CN115557892B - Synthesis method of bupivacaine impurity serving as local anesthetic - Google Patents
Synthesis method of bupivacaine impurity serving as local anesthetic Download PDFInfo
- Publication number
- CN115557892B CN115557892B CN202211084359.2A CN202211084359A CN115557892B CN 115557892 B CN115557892 B CN 115557892B CN 202211084359 A CN202211084359 A CN 202211084359A CN 115557892 B CN115557892 B CN 115557892B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- bupivacaine
- stirring
- mass
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000012535 impurity Substances 0.000 title claims abstract description 33
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 229960003150 bupivacaine Drugs 0.000 title claims abstract description 31
- 239000003589 local anesthetic agent Substances 0.000 title claims abstract description 25
- 238000001308 synthesis method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000002994 raw material Substances 0.000 claims abstract description 22
- QTUGGVBKWIYQSS-UHFFFAOYSA-N 2-iodo-1,3-dimethylbenzene Chemical compound CC1=CC=CC(C)=C1I QTUGGVBKWIYQSS-UHFFFAOYSA-N 0.000 claims abstract description 19
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 claims abstract description 13
- 230000002378 acidificating effect Effects 0.000 claims abstract description 8
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 6
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- 239000002798 polar solvent Substances 0.000 claims description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 13
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 claims description 13
- 238000010828 elution Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 238000005070 sampling Methods 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 239000012141 concentrate Substances 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 239000003480 eluent Substances 0.000 claims description 7
- 239000005457 ice water Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000010790 dilution Methods 0.000 claims description 4
- 239000012895 dilution Substances 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- 229910004298 SiO 2 Inorganic materials 0.000 claims description 3
- 238000010009 beating Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 238000002386 leaching Methods 0.000 claims description 3
- 238000011068 loading method Methods 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- 238000004537 pulping Methods 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 2
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 238000006237 Beckmann rearrangement reaction Methods 0.000 abstract description 2
- 238000006146 oximation reaction Methods 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 239000012071 phase Substances 0.000 description 17
- 238000003760 magnetic stirring Methods 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 229960001050 bupivacaine hydrochloride Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- JCQBWMAWTUBARI-UHFFFAOYSA-N tert-butyl 3-ethenylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(C=C)C1 JCQBWMAWTUBARI-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- -1 2, 6-dimethyl phenyl Chemical group 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229960005015 local anesthetics Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VDXLAYAQGYCQEO-UHFFFAOYSA-N 2-chloro-1,3-dimethylbenzene Chemical group CC1=CC=CC(C)=C1Cl VDXLAYAQGYCQEO-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical class NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000007830 nerve conduction Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- SBOJXQVPLKSXOG-UHFFFAOYSA-N o-amino-hydroxylamine Chemical class NON SBOJXQVPLKSXOG-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D223/08—Oxygen atoms
- C07D223/10—Oxygen atoms attached in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of a local anesthetic bupivacaine impurity, which comprises the steps of reacting 2-cyclohexenone with hydroxylamine hydrochloride to obtain ketoxime (a compound i), producing a seven-membered ring (a compound ii) by the compound i under the catalysis of an acidic medium, and condensing the compound ii with an onium salt formed by 1, 3-dimethyl iodobenzene and benzene to obtain bupivacaine impurity C. The synthesis method of the bupivacaine impurity of the local anesthetic provided by the invention has the advantages that the synthesis route is a brand new route which is explored, and the synthesis method of the bupivacaine impurity of the local anesthetic comprises the following steps: 2-cyclohexenone and 1, 3-dimethyl iodobenzene are used as raw materials, and are subjected to oximation, beckmann rearrangement, salification and substitution of four-step reaction to prepare bupivacaine impurities with quality standard which are determined by European pharmacopoeia.
Description
Technical Field
The invention relates to a synthesis method of a local anesthetic bupivacaine impurity, and belongs to the technical field of medicines.
Background
Local anesthetics are drugs that temporarily and completely block nerve conduction within a defined range within the body, i.e., lose sensation to a portion of the body without loss of consciousness, in order to perform surgery. The local anesthetic has wide application, and can effectively relieve the pain of the operation. The local anesthetics applied to clinic at present have various structural types such as amides, amino ethers, aminoketones, carbamates, amidines and the like, wherein the representative drug bupivacaine of the amide structure has wide clinical application.
