (2-haloacetamido) -5-nitro-2' -chlorobenzophenone as a starting material, prepares clonazepam by reaction in the presence of a cyclization agent, performs fractional purification, converts a crude product into clonazepam inorganic salt, adopts an alcohol solvent as a purification solvent, effectively improves the purification effect, and obtains high-quality clonazepam, thereby completing the invention.
The invention aims to provide a preparation method of high-purity clonazepam, which takes 2- (2-haloacetamido) -5-nitro-2' -chlorobenzophenone as a starting material and prepares clonazepam by reaction in the presence of a cyclization agent.
In the 2- (2-halogenated acetamido) -5-nitro-2' -chlorobenzophenone, the halogen substituent is iodine substituent, bromine substituent or chlorine substituent.
The cyclizing agent is selected from one or more of ammonia water, ammonium salt, ammonia gas and hexamethylenetetramine, preferably ammonium salt and/or hexamethylenetetramine, more preferably ammonium salt and hexamethylenetetramine. The ammonium salt is selected from one or more of ammonium carbonate, ammonium bicarbonate and ammonium chloride.
In a preferred embodiment of the invention, the cyclizing agent is ammonium chloride and hexamethylenetetramine.
The reaction is carried out in a solvent, the reaction solvent is selected from aromatic hydrocarbon solvents such as toluene, xylene and mesitylene, halogenated hydrocarbon solvents such as chloroform, methylene chloride, alcohol solvents such as methanol, ethanol, isopropanol and butanol, amide solvents such as one or more of N, N-dimethylformamide and N, N-dimethylacetamide, water, preferably a mixed solvent of water and alcohol solvents, and the alcohol solvents are selected from one or more of methanol, ethanol and isopropanol, more preferably a mixed solvent of water and ethanol. The water is selected from distilled water, deionized water or ultrapure water, preferably ultrapure water.
And after the reaction is finished, carrying out post-treatment on the obtained reaction liquid to obtain a clonazepam final product.
The salification and purification comprises the following steps:
and step 1-1, adding the clonazepam crude product into a solvent II to form a mixed solution, and heating and refluxing.
And (2) after the reflux is finished, cooling the mixed solution, and adding inorganic acid to carry out salt forming reaction.
And step 1-3, dissolving a filter cake obtained by salifying and purifying in a solvent III, adding an alkaline solution, adjusting the pH value to 7-9, and filtering to obtain a clonazepam primary product.
The preparation method of the high-purity clonazepam provided by the invention has the following beneficial effects:
(1) The preparation method of high-purity clonazepam provided by the invention has the advantages that the amination ring combination process is completed in one step, the reaction process is simple and feasible, the preparation can be completed in a common reaction kettle, equipment is not required to be modified, the total molar yield of the preparation method can reach more than 60%, the reaction solvent is environment-friendly, the recycling and the application can be realized, the consumption of the solvent and the production amount of waste liquid are reduced, and the preparation method is suitable for industrial production.
(2) In the preparation method of the clonazepam, the salt is formed by adding inorganic acid such as sulfuric acid into an alcohol solvent, the clonazepam inorganic salt is separated out from the alcohol solvent at 20-30 ℃, impurities are still dissolved in the alcohol solvent under an acidic condition, the clonazepam inorganic salt with higher purity can be easily separated out, the purification method is simple and easy to implement, and the used solvent is environment-friendly and is beneficial to popularization and application.
(3) In the preparation method of clonazepam, the purification process is simple, the purification effect is effectively improved, the high-purity product can be obtained, the maximum single impurity content is not more than 0.02%, the total impurity content is not more than 0.1%, the operation is simple and convenient, and the separation efficiency is high.
(4) The preparation method of clonazepam provided by the invention has the advantages of low production cost and high production safety, the materials and reagents used by the preparation method are materials with high safety, the irritation is small, the corrosiveness to equipment is small, no volatile substances are generated in the preparation process, and the personnel protection is simple.
Drawings
Fig. 1 shows the nuclear magnetic spectrum of the clonazepam end product obtained in example 3 of the present invention.
