CN114644570A - Method for removing impurity compounds in lidocaine and product obtained by method - Google Patents
Method for removing impurity compounds in lidocaine and product obtained by method Download PDFInfo
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- CN114644570A CN114644570A CN202011499737.4A CN202011499737A CN114644570A CN 114644570 A CN114644570 A CN 114644570A CN 202011499737 A CN202011499737 A CN 202011499737A CN 114644570 A CN114644570 A CN 114644570A
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- Prior art keywords
- lidocaine
- compound
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- gas
- acetone
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- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 title claims abstract description 94
- 229960004194 lidocaine Drugs 0.000 title claims abstract description 94
- 150000001875 compounds Chemical class 0.000 title claims abstract description 70
- 238000000034 method Methods 0.000 title claims abstract description 65
- 239000012535 impurity Substances 0.000 title abstract description 81
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 81
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 50
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000002360 preparation method Methods 0.000 claims abstract description 30
- 239000007789 gas Substances 0.000 claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000011261 inert gas Substances 0.000 claims abstract description 13
- 230000008569 process Effects 0.000 claims abstract description 11
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 9
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 36
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 31
- 239000000047 product Substances 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000006482 condensation reaction Methods 0.000 claims description 8
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- -1 Phenyl Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical group OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 230000001502 supplementing effect Effects 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 239000004973 liquid crystal related substance Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 34
- 229960004393 lidocaine hydrochloride Drugs 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 6
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 238000001514 detection method Methods 0.000 description 25
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 19
- 229940079593 drug Drugs 0.000 description 17
- 238000004519 manufacturing process Methods 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- FPQQSNUTBWFFLB-UHFFFAOYSA-N 2-chloro-n-(2,6-dimethylphenyl)acetamide Chemical compound CC1=CC=CC(C)=C1NC(=O)CCl FPQQSNUTBWFFLB-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 238000005516 engineering process Methods 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- XPHHNCMLCPTPTL-UHFFFAOYSA-N [ClH](CCCCCCCCCCCCCCC)NC=1C(=CC=CC=1C)C Chemical compound [ClH](CCCCCCCCCCCCCCC)NC=1C(=CC=CC=1C)C XPHHNCMLCPTPTL-UHFFFAOYSA-N 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- 238000011160 research Methods 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 206010067484 Adverse reaction Diseases 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 230000006838 adverse reaction Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- QGQXAMBOYWULFX-LZWSPWQCSA-N 2-morpholin-4-ylethyl (e)-6-(4,6-dihydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound OC=1C=2C(=O)OCC=2C(C)=C(O)C=1C\C=C(/C)CCC(=O)OCCN1CCOCC1 QGQXAMBOYWULFX-LZWSPWQCSA-N 0.000 description 1
- 125000006414 CCl Chemical group ClC* 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 230000002687 intercalation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
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- 239000002245 particle Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000275 quality assurance Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Abstract
The invention discloses a method for removing impurity compounds in lidocaine and an obtained product, which comprises the following steps: adjusting the pH value of a reaction liquid system of lidocaine, hydrochloric acid and acetone to 2.5-3.8 by using hydrogen chloride gas with or without inert gas protection, and then separating and purifying to obtain the lidocaine hydrochloride/acetone hydrochloride/lidocaine hydrochloride/acetone hydrochloride/lidocaine hydrochloride// hydrochloride// acetone; wherein the lidocaine contains a compound shown as a formula II. By the method, the lidocaine can be formed into hydrochloride and/or hydrate to improve water solubility and bioavailability, a small amount of newly-found impurity compounds in the lidocaine can be effectively removed, impurity limit control is carried out on the impurity compounds, and controllable quality of raw material medicine products is further ensured; moreover, the process conditions are mild, and the obtained productThe yield and purity of the lidocaine hydrochloride are high, the impurity content is low, the toxic and side effect is small, the safety is higher, and the safety, effectiveness and stability of the lidocaine hydrochloride (and/or hydrate thereof) and the preparation of the lidocaine hydrochloride can be obviously improved.
Description
Technical Field
The invention belongs to the field of drug (or intermediate product thereof) detection and impurity control, and particularly relates to a method for removing impurity compounds in lidocaine and an obtained product thereof.
Background
The medicine, including raw material medicines and preparations, is used as a special commodity for preventing, treating and/or diagnosing diseases, and the quality of the medicine is related to public health and safety. Therefore, the method ensures the safety, effectiveness and controllable quality, and is the important factor in all processes of research and development, production, storage, clinical application and the like. Whether various impurities in the medicine can be accurately identified and controlled is directly related to the quality controllability and safety of the medicine, is a key link for quality assurance and is an important index for medicine consistency evaluation.
Impurities refer to other substances present in the drug due to the manufacturing process, as well as raw materials, adjuvants, etc. One of the sources of impurities, introduced during the production of the drug, may be due to: (1) differences in process routes and process conditions; (2) the raw materials used are not pure; (3) incomplete reaction; (4) an intermediate product of the reaction; (5) side reaction occurs to generate a byproduct; (6) residues of auxiliary agents such as solvents and catalysts; and so on. The impurities introduced not only reduce the purity of the medicine, but also influence the actual curative effect of the medicine, and even serious patients can cause adverse reactions of the medicine users. Many drug safety incidents occurring at home and abroad in the past decades are mostly related to impurities in the drugs.
However, the problem has not attracted enough attention for a long time in the past, so that certain medicine varieties in China still have small differences in curative effect, adverse reaction and the like compared with imported medicines. However, with the promulgation of the technical guidance principle of chemical drug impurity research (2005) in China, the rudiment of drug impurity research is initially established, the situation of the gap is gradually closed, but the overall level still lags behind the developed countries in Europe and America.