Bupivacaine (Bupivacaine) is 1-butyl-N- (2, 6-dimethyl phenyl) -2-piperidine formamide, is a piperidine formamide compound with N-substituted side chains, and is a novel long-acting amide local anesthetic. The bupivacaine hydrochloride has a plurality of reported routes at present, and the classical synthetic route is obtained by taking 2-piperidinecarboxylic acid as a raw material and performing esterification, amidation and hydrochloride formation. Corresponding key impurities can be generated in the process of preparing bupivacaine hydrochloride; because the chemical formula and nuclear magnetic spectrum of all impurities need to be determined in the preparation process of the medicine, the high-purity anesthetic bupivacaine impurities need to be synthesized. The quality standard of bupivacaine hydrochloride is carried in British pharmacopoeia, european pharmacopoeia and United states pharmacopoeia, 6 related impurities A-F of bupivacaine hydrochloride are disclosed in the pharmacopoeia, the structure is shown as follows, few synthetic methods of impurity C are reported in literature, and the method for obtaining the impurity C standard substance is difficult.
Therefore, a synthesis method of impurity C with short synthesis line, simple process, controllable reaction and simple operation is needed.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a synthesis method of a local anesthetic bupivacaine impurity.
In order to solve the technical problems, the invention adopts the following technical scheme:
a synthesis method of local anesthetic bupivacaine impurity, 2-cyclohexenone reacts with hydroxylamine hydrochloride to get ketoxime, namely compound i, compound i produces seven-membered ring under the catalysis of acid medium, namely compound ii, compound ii is condensed with onium salt formed by 1, 3-dimethyl iodobenzene and benzene finally, get bupivacaine impurity C; the specific synthetic route is as follows:
a synthesis method of local anesthetic bupivacaine impurities comprises the following steps:
step one, adding 2-cyclohexenone into a reaction container I, wherein the mass ratio of the 2-cyclohexenone to the hydroxylamine hydrochloride is 10:7.88, and the ratio of the volume mL of the solvent I to the mass g of the 2-cyclohexenone is 10:1; after the addition, carrying out reaction at 60-78 ℃; the reaction is carried out until the raw materials are completely converted, the reaction is cooled to room temperature, the first solvent is removed by decompression concentration, and brown oily matter is obtained, namely the compound i is directly thrown into the next step without purification;
step two, adding an acidic medium into the reaction vessel two, and heating to 100-120 ℃; slowly adding the compound i into the reaction container II at the speed of 2-3 drops for 1 second, reacting at 100-120 ℃ until the reaction of the raw materials is finished, cooling the reactant to below 15 ℃, pouring the cooled reactant into a reaction container III containing ice water equivalent to 50 times of the mass of the compound i, slowly dropwise adding a saturated potassium carbonate aqueous solution into the reaction container III at the speed of 2-3 drops for 1 second, controlling the temperature in the dropwise adding process to be not more than 30 ℃, dropwise adding the solution to the pH=7, extracting six times by using dichloromethane DCM equivalent to 50 times of the mass of the compound i after quenching, merging organic phases, drying, concentrating to obtain a yellow oily compound ii, and directly using the yellow oily compound ii in the next step without purification;
step three, adding 1, 3-dimethyl iodobenzene and dichloromethane DCM into a reaction vessel four, wherein the ratio of the volume mL of the dichloromethane DCM to the mass g of the 1, 3-dimethyl iodobenzene is 100:13.35; stirring at room temperature, protecting with nitrogen, and adding m-chloroperoxybenzoic acid mCPBA into a reaction container IV, wherein the mass ratio of the m-chloroperoxybenzoic acid mCPBA to the 1, 3-dimethyl iodobenzene is 12.85:13.35; stirring until the mixture is dissolved; then dropwise adding benzene into a reaction vessel IV, wherein the mass ratio of benzene to 1, 3-dimethyl iodobenzene is 4.94:13.35, stirring at 20-50 ℃ for at least 30min, cooling to 0-10 ℃, and slowly dropwise adding the trifluoromethanesulfonic acid TFOH into a reaction vessel four by using a constant pressure dropping funnel at the speed of 1 second and 2-3 drops, wherein the mass ratio of the trifluoromethanesulfonic acid TFOH to the 1, 3-dimethyl iodobenzene is 17.27:13.35; stirring after dripping until the raw materials are completely reacted, concentrating dichloromethane DCM under reduced pressure to obtain concentrated solution, adding small polar solvent with the mass volume of 5-10 times of the concentrated solution for recrystallization, and stirring at 0-10 ℃ for crystallization; suction filtering, and separating and purifying the filter cake by an automatic column passing machine to obtain a compound iii;