Detailed Description
The features and advantages of the present invention will become more apparent and evident from the following detailed description of the invention.
The invention provides a preparation method of high-purity clonazepam, which takes 2- (2-haloacetamido) -5-nitro-2' -chlorobenzophenone as a starting material and prepares clonazepam by reaction in the presence of a cyclization agent.
In the 2- (2-haloacetamido) -5-nitro-2 '-chlorobenzophenone, the halogen substituent is an iodine substituent, a bromine substituent or a chlorine substituent, and preferably, the 2- (2-haloacetamido) -5-nitro-2' -chlorobenzophenone is 2- (2-bromoacetamido) -5-nitro-2 '-chlorobenzophenone or 2- (2-chloroacetamido) -5-nitro-2' -chlorobenzophenone.
The 2- (2-haloacetamido) -5-nitro-2' -chlorobenzophenone can be purchased in the market and also can be prepared by itself, and the invention is not particularly limited.
The cyclizing agent is selected from one or more of ammonia water, ammonium salt, ammonia gas and hexamethylenetetramine, preferably ammonium salt and/or hexamethylenetetramine, more preferably ammonium salt and hexamethylenetetramine. The ammonium salt is selected from one or more of ammonium sulfate, ammonium bisulfate and ammonium chloride.
In a preferred embodiment of the invention, the cyclizing agent is ammonium chloride and hexamethylenetetramine.
The molar ratio of the ammonium salt to hexamethylenetetramine is (1-7): 1, preferably (1.5-5): 1, more preferably (2-3): 1.
The molar ratio of the 2- (2-haloacetamido) -5-nitro-2' -chlorobenzophenone to the cyclization mixture is 1 (4-20), preferably 1 (6-15), and more preferably 1 (8-11).
The reaction is carried out in a solvent, the reaction solvent is selected from aromatic hydrocarbon solvents such as toluene, xylene and mesitylene, halogenated hydrocarbon solvents such as chloroform, methylene chloride, alcohol solvents such as methanol, ethanol, isopropanol and butanol, amide solvents such as one or more of N, N-dimethylformamide and N, N-dimethylacetamide, water, preferably a mixed solvent of water and alcohol solvents, and the alcohol solvents are selected from one or more of methanol, ethanol and isopropanol, more preferably a mixed solvent of water and ethanol. The water is selected from distilled water, deionized water or ultrapure water, preferably ultrapure water. The solvent used in the invention can be recycled after the reaction is finished, thereby greatly reducing the generation of three wastes. In the preferred embodiment of the invention, ethanol and water are used as reaction solvents, so that the solvent toxicity is low, the method is environment-friendly, and the method is easier to separate from products, is beneficial to the realization of the synthesis process, and can obtain safe and reliable clonazepam products.
The volume ratio of water to alcohol solvent is 1 (1-9), preferably 1 (2-7), more preferably 1 (3-5), such as 1:4.
The molar volume ratio of the 2- (2-haloacetamido) -5-nitro-2' -chlorobenzophenone to the solvent is 0.3mol (250-750) mL, preferably 0.3mol (350-650) mL, more preferably 0.3mol (450-550) mL, such as 1:4.
The reaction temperature is 40 to 95 ℃, preferably 50 to 85 ℃, more preferably 60 to 75 ℃. The reaction time is 8 to 32 hours, preferably 12 to 28 hours, more preferably 16 to 24 hours.
And after the reaction is finished, carrying out post-treatment on the obtained reaction liquid to obtain a clonazepam final product. The purity of the clonazepam final product is more than 99.9%, the maximum single impurity content is less than 0.02%, for example, the purity of the clonazepam final product is 99.98%, and the maximum single impurity content is 0.016%.
The post-treatment comprises the steps of removing a reaction solvent, distilling and purifying, salifying and purifying, and refluxing and purifying.
The reaction solvent is removed by normal pressure distillation, and the solvent can be reused to obtain residual reaction liquid.