The technical problem of impurity control in drugs is basically summarized into three stages: a medicine purity control stage, an impurity limit control stage and an impurity spectrum control stage. In the past, due to the limitation of the technical level, the control of impurities in the medicine is mainly achieved indirectly by controlling the purity of an API (Active Pharmaceutical Ingredient), but the method has poor specificity, cannot achieve accurate quantification of each impurity, and is gradually replaced by the control technology of impurity limit and impurity mass spectrum. That is, impurity limit control and impurity spectrum control represent the development trend of this technology in the preparation or production of drugs (see: Wangweishu. drug impurity control and evaluation Key technology research [ D ]. Shandong university doctor academic thesis, 2016: "1.2 research concept" section).
Furthermore, the british pharmacopoeia (1988 edition) also specifies: "discovery and control of unknown impurities is more important than known impurities in pharmaceutical products. Under normal production conditions, the drug product should not contain impurities in uncontrolled amounts and of unknown nature ". In the current medicine production and quality standards at home and abroad, the content of impurities is basically detected directly by means of related substances (impurities), residual solvents and the like (see: Wangweishu, medicine impurity control and evaluation Key technology research [ D ]. doctor academic thesis of Shandong university, 2016: 1.2 research concept part), and then technical means which can be devised and tried are removed and/or controlled in the preparation or production process.
In particular to lidocaine, the chemical name is: n- (2, 6-xylyl) -2- (diethylamino) acetamide is a medicament which is clinically applied for many years, has the advantages of quick action, safety, effectiveness, less side effect and the like, and is widely used for local anesthesia and ventricular arrhythmia and the like caused by various reasons. Because lidocaine is hardly soluble in water, and affects absorption and bioavailability of the drug, hydrochloride and/or hydrate thereof are mostly used clinically, wherein lidocaine hydrochloride monohydrate is more common, and the structural formula is as follows:
lidocaine hydrochloride monohydrate
Currently, the related research on the problem of impurity control in the preparation or production of lidocaine is still very crude and still in the initial stage of indirectly achieving impurity control in the drug by controlling the purity of API, such as: CN 102070483A, CN 105294477A, CN 110590590 a, etc., which are not capable of realizing qualitative and/or quantitative detection of impurities in lidocaine production process, are not beneficial to finding new unknown impurities and controlling by methods in the preparation or production process, nor are beneficial to ensuring the product quality of medicines, and further can affect the safety of public medication and the continuous and healthy development of the pharmaceutical industry in China.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
In view of the problems and/or disadvantages of the prior art, it is an object of the present invention to provide a method for removing impurity compounds in lidocaine. By the method, the lidocaine can be formed into hydrochloride (and/or hydrate) to improve water solubility and bioavailability, a small amount of newly-found impurity compounds in the lidocaine can be effectively removed, impurity limit control is carried out on the impurity compounds, and controllable quality of raw material medicine products is further ensured; moreover, the process conditions are mild, the obtained product has high yield and purity, low impurity content, small toxic and side effects and higher safety, and the safety, effectiveness and stability of the lidocaine hydrochloride (and/or hydrate thereof) and the preparation thereof can be obviously improved.
The invention provides a method for removing a compound shown in a formula II in lidocaine, which comprises the following steps: adjusting the pH value of a reaction liquid system of lidocaine, hydrochloric acid and acetone to 2.5-3.8 (such as 3.0, 3.2, 3.4, 3.5, 3.6 and the like) by using hydrogen chloride gas with or without inert gas protection, and then separating and purifying;
wherein the lidocaine contains a compound shown as a formula II;
in the formula, R1Is a carboxyl group, R 21 to 3C1～C3Alkyl-substituted phenyl, R3、R4And R5Independently selected from H, halogen or NR11R12，R11And R12Independently selected from C1～C3An alkyl group.
Further, the air conditioner is provided with a fan,
in the above method for removing a compound represented by the formula II of lidocaine, some reaction parameters may be as follows, and reaction parameters not involved may be as described in any embodiment of the present invention (hereinafter, simply referred to as "the method for removing a compound represented by the formula II of lidocaine"), wherein the compound represented by the formula II is
In the formula, R2Phenyl substituted with 2 methyl groups; preferably, the compound shown as the formula II is
(impurity B).
Further, the air conditioner is provided with a fan,
in the method for removing the compound represented by the formula II in the lidocaine, the content of the compound represented by the formula II in the lidocaine is 0.5% to 50% (for example, 1.0%, 1.5%, 2%, 3%, 5%, 8%, 10%, 20%, 40%, etc.); preferably, the content of the compound shown in the formula II in the lidocaine is 0.5% -5%; more preferably, the content of the compound shown in the formula II in the lidocaine is 0.8% -2.5%.
Further, the air conditioner is provided with a fan,
in the method for removing the compound shown in the formula II in the lidocaine, the pH value of the reaction liquid system is adjusted to 3.0-3.8; preferably, the pH value of the reaction liquid system is adjusted to 3.4-3.6 (namely, 3.5 +/-0.1).
Further, the air conditioner is provided with a fan,
in the method for removing the compound shown in the formula II in the lidocaine, the amount of acetone used per kilogram of lidocaine is 1-20L (including but not limited to 2L, 3L, 5L, 8L, 10L, 15L and the like); preferably, the amount of acetone used per kilogram of lidocaine is 2.5-5L.
In the above method for removing the compound of formula II in lidocaine, the amount of hydrochloric acid may be selected conventionally, for example: the dosage of the hydrochloric acid corresponding to each kilogram of lidocaine is 0.01-0.2 kg (including but not limited to 0.02kg, 0.05kg, 0.1kg, 0.12kg, 0.13kg, 0.15kg and the like); preferably, the dosage of the hydrochloric acid corresponding to each kilogram of lidocaine is 0.1-0.14 kg.