step four, sequentially adding a compound iii, a compound ii, a base and N, N-dimethylformamide DMF, wherein the mass ratio of the compound ii to the base is 5.74 to a reaction vessel five: 4.19:2.82; the ratio of the volume mL of N, N-dimethylformamide DMF to the mass g of compound iii is 180:5.74; stirring at room temperature, after nitrogen is replaced for at least 3 times, transferring the reaction vessel five into an oil bath, heating and stirring, starting timing reaction when the internal temperature of the reaction vessel five reaches 100 ℃, reacting for 4 hours, detecting by a sampling point plate, taking out the reaction vessel five after the raw materials are reacted completely, concentrating under reduced pressure to remove N, N-dimethylformamide DMF to obtain a concentrate, adding ethyl acetate EA to the concentrate for dilution, adding 1.67 times of the amount of the ethyl acetate EA to the concentrate, washing and separating the diluted ethyl acetate EA by using a saturated sodium chloride aqueous solution, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating the organic phase, adding a weak polar solvent into the concentrated organic phase for pulping, adding 1/6 of the amount of the ethyl acetate EA, filtering, leaching by using the weak polar solvent, obtaining a filter cake, and drying a filter cake to obtain a product.
The first reaction container is a three-mouth bottle; the second reaction container is a three-mouth bottle; the third reaction container is a beaker; the reaction container IV is a single-mouth bottle; the fifth reaction vessel is a three-mouth bottle.
In the fourth step, the alkali is one of potassium tert-butoxide, sodium hydride and potassium hydroxide.
The first solvent is absolute ethyl alcohol.
The acidic medium comprises polyphosphoric acid PPA or phosphorus pentachloride.
The small polar solvent includes isopropyl ether or methyl tertiary butyl ether.
The times of washing and separating the liquid by the saturated sodium chloride is at least 4 times; the amount of saturated sodium chloride used is the same as the amount of the weak polar solvent used for beating each time.
The less polar solvent comprises methyl tertiary butyl ether or isopropyl ether.
The automatic column passing machine type number: biotage Iso-1LSV, column: welflash SiO 2 II, 120gFlash Column,40-63. Mu.m; max pressure 200psi, wet loading diluent is a mixed solvent of dichloromethane DCM and methanol MeOH, wherein DCM: meoh=30: 1, eluting solvent: a: dichloromethane DCM, B: methanol, elution flow rate: 140mL/min,254nm, elution method: A/B,0% -0%3CV,0% -2%2CV,2% -2%3CV,2% -3%3CV,3% -3%5CV,3% -4%3CV,4% -4%5CV,4% -5%3CV, 100 mL/bottle of automatic sample collection, and collection of eluent of 3% -4%3CV and 4% -4%5CV for concentration.
The invention has the beneficial effects that:
the synthetic route of the invention is a brand new route which is explored, and the synthetic method of the bupivacaine impurity of the local anesthetic comprises the following steps: 2-cyclohexenone and 1, 3-dimethyl iodobenzene are used as raw materials, and are subjected to oximation, beckmann rearrangement, salification and substitution of four-step reaction to prepare bupivacaine impurities with quality standard which are determined by European pharmacopoeia.
Drawings
FIG. 1 shows the local anesthetic bupivacaine impurity obtained by the synthesis of the present invention 1 H nuclear magnetic spectrogram;
FIG. 2 shows the local anesthetic bupivacaine impurity obtained by the synthesis of the present invention 13 C nuclear magnetic spectrogram.
Detailed Description
The present invention will be explained in more detail below with reference to the drawings, examples or experimental examples, which are only for illustrating the technical aspects of the present invention, and do not limit the spirit and scope of the present invention.