The distillation and purification are carried out by adding solvent I into residual reaction liquid, then carrying out atmospheric distillation, and heating the fraction to temperature T 0 And (3) cooling, namely cooling to 20-30 ℃, filtering, washing a filter cake with ultrapure water for three times, and drying to constant weight to obtain a clonazepam crude product. Said temperature T 0 Is a temperature 5 ℃ lower than the boiling point of the solvent I. The clonazepam crude product can be completely dissolved in the solvent I to better remove inorganic salts in the crude product.
The solvent I is selected from one or more of water and alcohol solvents, preferably one or more of water, methanol, ethanol and isopropanol, more preferably water; the water is selected from distilled water, deionized water, and ultrapure water, preferably ultrapure water. The drying temperature is 50-75deg.C, preferably 60-65deg.C.
The salification and purification comprises the following steps:
and step 1-1, adding the clonazepam crude product into a solvent II to form a mixed solution, and heating and refluxing.
The solvent II is selected from one or more of alcohol solvents with boiling point above 70deg.C, preferably one or more of ethanol, propanol and isopropanol, more preferably ethanol or isopropanol, such as ethanol. The reflux temperature is 70 ℃ or higher, preferably 75-95 ℃, more preferably 75-85 ℃; the reflux time is 1-2 hours, such as 1 hour. The purpose of the reflux is to ensure that the clonazepam is completely dissolved in the ethanol, and impurities can be fully dissolved in the ethanol in the later salt forming process, so that incomplete dissolution and impurity entrainment are avoided, and the impurity removal effect is not ideal.
And (2) after the reflux is finished, cooling the mixed solution, and adding inorganic acid to carry out salt forming reaction.
After the reflux is finished, the temperature of the mixed solution is reduced to 60-65 ℃, inorganic acid is added, after stirring and full reaction, the temperature is reduced to 10-20 ℃, the clonazepam inorganic salt is gradually separated out, the filtration is carried out, the filter cake is washed for a plurality of times by using a solvent II, and the suction filtration is carried out until no liquid drops.
The inorganic acid is selected from one or more of hydrochloric acid, nitric acid and sulfuric acid, preferably nitric acid or sulfuric acid, and more preferably sulfuric acid. According to the invention, in the purification process, inorganic acid is added to enable the clonazepam to form clonazepam inorganic salt, so that a crude product can be completely dissolved in a solvent II, and after the temperature is reduced, the clonazepam inorganic salt can be separated out from the purification solvent for crystallization, and impurities are dissolved in the solvent II, so that the impurities in the crude product are effectively removed. In particular to clonazepam sulfate (compared with the existing purification process using organic solvents with stronger toxicity, such as chloroform, the residual amount is required to be below 60ppm, which brings great difficulty to product detection, and the use of alcohol solvents, such as ethanol, in the production of raw medicines should be avoided as much as possible.
And step 1-3, dissolving the filter cake obtained in the step 1-2 in a solvent III, adding an alkaline solution for neutralization, adjusting the pH value to 7-9, preferably 8-9, filtering, washing with the solvent III, and drying to obtain a clonazepam primary product.
Under neutral or weak alkaline condition, the inorganic salt of clonazepam is converted into clonazepam, so that the clonazepam is separated out from the solvent III to achieve the aim of purification
The solvent III is selected from one or more of water and alcohol solvents, preferably one or more of water, methanol, ethanol and isopropanol, more preferably water; the water is selected from distilled water, deionized water, and ultrapure water, preferably ultrapure water.
The alkaline solution is sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution, sodium bicarbonate solution, or potassium bicarbonate solution. The drying temperature is 50-75deg.C, preferably 60-65deg.C.
And the reflux purification comprises the steps of dispersing a clonazepam primary product into an alcohol solvent, adding active carbon, heating and refluxing, stirring for 0.5-1.5 hours, filtering the active carbon while the active carbon is hot, cooling the filtrate to-20-5 ℃, preferably-10-0 ℃, precipitating clonazepam, filtering and drying to obtain a clonazepam final product. The alcohol solvent is one or more of methanol, ethanol, 95% ethanol and isopropanol, preferably 95% ethanol.