In the above method for removing the compound of formula II in lidocaine, the concentration of hydrochloric acid may be selected conventionally, for example: the molar concentration of the hydrochloric acid is 2-12.5 mol/L (including but not limited to 3mol/L, 5mol/L, 8mol/L, 10mol/L and the like); preferably, the hydrochloric acid is concentrated hydrochloric acid.
In the method for removing the compound shown in the formula II in the lidocaine, the temperature is controlled to be 5-15 ℃ in the process of adjusting the pH value of a reaction liquid system by using hydrogen chloride gas.
In the above method for removing the compound represented by the formula II in lidocaine, the separation and purification comprises the following steps: heating the reaction solution to 45-60 ℃ (including but not limited to 50-57 ℃), then cooling to 0-12 ℃ (including but not limited to 2 ℃, 5 ℃, 10 ℃ and the like), separating out a solid, separating out a target product (lidocaine hydrochloride and/or hydrate thereof), and then recrystallizing by using acetone and water as solvents;
preferably, the volume ratio of acetone to water in the recrystallization solvent is 1 (0.01-0.05), and more preferably 1 (0.02 +/-0.01) (namely 1: 0.01-0.03);
more preferably, said recrystallization comprises the steps of: dissolving the separated target product in acetone and water at the temperature of 45-60 ℃ with or without inert gas protection, then cooling to 30-40 ℃, filtering, concentrating the filtrate, supplementing acetone, then cooling to 0-12 ℃, precipitating solids, separating and drying; wherein, the dosage of acetone and water corresponding to each kilogram of target product is 1-20L (including but not limited to 3L, 5L, 8L, 10L, 15L and the like, the dosage refers to the total dosage of acetone and water), and more preferably, the dosage of acetone and water corresponding to each kilogram of target product is 2-5L.
Further, the air conditioner is characterized in that,
in the method for removing the compound shown in the formula II in the lidocaine, the lidocaine is prepared by the method comprising the following steps:
wherein X is halogen, preferably chlorine or bromine;
the condensation reaction of the compound C with diethylamine (which may be carried out in the absence of a basic substance and a solvent, such as CN 111253273A, or in the presence of a solvent, such as CN 110938012A, or in the presence of a carbonate and a solvent, such as CN 102070483A) with or without inert gas protection to form lidocaine; preferably, the first and second electrodes are formed of a metal,
the compound C comprises
(impurity A), preferably in Compound C
In an amount of0.5％～1.8％。
In the above-mentioned method for preparing lidocaine, some reaction parameters may be as follows, and the reaction parameters not mentioned are as defined in any embodiment of the present invention (hereinafter, referred to as "in the above-mentioned method for preparing lidocaine"), the molar ratio of compound C to diethylamine is 1 (1 to 5) (including but not limited to 1:1.2, 1:1.3, 1:1.5, 1:1.8, 1:2, 1:2.5, 1:3.5, etc.), preferably 1 (1.5 to 3).
In the preparation method of the lidocaine, the condensation reaction is carried out at a reaction temperature of 30-60 ℃, preferably 50-57 ℃.
In the above-mentioned method for producing lidocaine, the end point of the condensation reaction can be controlled and determined by the reaction time and/or the remaining amount of the starting material (compound C) in the reaction solution (as monitored by HPLC, TLC, etc.), for example: the end point of the reaction was regarded as the point at which compound C substantially disappeared (residual amount in the reaction solution: 2 wt%).
Further, the air conditioner is provided with a fan,
in the above-mentioned method for producing lidocaine, the compound C is subjected to a condensation reaction with diethylamine in the presence of a carbonate and a condensation solvent.
In the above method for producing lidocaine, the carbonate is an alkali metal carbonate, preferably sodium carbonate or potassium carbonate.
In the above method for producing lidocaine, the condensation solvent (which is a solvent used in the condensation reaction) is selected from acetone, toluene, or n-hexane, and preferably acetone.
In the preparation method of the lidocaine, the molar ratio of the compound C to the carbonate is 1 (0.5-5) (including but not limited to 1:0.6, 1:0.7, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, 1:2.5, 1:3.5 and the like), and is preferably 1 (0.75-1.2).
In the preparation method of lidocaine, the amount of the condensation solvent used per kilogram of compound C is 1-20L (including but not limited to 2L, 3L, 5L, 8L, 10L, 15L, etc.), and preferably 1.5-6L.
Further, the air conditioner is provided with a fan,
in the method for removing the compound shown in the formula II in the lidocaine, the compound C is prepared by the method comprising the following steps:
wherein X is halogen, preferably chlorine or bromine;
substitution reaction of 2, 6-dimethylaniline with compound Y in the presence of an organic solvent and a basic substance (NH on 2, 6-dimethylaniline) with or without inert gas protection2Substituted with a halogenated acetyl group of compound Y) to form compound C.
In the above-mentioned process for producing compound C, some reaction parameters may be as follows, and reaction parameters not referred to are as described in any of the above schemes (hereinafter referred to as "in the above-mentioned process for producing compound C"): the organic solvent may be a common solvent for such reactions, for example: the organic solvent is selected from dichloromethane, acetone, acetic acid, n-heptane, butyl acetate, isopropyl acetate or methyl tert-butyl ether, etc., and dichloromethane is more preferable.
In the above method for producing compound C, the basic substance is a hydrogen carbonate, a carbonate or an acetate, and more preferably sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate or potassium acetate.
In the above method for producing compound C, the molar ratio of 2, 6-dimethylaniline to compound Y is 1 (1-5) (including but not limited to 1:1.2, 1:1.3, 1:1.5, 1:1.8, 1:2, 1:2.5, 1:3.5, etc.), and more preferably 1 (1.05-1.5).
In the above method for producing compound C, the molar ratio of 2, 6-dimethylaniline to the basic substance is 1 (0.5 to 5) (including but not limited to 1:0.6, 1:0.7, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, 1:2.5, 1:3.5, etc.), and more preferably 1 (0.75 to 1.2).