Example 1
In the embodiment, a synthesis method of a local anesthetic bupivacaine impurity comprises the steps of reacting 2-cyclohexenone with hydroxylamine hydrochloride to obtain ketoxime (a compound i), producing a seven-membered ring (a compound ii) by the compound i under the catalysis of an acidic medium, and condensing the compound ii with an onium salt formed by 1, 3-dimethyl iodobenzene and benzene to obtain bupivacaine impurity C. The specific synthetic route is as follows:
the embodiment provides a synthesis method of local anesthetic bupivacaine impurities, which comprises the following steps:
(a) Taking 250mL three-necked flask, inserting the flask into a thermometer, setting up magnetic stirring and a reflux pipe, sequentially adding 2-cyclohexenone (10.0 g), hydroxylamine hydrochloride (7.88 g) and 100mL absolute ethanol, stirring, and reacting at 78 ℃ after adding; the reaction is stopped until the raw materials are completely converted; after the reaction is finished, cooling to room temperature, and removing absolute ethyl alcohol serving as a solvent by screwing to obtain a brown oily substance which is 9.83g of a target product, and directly throwing the target product into the next step without purification.
(b) A100 mL three-necked flask was taken, inserted into a thermometer, magnetically stirred, 80mL polyphosphoric acid (PPA) was first added, and the temperature was raised to 120℃with stirring in an oil bath. Slowly adding 9.83g of a product i into the system, after the addition, carrying out heat preservation reaction for 2 hours, completely reacting the raw materials, stopping the reaction, extracting an oil bath, cooling to room temperature, preparing a 2L beaker, adding a proper amount of ice water, pouring the reaction liquid into the ice water, slowly dropwise adding a saturated potassium carbonate aqueous solution into the beaker through magnetic stirring, controlling the temperature of the liquid solution in the beaker to be below 15 ℃, measuring the pH=7 of the beaker solution, after the quenching is finished, extracting with DCM (400 mL of x 6), merging the organic phases, washing the organic phases once with a saturated sodium chloride aqueous solution (60 mL of x 1), drying the organic phases by adding anhydrous sodium sulfate, and concentrating to obtain yellow oily substance, thereby obtaining the compound ii7.36g.
(c) A500 mL single-port bottle is taken, a thermometer is inserted, magnetic stirring is carried out, 1, 3-dimethyl iodobenzene (13.35 g) and DCM (100 mL) are added, stirring is carried out at room temperature, nitrogen protection is carried out, mCPBA (12.85 g) is added into the system, stirring is carried out until the mixture is clear, benzene (4.94 g) is dropwise added into the system, stirring is carried out at room temperature for 30min, the mixture is transferred into an ice water bath for cooling to about 0 ℃ at the inner temperature, TFOH (17.27 g) is dropwise added into the system by using a constant pressure dropping funnel, the ice water bath is removed after the dropwise adding, a sampling point plate is removed for 0.5-2 h, the raw materials are completely reacted, DCM is concentrated under reduced pressure, and 10 equivalent mass volume isopropyl ether (130 mL) is added, and stirring crystallization is carried out under the ice water bath. Suction filtration, and separating and purifying the filter cake by an automatic column machine to obtain a compound iii 10.33g, ESI-MS m/z calcd: c (C) 15 H 14 F 3 IO 3 S([M+H] + );309.03,found:309.01。
Automatic column passing model number: biotage Iso-1LSV; column: welflash SiO 2 -ii, 120g Flash Column,40-63 μm Max pressure 200psi (14 bar), wet loading (diluent is DCM and MeOH mixed solvent, DCM: meoh=30:1), eluting solvent: a: dichloromethane DCM, B: methanol, elution flow rate: 140mL/min,254nm, elution method: A/B,0% -0%3CV,0% -2%2CV,2% -2%3CV,2% -3%3CV,3% -3%5CV,3% -4%3CV,4% -4%5CV,4% -5%3CV, 100 mL/bottle of automatic sample collection, and collection of 3% -4%3CV,4% -4%5CV of eluent for concentration.
CV represents column volume.
0% -0%2CV represents 100% of phase A and 0% of phase B;
0% -0%3CV represents 100% phase A elution 3 column volumes.