According to the preparation method of high-purity clonazepam, the amination ring combination process is completed in one step, the reaction process is simple and feasible, special equipment is not needed, the reaction solvent is environment-friendly, the solvent can be recycled, and the total yield reaches more than 60%. In the purification process, the high-purity clonazepam inorganic salt is separated by utilizing the solubility of the clonazepam inorganic salt and impurities in an alcohol solvent, so that the aim of improving the purification effect is fulfilled. The preparation method and the purification process are simple, can obtain high-quality clonazepam, and are suitable for industrial production.
Examples
Example 1
400mL of absolute ethyl alcohol and 100mL of ultrapure water are added into a reactor, 100g of ammonium chloride, 100g of hexamethylenetetramine (purchased from Aba Ding Shiji, analytically pure, purity is more than or equal to 99.0%) and 100g of 2- (2-chloroacetamido) -5-nitro-2' -chlorobenzophenone (purchased from Beijing carbofuran technology Co., ltd., product No. 1284367, purity is 99%) are added into the reactor in sequence, stirring is started, the temperature is raised to 60-75 ℃, and the reaction is carried out for 16-24 hours under heat preservation. The reaction solution was distilled at normal pressure to recover the solvent.
After recovering the solvent, 600mL of ultrapure water was added to the residual reaction solution, and the distillation was continued under normal pressure until the internal temperature reached 90 to 95 ℃. Cooling to 20-30 ℃, filtering, washing the filter cake with ultrapure water for three times, and drying at 60 ℃ to constant weight. 74.8g of yellow clonazepam crude product are obtained. The crude clonazepam product was tested using High Performance Liquid Chromatography (HPLC).
The chromatographic test data are as follows:
example 2
2100mL of absolute ethyl alcohol and 70g of the clonazepam crude product prepared according to example 1 are added into a reactor, heated to reflux, stirred for 1 hour, cooled to 60-65 ℃, added with 40g of 98wt% concentrated sulfuric acid dropwise, stirred for reaction, cooled to 10-20 ℃, filtered, and a filter cake is washed three times with 300mL of absolute ethyl alcohol and filtered until no liquid drips.
At room temperature, putting the filter cake into a beaker, adding 3500mL of ultrapure water, starting stirring, regulating the pH value of the solution to 8-9 by using 20wt% of NaOH solution, continuously stirring for 4 hours, filtering, washing the obtained filter cake by using 2000mL of ultrapure water, filtering, drying to constant weight at 60 ℃ to obtain 58.9g of white clonazepam primary product, and testing the purity of the white clonazepam primary product by using High Performance Liquid Chromatography (HPLC) to be 99.96%, wherein the single maximum impurity is 0.03%.
The chromatographic test data are as follows:
example 3
Adding 800mL of 95% ethanol into a reaction vessel, purifying in example 2 to obtain 25g of initial product of clonazepam and 5g of active carbon, heating to reflux, preserving heat and stirring for 1 hour, performing heat filtration, cooling filtrate to-10-0 ℃, filtering, drying filter cake at 60 ℃ to constant weight to obtain 22.7g of final product of clonazepam, testing the purity of the final product of clonazepam to 99.98% by High Performance Liquid Chromatography (HPLC), and the maximum single impurity content of 0.016%. The nuclear magnetic hydrogen spectrum of the clonazepam end product is shown in figure 1.