In the preparation method of the compound C, the amount of the organic solvent used per kg of 2, 6-dimethylaniline is 1-20L (including but not limited to 2L, 3L, 5L, 8L, 10L, 15L, etc.), and more preferably 4-10L per kg of 2, 6-dimethylaniline.
In the preparation method of the compound C, the reaction temperature of the substitution reaction is-8-20 ℃, and preferably-5-15 ℃;
the end point of the substitution reaction can be controlled and determined by the reaction time and/or the amount of the starting material (2, 6-dimethylaniline) remaining in the reaction solution (monitored by TLC or the like), for example: the end point of the reaction is the point at which the 2, 6-dimethylaniline is substantially disappeared (the remaining amount in the reaction solution is less than or equal to 2 wt%).
Another object of the present invention is to provide a pharmaceutical composition with high safety, wherein the pharmaceutical composition has low content of impurity compounds (especially impurity compound B), has few adverse reactions, and effectively controls the content of impurity compounds in raw material drugs such as lidocaine hydrochloride, lidocaine hydrochloride hydrate, etc. or preparations thereof, so as to improve the safety, effectiveness and stability of lidocaine hydrochloride (and/or hydrate thereof) and preparations thereof.
The pharmaceutical composition comprises a lidocaine hydrochloride hydrate and a compound shown as a formula II, wherein the content of the lidocaine hydrochloride hydrate is not less than 99.0% (such as 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% and the like), and the content of the compound shown as the formula II is not more than 0.25%;
in the formula, R1Is a carboxyl group, R 21 to 3C1～C3Alkyl-substituted phenyl, R3、R4And R5Independently selected from H, halogen or NR11R12，R11And R12Independently selected from C1～C3An alkyl group.
In the pharmaceutical composition, preferably, the lidocaine hydrochloride hydrate is lidocaine hydrochloride monohydrate.
In the pharmaceutical composition, preferably, the formula II is shown inThe compound is
In the formula, R2Phenyl substituted with 2 methyl groups; more preferably, the compound represented by the formula II is
(impurity B).
In the pharmaceutical composition, preferably, the content of the compound shown in the formula II is not higher than 0.05%; more preferably, the content of the compound represented by the formula II is not more than 0.02%.
In the pharmaceutical composition, preferably, the pharmaceutical composition is a product obtained by the method for removing the compound shown in the formula II in any one of the lidocaine.
In the invention, the impurity compound can be prepared by the following method:
for example: impurity a, which can be obtained by collecting an eluate having a retention time of about 22.581min (unless otherwise specified, generally referred to as a relative retention time) under the chromatography conditions of the detection method by high performance liquid chromatography using chloroacetyl-2, 6-dimethylaniline obtained in the present invention as a starting material, and removing the solvent to obtain impurity a compound; alternatively, the compound of impurity A can be prepared by the same reaction in the art or a method similar thereto (for example, the method for preparing chloroacetyl-2, 6-dimethylaniline in example 1) using 2, 6-dimethylaniline and dichloroacetyl chloride (CAS number: 79-36-7) as starting materials;
for another example: the impurity B, which can be prepared by using the lidocaine prepared by the present invention as a raw material, collecting the eluent with a retention time of about 9.33min according to the chromatographic conditions of the high performance liquid chromatography detection method in example 1, and removing the solvent to obtain an impurity B compound; alternatively, the impurity compound B may be prepared according to a conventional method in the same reaction or a similar reaction in the art.
Unless otherwise indicated, such data as purity, impurity content, etc. of the target product in the present invention generally refer to the result obtained by HPLC detection and calculation according to the area normalization method.
Unless otherwise indicated, the amounts recited herein generally refer to weight percent amounts.
The invention has the following beneficial effects:
(1) in the preparation of lidocaine or its intermediates, two new impurity compounds were detected and identified for the first time, in addition to the known impurities: the impurity A and the impurity B provide a reliable research foundation for realizing the transformation and upgrading of the technology to the impurity limit control technology and/or the impurity spectrum control technology;
(2) on the basis of the discovery of new impurity problems, solutions are provided: the method realizes qualitative and/or quantitative detection of the impurity A and the impurity B by using an HPLC method, has strong specificity and high separation degree, meets the related requirements on accuracy and precision, and provides necessary support for the smooth implementation of an impurity limit control technology and/or an impurity spectrum control technology, so that the product quality of lidocaine or the salt and hydrate thereof can be monitored more effectively, and the safety of the medicament is guaranteed practically;
(3) the HPLC detection method for the impurity compounds A and/or B has no obvious interference among various spectral peaks, has high separation degree, can realize accurate detection on target products and impurity compounds, is convenient to operate and control, has accurate and reliable detection results, and provides an effective method for monitoring the content of new impurities in lidocaine or intermediates, salts and hydrates thereof;
(4) on the basis of the discovery of new impurity problems, solutions are provided: by utilizing the difference of the structure (whether H in NHC ═ O is substituted by COOH) and the property (the salt forming capability of NH in NHC ═ O and hydrochloric acid is strong, and the salt forming capability of H in NHC ═ O is deteriorated after H in NHC ═ O is substituted by COOH), the lidocaine can form the hydrochloride (and/or hydrate) thereof to improve the water solubility and bioavailability, and can effectively remove a small amount of impurity B in the lidocaine, control the impurity limit of the lidocaine, and further ensure that the product quality is controllable;
(5) the method for removing the impurity compounds in the lidocaine has mild process conditions, the obtained product has high yield and purity, low impurity content, small toxic and side effects, less adverse reactions and higher safety, and the safety, effectiveness and stability of the lidocaine hydrochloride (and/or hydrate thereof) and the preparation of the lidocaine hydrochloride (and/or hydrate thereof) can be obviously improved.
Drawings
FIG. 1 is an HPLC chart of chloroacetyl-2, 6-dimethylaniline, the product obtained in example 1.