0% -2%2CV represents elution with 2 column volumes of eluent, increasing the proportion of phase B from 0% isocratic to 2% and decreasing the proportion of phase A from 100% to 98%;
2% -2%3CV represents 98% of phase A and 2% of phase B, and the ratio is kept unchanged for eluting 3 column volumes;
2% -3%3cv represents elution with 3 column volumes of eluent, wherein phase B is increased from 2% isocratic to 3% and phase a is reduced from 98% to 97%;
3% -3%5CV represents 97% of phase A and 3% of phase B, and the elution is carried out for 5 column volumes while keeping the ratio unchanged;
3% -4%3CV represents elution with 3 column volumes of eluent, wherein phase B is increased from 3% isocratic to 4% and phase A is reduced from 97% to 96%;
4% -4%5CV represents 96% of phase A and 4% of phase B, and the elution is carried out for 5 column volumes while keeping the ratio unchanged;
4% -5%3CV represents elution with 3 column volumes of eluent, wherein phase B is increased from 4% isocratic to 5% and phase A is reduced from 96% to 95%.
(d) Taking 500mL three-port bottles, setting up magnetic stirring, sequentially adding a compound iii (5.74 g), a compound ii (4.19 g), potassium tert-butoxide (2.82 g), stirring at room temperature for 3 times, transferring into an oil bath, heating and stirring at an internal temperature of 100 ℃, starting timing reaction, reacting for 4 hours, detecting a sampling point plate, completely reacting the raw materials, taking out, concentrating under reduced pressure to remove DMF, diluting with 300mL EA, washing and separating with a saturated sodium chloride aqueous solution (50 mL of 4), drying an organic phase with a proper amount of anhydrous sodium sulfate, filtering, concentrating the organic phase, adding 50mL of methyl tert-butyl ether for pulping, filtering, and leaching a filter cake to obtain a pure product. The filter cake was dried in vacuo at 55deg.C for 4h to give 1.74g of product. Yield: 64.4%. The yield of this example was molar. The nuclear magnetism is as follows: as shown in figure 1 of the drawings, 1 H NMR(500MHz,CDCl 3 )δ7.14–7.07(m,3H),6.36(dt,J=12.1,5.1Hz,1H),6.13(dt,J=12.3,1.4Hz,1H),3.61–3.54(m,2H),2.51(qd,J=6.8,1.4Hz,2H),2.24(s,6H),2.19–2.13(m,2H)。
as shown in the figure 2 of the drawings, 13 C NMR(126MHz,CDCl 3 )δ167.88ppm,142.73ppm,139.29ppm,135.06ppm,128.79ppm,127.58ppm,127.26ppm,50.03ppm,28.94ppm,28.45ppm,18.69ppm。
ESI-MS m/z calcd:C 14 H 17 NO([M+H] + );216.07,found:216.17。
example 2
This example provides a method for preparing a synthetic method for the local anesthetic bupivacaine impurity, which is substantially identical to that of example 1, except that: in the step (b), the acidic medium is phosphorus pentachloride, and the other operation steps have the same feeding amount and operation method, and finally the product of 1.68g is obtained. Yield: 62.2%.
Example 3
This example provides a method for synthesizing bupivacaine impurity as a local anesthetic, which is substantially the same as in example 1, except that: in the step (c), methyl tertiary butyl ether serving as a small polar solvent is added, and other operation steps are carried out, wherein the feeding amount is the same as that of the operation method, and finally, 1.39g of a product is obtained. Yield: 51.2%.
Example 4
This example provides a method for synthesizing bupivacaine impurity as a local anesthetic, which is substantially the same as in example 1, except that: in the step (d), isopropyl ether serving as a weak polar solvent is added, and other operation steps are carried out, wherein the feeding amount is the same as that of the operation method, and finally 1.55g of a product is obtained. Yield: 57.4%.
Example 5
This example provides a method for synthesizing bupivacaine impurity as a local anesthetic, which is substantially the same as in example 1, except that: in the step (a), the operation method and the feeding amount are kept consistent, except that the reaction is carried out at 60 ℃ to obtain brown oily matter which is the target product i 7.42g, and the reaction is directly fed into the next step without purification. In the step (b), the operation method, the feeding amount and the post-treatment mode are kept consistent, the reaction is carried out at 100 ℃ after different feeding, and the yellow oily matter is obtained by concentration, so that the compound i6.38g is obtained. Step C remained the same as in example 1. In the step (d), sodium hydride is selected as the base, the operation method, the feeding amount and the post-treatment mode are kept consistent, and finally 1.04g of product is obtained. Yield: 38.7%.