The chromatographic test data are as follows:
nuclear magnetic hydrogen spectrum data of clonazepam end product:
1H NMR(400MHz，Chloroform-d)δ9.89(s,1H),8.35(dd,J＝8.9,2.6Hz,1H),8.00(d,J＝2.6Hz,1H),7.68-7.59(m,1H),7.51-7.44(m,2H),7.42-7.38(m,1H),7.34(d,J＝8.9Hz,1H),4.49(s,2H).
comparative example
Comparative example 1
70g of yellow clonazepam crude product were prepared as in example 1. 1300ml of chloroform was added thereto and dissolved with stirring. After washing with 260ml of ultrapure water 3 times and separating the aqueous layer, 110ml of diluted nitric acid (3 mol/L) was added dropwise to the chloroform solution at room temperature, whereby yellow solid particles were gradually precipitated. After the dripping is finished, stirring and reacting for 2 hours at 20-25 ℃. Filtering, adding the filter cake into 1000ml of ultrapure water, stirring for 1 hour, cooling to below 10 ℃, dropwise adding a saturated sodium bicarbonate pure water solution, and adjusting the pH value to 8.2. Continuously cooling to below 5 ℃ and standing for 2 hours. Filtering, washing with purified water and drying to obtain 27g of clonazepam. The purity was 95.62% by HPLC and the maximum single impurity content was 3.53%.
The chromatographic test data are as follows:
in the purification process of comparative example 1, chloroform is used as a purification solvent, and 3mol/L of aqueous dilute nitric acid is used for salifying, so that tests show that the obtained clonazepam has the advantages of unobvious purification effect, higher content of the largest single impurity and poor purification effect.
Comparative example 2
A yellow clonazepam crude product was prepared as in example 1. The purification was carried out according to the method of comparative example 1 to obtain clonazepam.
Adding 800mL of methanol, absolute ethyl alcohol, isopropanol and 95% ethanol plus ethyl acetate (the volume ratio of the absolute ethyl alcohol to the ethyl acetate is 1:1) into a reaction container respectively, adding 25g of clonazepam respectively, heating to reflux, carrying out heat preservation and stirring for 1 hour, carrying out heat filtration, cooling filtrate to-10-0 ℃, filtering, and drying a filter cake at 60 ℃ to constant weight to obtain a clonazepam final product respectively.
Adding 800mL of 95% ethanol into a reaction vessel, respectively adding 25g of clonazepam, heating to reflux, preserving heat and stirring for 1 hour, performing hot filtration, cooling filtrate to-10-0 ℃, filtering, and drying at 60 ℃ to constant weight to obtain a clonazepam final product. And (3) refining the clonazepam final product with 95% ethanol for the second time, and repeating the above process to obtain the clonazepam final product again.
And testing the obtained clonazepam final product by using HPLC liquid chromatography.
The chromatographic test data are as follows:
as can be seen from the comparison of the data in the example 3 and the comparative example 2, the purity of the clonazepam final product obtained by the purification method provided by the invention can reach 99.98%, and the maximum single impurity content is only 0.016%; in contrast, in comparative example 2, the final clonazepam product had a purity of only 99.78% at the highest and a maximum single impurity content of 0.13%. The method in the embodiment 3 of the invention has good purification effect, and the obtained product has high purity and lower content of single impurity.
The present invention has been described in detail in connection with the detailed description and/or the exemplary examples and the accompanying drawings, but the description is not to be construed as limiting the invention. It will be understood by those skilled in the art that various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its embodiments without departing from the spirit and scope of the present invention, and these fall within the scope of the present invention. The scope of the invention is defined by the appended claims.
Claims (10)
1. The preparation method of the high-purity clonazepam is characterized in that 2- (2-haloacetamido) -5-nitro-2' -chlorobenzophenone is used as a starting material, and the clonazepam is prepared by reaction in the presence of a cyclization agent;
in the 2- (2-halogenated acetamido) -5-nitro-2' -chlorobenzophenone, halogen substituent is iodine substituent, bromine substituent or chlorine substituent;
the cyclization agent is one or more selected from ammonia water, ammonium salt, ammonia gas and hexamethylenetetramine.
2. The method of claim 1, wherein the step of determining the position of the substrate comprises,
the cyclic mixture is ammonium salt and/or hexamethylenetetramine, preferably ammonium salt and hexamethylenetetramine; the ammonium salt is selected from one or more of ammonium sulfate, ammonium bisulfate and ammonium chloride;
preferably, the cyclizing agent is ammonium chloride and hexamethylenetetramine.