FIG. 2 shows the impurity A1H-NMR chart.
FIG. 3 shows the impurity A13C-NMR chart.
FIG. 4 is an HPLC chart of lidocaine, a product obtained in example 1.
FIG. 5 shows the impurity B1H-NMR chart.
FIG. 6 shows the impurity B13C-NMR chart.
FIG. 7 is an HPLC chart of the product lidocaine hydrochloride monohydrate obtained in example 1.
FIG. 8 shows lidocaine hydrochloride monohydrate1H-NMR chart.
FIG. 9 shows lidocaine hydrochloride monohydrate13C-NMR chart.
FIG. 10 is a chart showing the results of DSC measurement of lidocaine hydrochloride monohydrate.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention thereto.
In the present invention, those who do not specify the conditions are performed according to the conventional conditions or the conditions recommended by the manufacturer, and the reagents or apparatuses used are not specified by the manufacturer, and can be obtained by purchasing commercially available products or prepared by known methods.
According to the official literature of the references from Waters Corporation (Watts Corporation), Xterra RP 18 columns are designed to incorporate polar groups (polar intercalation type stationary phases) between the alkyl group and the silica matrix, and have the following schematic structure:
xterra RP 18 and Xterra MS C18, Xterra Phenyl, X-Bridge, ACQUITY UPLC BEH, etc., are among the hybrid particle columns.
See:
1. high performance liquid chromatography column and consumer brief guide 2008-: https:// wenku. ***.com/view/0 baf3d4f240c844768ee62. html, 2015/10/17 upload.
2. Liquid chromatography actual combat discussion (Waters Corporation). https:// www.doc88.com/p-9933637355110.html, upload date: 2014/11/05.
With respect to definitions of terms used herein, the initial definitions provided for the terms herein apply to the terms throughout, unless otherwise specified; terms not specifically defined herein should be given their meanings to those skilled in the art in light of the disclosure and/or the context. In addition, in some cases, the reaction intermediate may be used in subsequent steps without isolation and/or purification.
Example 1
1. Preparation of chloroacetyl-2, 6-dimethylaniline
The method comprises the following steps:
a. under the protection of inert gas (nitrogen), adding 16kg (about 132mol) of 2, 6-dimethylaniline, 11.09kg (about 132mol) of sodium bicarbonate and 96L of dichloromethane into a reaction kettle, uniformly stirring, adding 16.4kg (about 145mol) of chloroacetyl chloride (controlling the temperature in the kettle to be between 5 ℃ below zero and 15 ℃), stirring for reaction for 1 hour at the temperature of between 5 ℃ below zero and 15 ℃, and finishing after the reaction is basically completed (the residual amount of the 2, 6-dimethylaniline is less than or equal to 2 wt%) monitored by GC (gas chromatography) or TLC (thin-layer chromatography);
b. adding 16kg of purified water into a kettle, uniformly stirring, then distilling under reduced pressure (the vacuum degree is less than or equal to-0.09 MPa, and the temperature is 40-45 ℃) until no fraction is produced basically, then adding 176kg of purified water into the kettle, stirring for 2 hours at 15-35 ℃, centrifuging, and drying by air blowing (50-60 ℃) to obtain chloroacetyl-2, 6-dimethylaniline, white powdery solid, and the yield is 97.88% (calculated on the 2, 6-dimethylaniline).
Detecting the product chloracetyl-2, 6-dimethylaniline by High Performance Liquid Chromatography (HPLC), wherein the chromatographic conditions are as follows:
a chromatographic column: waters Xterra RP 18, 4.6 mm. times.250 mm, 5 μm;
mobile phase: 4.85g/L potassium dihydrogen phosphate in water (pH adjusted to 8.0 with sodium hydroxide) -methanol-acetonitrile (60:20: 20);
flow rate: 1.0 mL/min;
a UV detector (detection wavelength 230 nm);
column temperature: 30 ℃;
solvent: water-acetonitrile (1: 1);
the injection volume is 20 mu L;
the HPLC detection result is shown in FIG. 1, the purity of the chloracetyl-2, 6-dimethylaniline (retention time: 10.188min) is 98.98%, and the content of the impurity A (retention time: 22.581min) is 1.00%; the detection method meets the related requirements of accuracy and precision in Chinese pharmacopoeia (2015 edition), and has strong specificity and high separation degree.
Of impurity A1H-NMR(CDCl3See fig. 2)),13C-NMR(CDCl3see fig. 3) and IR detection results, respectively, shown in tables 1-3.
TABLE 1 of impurities A1H-NMR(CDCl3) Detecting data
TABLE 2 of impurities A13C-NMR(CDCl3) Detecting data
TABLE 3 IR detection data of impurity A
| Absorption wave number (cm)-1) | Attribution |
| 2924、2857 | Methyl C-H stretching vibration |
| 1470 | Methyl C-H in-plane rocking |
| 1379 | Methyl C-H shear mode vibration |
| 1541、1604 | C-ring stretching vibration |
| 3038、3008 | C-H stretching vibration of benzene ring |
| 707 | C-Cl stretching vibration |
| 1675 | Amide C ═ O stretching vibration |
| 3442 | N-H stretching vibration |
MS detection of impurity a: m + H+＝231.94。
UV detection of impurity A: the maximum absorption wavelength in acetonitrile-water (1:1) solution was 194.80 nm. Finally, it was determined that impurity a has the following structural formula:
2. preparation of lidocaine
The method comprises the following steps:
i. under the protection of inert gas (nitrogen), adding 24kg (about 121.5mol) of chloroacetyl-2, 6-dimethylaniline (obtained in the previous step), 17.76kg (about 242.8mol) of diethylamine, 13.43kg (about 97.2mol) of potassium carbonate and 120L of acetone into a reaction kettle, stirring and reacting for 10 hours at 50-57 ℃, and finishing after the reaction is basically completed (the residual amount of the chloroacetyl-2, 6-dimethylaniline is less than or equal to 2 wt%) monitored by HPLC (high performance liquid chromatography) or TLC;
ii. Cooling the reaction liquid in the reaction kettle to 20-30 ℃, carrying out suction filtration, leaching a filter cake twice (5kg multiplied by 2) with acetone to obtain a filtrate, carrying out reduced pressure distillation (the vacuum degree is less than or equal to-0.09 MPa, and the temperature is 40-45 ℃) until no fraction is obtained basically, adding 96kg of purified water, stirring for 5 hours at 15-35 ℃, centrifuging, carrying out forced air drying (40-50 ℃) to obtain lidocaine and a white powdery solid, wherein the yield is 95.05% (calculated by chloroacetyl-2, 6-dimethylaniline).
And (3) carrying out High Performance Liquid Chromatography (HPLC) detection on the lidocaine product, wherein the chromatographic conditions are as follows:
a chromatographic column: waters Xterra RP 18, 3.9 mm. times.150 mm, 5 μm;
mobile phase: 4.85g/L potassium dihydrogen phosphate in water (pH adjusted to 8.0 with sodium hydroxide) -acetonitrile (70: 30);
flow rate: 1.0 mL/min;
UV detector (detection wavelength 230 nm);
column temperature: 30 ℃;
solvent: a mobile phase;
the injection volume is 20 mu L;
as a result of HPLC, as shown in fig. 4, the purity of lidocaine (retention time: 14.913min) was 97.95%, the content of impurity B (retention time: 9.330min) was 1.63%, and the content of chloroacetyl-2, 6-dimethylaniline (retention time: 5.520min) was 0.23%; the detection method meets the related requirements of accuracy and precision in Chinese pharmacopoeia (2015 edition), and has strong specificity and high separation degree.
Of impurities B1H-NMR(CDCl3See fig. 5),13C-NMR(CDCl3See fig. 6) and IR detection results, respectively, shown in tables 4-6.
TABLE 4 of impurities B1H-NMR(CDCl3) Detecting data
TABLE 5 of impurities B13C-NMR(CDCl3) Detecting data
TABLE 6 IR detection data of impurity B
| Absorption wave number (cm)-1) | Attribution |
| 2966、2930 | Methyl C-H stretching vibration |
| 1461 | Methyl C-H in-plane wobble |
| 1380 | Methyl C-H shear mode vibration |
| 1537、1603 | C-ring stretching vibration |
| 3048 | C-H stretching vibration of benzene ring |
| 1675 | Amide C ═ O stretching vibration |
MS detection of impurity B: m + Na+＝301.00。
UV detection of impurity B: the maximum absorption wavelength in acetonitrile solution was 194.40 nm. It was finally determined that the structural formula of impurity B is as follows:
3. preparation and purification of lidocaine hydrochloride monohydrate
The method comprises the following steps:
under the protection of inert gas (nitrogen), adding 26kg of lidocaine (obtained in the previous procedure), 3.17kg of concentrated hydrochloric acid (with the concentration of 36-38%) and 78L of acetone into a reaction kettle, stirring and dissolving, introducing hydrogen chloride gas (about 2.8kg of HCl is added) until the pH value of liquid in the kettle is detected to be 3.5 +/-0.1, and controlling the temperature of the liquid in the kettle to be 5-15 ℃ in the process;
secondly, heating the reaction solution in the reaction kettle to 50-57 ℃, stirring for 2h, then cooling to 0-10 ℃, continuing stirring for 8h, centrifuging, and performing vacuum drying (the vacuum degree is less than or equal to-0.09 MPa, and the temperature is 40-45 ℃) to obtain a crude product;
and (3) further purification:
adding 27kg of crude product into 81L of acetone and 1.68kg of purified water under the protection of inert gas (nitrogen), heating to 50-57 ℃, stirring for 2h, then cooling to 30-40 ℃, performing suction filtration, leaching a filter cake twice (5kg multiplied by 2) with acetone to obtain a filtrate, performing reduced pressure distillation (the vacuum degree is less than or equal to-0.09 MPa, the temperature is 25-35 ℃) until no fraction is produced basically, adding 54L of acetone, uniformly stirring, then cooling to 0-10 ℃, continuing stirring for 5h, centrifuging, performing vacuum drying (the vacuum degree is less than or equal to-0.09 MPa, the temperature is 30-50 ℃) to obtain lidocaine hydrochloride monohydrate, white powdery solid with the yield of 81.5%, and the HPLC detection result is shown in figure 7, the product purity is 99.98%, the content of impurity B is less than or equal to 0.02%, the melting point is 75.5-78.5 ℃, and the water content detection value is 6.3% (the theoretical value is 6.23%).
The prepared lidocaine hydrochloride monohydrate was detected as follows:
1H-NMR(D2o) the results of the detection, as shown in FIG. 8;13C-NMR(D2o) detection results, as shown in fig. 9; DSC (Differential Scanning Calorimetry) test results are shown in fig. 10.
The results of X-ray diffraction measurements (instrument model: X-ray diffractometer model XD-6, start angle: 3 °, end angle: 60 °, scanning speed 8 °/min, sampling step width: 0.01, high voltage setting: 36kV, current: 20mA, power: 1.5kW, PEAK: 41-pts/Parabalc Filter, Threshold ═ 5.0, Cutoff ═ 10.0%, BG ═ 5/1.0, Peak-Top ═ Summit) are shown in Table 7.
TABLE 7X-ray diffraction test results for lidocaine hydrochloride monohydrate
Meanwhile, combining the data results of the elemental analysis: c58.58% (theoretical value 58.22%), H8.704% (theoretical value 8.73%), N9.45% (theoretical value 9.70%), and finally it was confirmed that lidocaine hydrochloride monohydrate was obtained.