3. A method according to claim 1 or 2, characterized in that,
the molar ratio of the 2- (2-haloacetamido) -5-nitro-2' -chlorobenzophenone to the cyclization mixture is 1 (4-20), preferably 1 (6-15), and more preferably 1 (8-11);
when the cyclic agent is an ammonium salt and hexamethylenetetramine, the molar ratio of the ammonium salt to hexamethylenetetramine is (1-7): 1, preferably (1.5-5): 1, and more preferably (2-3): 1.
4. The process according to claim 1, wherein the reaction is carried out in a solvent selected from aromatic hydrocarbon solvents such as toluene, xylene, mesitylene, halogenated hydrocarbon solvents such as chloroform, methylene chloride, alcohol solvents such as methanol, ethanol, isopropanol, butanol, amide solvents such as N, N-dimethylformamide, N-dimethylacetamide, one or more of water, preferably a mixed solvent of water and alcohol solvents selected from one or more of methanol, ethanol and isopropanol, more preferably a mixed solvent of water and ethanol;
the molar volume ratio of the 2- (2-haloacetamido) -5-nitro-2' -chlorobenzophenone to the solvent is 0.3mol (250-750) mL, preferably 0.3mol (350-650) mL, more preferably 0.3mol (450-550) mL.
5. The method according to claim 1, wherein after the completion of the reaction, the obtained reaction solution is subjected to a post-treatment comprising removal of the reaction solvent, distillation purification, salification purification, reflux purification.
6. The method of claim 5, wherein the step of determining the position of the probe is performed,
the reaction solvent removal is performed by normal pressure distillation to recover the solvent, so as to obtain residual reaction liquid;
the distillation and purification are carried out by adding solvent I into residual reaction liquid, then carrying out atmospheric distillation, and heating the fraction to temperature T 0 Above, start cooling, cool to 20-30 deg.C, filter to get the crude product of clonazepam; said temperature T 0 Is a temperature 5 ℃ lower than the boiling point of the solvent I;
the solvent I is selected from one or more of water and alcohol solvents, preferably one or more of water, methanol, ethanol and isopropanol, more preferably water.
7. The method of claim 5, wherein the salification purification comprises the steps of:
step 1-1, adding a clonazepam crude product into a solvent II to form a mixed solution, and heating and refluxing;
step 1-2, after the reflux is finished, cooling the mixed solution, and adding inorganic acid to carry out salt forming reaction;
and step 1-3, dissolving the filter cake obtained in the step 1-2 in a solvent III, adding an alkaline solution, adjusting the pH value to 7-9, and filtering to obtain a clonazepam primary product.
8. The method according to claim 7, wherein, in step 1-1,
the solvent II is selected from one or more of alcohol solvents with boiling points above 70 ℃, preferably one or more of ethanol, propanol and isopropanol, more preferably ethanol or isopropanol;
the reflux temperature is 70 ℃ or higher, preferably 75 to 95 ℃, more preferably 75 to 85 ℃.
9. The method of claim 7, wherein the step of determining the position of the probe is performed,
in the step 1-2, after the reflux is finished, the temperature of the mixed solution is reduced to 60-65 ℃, inorganic acid is added, after the mixture is stirred and fully reacted, the temperature is reduced to 10-20 ℃, and the clonazepam inorganic salt is gradually separated out; the inorganic acid is selected from one or more of hydrochloric acid, nitric acid and sulfuric acid, preferably nitric acid or sulfuric acid, and more preferably sulfuric acid;
in step 1-3, the solvent III is selected from one or more of water and alcohol solvents, preferably one or more of water, methanol, ethanol and isopropanol, more preferably water.
10. The method according to claim 5, wherein the reflux purification comprises dispersing the initial clonazepam product in an alcohol solvent, adding activated carbon, heating and refluxing, stirring for 0.5-1.5 hours, filtering the activated carbon while the activated carbon is hot, cooling the filtrate to-20-5 ℃, preferably-10-0 ℃, precipitating clonazepam, filtering and drying to obtain the final clonazepam product.
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