Examples 2 and 3
The same contents as in example 1 are not repeated, except that in the step a of preparing chloroacetyl-2, 6-dimethylaniline, the amount of chloroacetyl chloride is changed to 132mol and 158.4mol, respectively, that is: 1 equivalent and 1.2 equivalents to finally obtain chloracetyl-2, 6-dimethylaniline and white powdery solid, wherein the yield is more than or equal to 90 percent (calculated by 2, 6-dimethylaniline), the HPLC purity is more than or equal to 98 percent, and the content of the impurity A is within the range of 0.6 to 1.5 percent.
Examples 4 to 6
The same contents as in example 1 are not repeated, except that in the step a of preparing chloroacetyl-2, 6-dimethylaniline, the amount of sodium hydrogencarbonate used was changed to 106mol, 158.4mol, 198mol, respectively, that is: 0.8 equivalent, 1.2 equivalent and 1.5 equivalent to finally obtain the chloracetyl-2, 6-dimethylaniline as white powdery solid, the yield is more than or equal to 95 percent (calculated by 2, 6-dimethylaniline), the HPLC purity is more than or equal to 98 percent, and the content of the impurity A is within the range of 0.6 to 1.5 percent.
Examples 7 and 8
The same contents as in example 1 are not repeated, except that in step i of preparing lidocaine, the amounts of diethylamine used are changed to 121.5mol and 364.5mol, respectively, that is: 1 equivalent and 3 equivalents to finally obtain the lidocaine and the white powdery solid, wherein the yields are 77.4 percent and 96.5 percent respectively (calculated by chloracetyl-2, 6-dimethylaniline), the HPLC purities are more than or equal to 98 percent, and the content of the impurity B is within the range of 1.0 to 2.5 percent.
Examples 9 and 10
The same contents as in example 1 are not repeated, except that in the step i of preparing lidocaine, the amount of potassium carbonate is changed to 48.6mol and 121.5mol, respectively, that is: 0.4 equivalent and 1 equivalent to finally obtain the lidocaine and the white powdery solid, wherein the yield is more than or equal to 80 percent (calculated by chloracetyl-2, 6-dimethylaniline), the HPLC purity is more than or equal to 98 percent, and the content of the impurity B is within the range of 1.0 to 2.5 percent.
Example 11
The same contents as those in the example 1 are not repeated, except that in the step i for preparing the lidocaine, the reaction temperature is adjusted to be 30-35 ℃, the lidocaine is finally obtained, white powdery solid is obtained, the yield is more than or equal to 80% (calculated by chloracetyl-2, 6-dimethylaniline), the HPLC purity is more than or equal to 90%, the content of the impurity B is within the range of 1.0-2.5%, and the content of the chloracetyl-2, 6-dimethylaniline is within the range of 7.0-9.5%.
Examples 12 to 14
The same contents as those in example 1 are not repeated, except that in the first step of preparing lidocaine hydrochloride monohydrate, the amounts of hydrogen chloride gas introduced into the reaction vessel were adjusted to pH values of the liquids in the reaction vessel of 1.0 ± 0.1, 2.0 ± 0.1 and 4.0 ± 0.1, respectively, to finally obtain the lidocaine hydrochloride monohydrate as a white powdery solid, and the yield, HPLC purity and content of impurity B thereof are shown in table 8.
TABLE 8 influence of pH adjustment by hydrogen chloride gas introduction
| Example 12 | Example 13 | Example 1 | Example 14 | |
| Adjusting the pH value | 1.0±0.1 | 2.0±0.1 | 3.5±0.1 | 4.0±0.1 |
| Yield of | 50.2％ | 59.1％ | 81.5％ | 68.5％ |
| HPLC purity | ≥98％ | ≥98％ | 99.98％ | ≥98％ |
| Content of impurity B | Not detected | Not detected | ≤0.02％ | 0.23％ |
While specific embodiments of the invention have been described above, it will be understood by those skilled in the art that this is by way of example only, and that the scope of the invention is defined by the appended claims. Various changes and modifications to these embodiments may be made by those skilled in the art without departing from the spirit and scope of the invention, and these changes and modifications are within the scope of the invention.
Claims (10)
1. The method for removing the compound shown in the formula II in the lidocaine is characterized by comprising the following steps: adjusting the pH value of a reaction liquid system of lidocaine, hydrochloric acid and acetone to 2.5-3.8 by using hydrogen chloride gas with or without inert gas protection, and then separating and purifying to obtain the compound preparation;
wherein the lidocaine contains a compound shown as a formula II;
in the formula, R1Is a carboxyl group, R21 to 3C1～C3Alkyl-substituted phenyl, R3、R4And R5Independently selected from H, halogen or NR11R12，R11And R12Independently selected from C1～C3An alkyl group.
2. The method of claim 1 for removing a compound of formula II from lidocaine, wherein the compound of formula II is
In the formula, R2Phenyl substituted with 2 methyl groups;
preferably, the compound shown as the formula II is
3. The method for removing the compound shown in the formula II in the lidocaine according to claim 1 or 2, wherein the content of the compound shown in the formula II in the lidocaine is 0.5% -50%; preferably, the content of the compound shown in the formula II in the lidocaine is 0.5% -5%; more preferably, the content of the compound shown in the formula II in the lidocaine is 0.8% -2.5%.
4. The method for removing the compound shown in the formula II in the lidocaine as claimed in claim 1 or 2, wherein the pH value of the reaction liquid system is adjusted to 3.0-3.8; preferably, the pH value of the reaction liquid system is adjusted to 3.4-3.6.
5. The method for removing a compound of formula II from lidocaine of claim 1 or 2,
the dosage of acetone corresponding to each kilogram of lidocaine is 1-20L; preferably, the dosage of acetone corresponding to each kilogram of lidocaine is 2.5-5L;
and/or the presence of a gas in the gas,
the dosage of the hydrochloric acid corresponding to each kilogram of lidocaine is 0.01-0.2 kg; preferably, the dosage of the hydrochloric acid corresponding to each kilogram of lidocaine is 0.1-0.14 kg;
and/or the presence of a gas in the atmosphere,
the molar concentration of the hydrochloric acid is 2-12.5 mol/L; preferably, the hydrochloric acid is concentrated hydrochloric acid;
and/or the presence of a gas in the atmosphere,
and controlling the temperature to be 5-15 ℃ in the process of adjusting the pH value of the reaction liquid system by using hydrogen chloride gas.
6. The method for removing the compound shown in the formula II in lidocaine according to claim 1 or 2, wherein the separation and purification comprises the following steps: heating the reaction solution to 45-60 ℃, then cooling to 0-12 ℃, separating out solids, separating out a target product, and then recrystallizing by using acetone and water as solvents;
preferably, the volume ratio of acetone to water in the recrystallization solvent is 1: 0.01-0.05, and more preferably 1:0.02 +/-0.01;
more preferably, said recrystallization comprises the steps of: dissolving the separated target product in acetone and water at the temperature of 45-60 ℃ with or without inert gas protection, then cooling to 30-40 ℃, filtering, concentrating the filtrate, supplementing acetone, then cooling to 0-12 ℃, precipitating solids, separating and drying; the dosage of acetone and water corresponding to each kilogram of target product is 1-20L, and preferably 2-5L.
7. The method for removing the compound shown in the formula II in the lidocaine of claim 1 or 2, wherein the lidocaine is prepared by a method comprising the following steps:
wherein X is halogen, preferably chlorine or bromine;
with or without inert gas protection, carrying out condensation reaction on the compound C and diethylamine to generate lidocaine;
preferably, the first and second liquid crystal display panels are,
the compound C comprises
Preferred compounds are compounds C
The content of (A) is 0.5% -1.8%;
and/or the presence of a gas in the gas,
the molar ratio of the compound C to diethylamine is 1: 1-5, preferably 1: 1.5-3;
and/or the presence of a gas in the atmosphere,
the reaction temperature of the condensation reaction is 30-60 ℃, and preferably 50-57 ℃.
8. The method for removing the compound of formula II in lidocaine according to claim 7, wherein in the method for preparing lidocaine, compound C is subjected to condensation reaction with diethylamine in the presence of carbonate and a condensation solvent;
preferably, the first and second electrodes are formed of a metal,
in the preparation method of lidocaine, the carbonate is an alkali metal carbonate, preferably sodium carbonate or potassium carbonate;
and/or the presence of a gas in the gas,
in the preparation method of lidocaine, the condensation solvent is selected from acetone, toluene or n-hexane, preferably acetone;
and/or the presence of a gas in the gas,
in the preparation method of the lidocaine, the molar ratio of the compound C to the carbonate is 1: 0.5-5, preferably 1: 0.75-1.2;
and/or the presence of a gas in the atmosphere,
in the preparation method of the lidocaine, the dosage of the condensation solvent corresponding to each kilogram of the compound C is 1-20L, and preferably 1.5-6L.
9. The method for removing the compound of formula II in lidocaine of claim 7, wherein the compound C is prepared by a method comprising the steps of:
wherein X is halogen, preferably chlorine or bromine;
carrying out substitution reaction on 2, 6-dimethylaniline and a compound Y in the presence of an organic solvent and an alkaline substance with or without inert gas protection to generate a compound C;
preferably, the first and second electrodes are formed of a metal,
in the preparation method of the compound C, the organic solvent is selected from dichloromethane, acetone, acetic acid, n-heptane, butyl acetate, isopropyl acetate or methyl tert-butyl ether, and dichloromethane is more preferable;
and/or the presence of a gas in the gas,
in the preparation method of the compound C, the alkaline substance is bicarbonate, carbonate or acetate, and is preferably sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium acetate or potassium acetate;
and/or the presence of a gas in the gas,
in the preparation method of the compound C, the molar ratio of the 2, 6-dimethylaniline to the compound Y is 1: 1-5, and preferably 1: 1.05-1.5;
and/or the presence of a gas in the gas,
in the preparation method of the compound C, the molar ratio of the 2, 6-dimethylaniline to the alkaline substance is 1: 0.5-5, and the preferable molar ratio is 1: 0.75-1.2;
and/or the presence of a gas in the atmosphere,
in the preparation method of the compound C, the dosage of the organic solvent corresponding to each kilogram of 2, 6-dimethylaniline is 1-20L, and the dosage of the organic solvent corresponding to each kilogram of 2, 6-dimethylaniline is 4-10L preferably;
and/or the presence of a gas in the gas,
in the preparation method of the compound C, the reaction temperature of the substitution reaction is-8-20 ℃, and preferably-5-15 ℃.
10. The pharmaceutical composition is characterized by comprising lidocaine hydrochloride hydrate and a compound shown as a formula II, wherein the content of the lidocaine hydrochloride hydrate is not less than 99.0%, and the content of the compound shown as the formula II is not more than 0.25%;
in the formula, R1Is a carboxyl group, R21 to 3C1～C3Alkyl-substituted phenyl, R3、R4And R5Independently selected from H, halogen or NR11R12，R11And R12Is independently selected from C1～C3An alkyl group;
preferably, the lidocaine hydrochloride hydrate is lidocaine hydrochloride monohydrate;
preferably, the compound shown as the formula II is
In the formula, R2Phenyl substituted with 2 methyl groups; more preferably, the compound represented by the formula II is
Preferably, the content of the compound shown in the formula II is not higher than 0.05%; more preferably, the content of the compound represented by the formula II is not higher than 0.02%;
preferably, the pharmaceutical composition is a product obtained by the method for removing the compound shown in the formula II in the lidocaine according to any one of claims 1 to 9.
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