Example 6
This example provides a method for synthesizing bupivacaine impurity as a local anesthetic, which is substantially the same as in example 1, except that: in the step (d), the alkali is sodium tert-butoxide, and other operation steps, the feeding amount and the post-treatment method are the same, so that 1.21g of a product is obtained. Yield: 44.7%.
Example 7
This example provides a method for synthesizing bupivacaine as a local anesthetic, which differs from that in example 1 in that: in the step (d), 50mL of a three-port bottle is taken, magnetic stirring is carried out, compound iii (0.50 g), compound ii (0.36 g), potassium hydroxide (0.12 g), 10mL of LDMF (methyl tert-butyl ether) are sequentially added, stirring is carried out at room temperature, nitrogen is replaced for 3 times, the mixture is transferred into an oil bath, heating and stirring are carried out, the reaction is carried out at an inner temperature of 100 ℃, the sampling point plate is used for detecting that the raw materials are not reacted completely, the sampling point plate is used for monitoring that the raw materials are still not reacted completely, the post-treatment is directly carried out, the DMF is taken out, reduced pressure concentration is carried out to remove DMF, 50mL of EA is added for dilution, saturated sodium chloride aqueous solution is used for washing and separating liquid (25 mL of 4), the organic phase is dried by a proper amount of anhydrous sodium sulfate, filtration and concentrated organic phase is added with 50mL of methyl tert-butyl ether for beating, suction filtration and 10mL of methyl tert-butyl ether is leached, and a filter cake is a pure product. The filter cake was dried in vacuo at 55deg.C for 4h to give 0.07g of product. Yield: 29.2%.
Comparative example 1
Taking a 250mL three-port bottle, setting up magnetic stirring, sequentially adding 2-chloro-m-xylene (1.10 g), a compound ii (5.00 g), cuprous iodide (0.86 g), 100mL acetonitrile, N, N-dimethyl ethylenediamine (0.20 g), sodium hydride (3.60 g), stirring at room temperature, replacing nitrogen for 3 times, transferring to an oil bath, heating, refluxing and stirring for reaction for 10 hours, detecting a sampling point plate, wherein raw materials are not reacted completely, no obvious new points are generated, and a final product cannot be obtained.
Comparative example 2
Taking a 100mL three-necked flask, setting up magnetic stirring, sequentially adding 1, 3-dimethyl-2-iodobenzene (0.50 g), a compound ii (0.36 g), potassium carbonate (0.86 g), cuprous iodide (0.04 g), 10mL DMSO, stirring at room temperature, replacing nitrogen for 3 times, transferring to an oil bath, heating to 110 ℃ for reaction for 16 hours, detecting a sampling point plate, wherein the raw materials are unreacted, no obvious new point is generated, and the final product cannot be obtained.
The alkali is changed into strong alkali such as sodium hydride, potassium phosphate, sodium methoxide, potassium tert-butoxide and the like, and the raw materials are unreacted and have no new point.
The solvent is changed into toluene, 1, 4-dioxane, DMF, xylene and other solvents, and the raw materials are unreacted and have no new point. Indicating that the final product was not obtained.
Comparative example 3
Taking 100mL three-port bottles, carrying out magnetic stirring, sequentially adding 1, 3-dimethyl-2-iodobenzene (1.04 g), a compound ii (0.50 g), sodium methoxide (0.61 g), N, N-dimethyl ethylenediamine (0.08 g), cuprous iodide (0.43 g), 15mL DMF, stirring at room temperature, replacing nitrogen for 3 times, transferring to an oil bath, heating to 150 ℃ for reaction for 24 hours, detecting a sampling point plate, and obtaining a final product of 0.10g with a yield less than 1.0% when the raw materials are not fully reacted but new points are generated.
The foregoing is only a preferred embodiment of the invention, it being noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the invention.
Claims (7)
1. A synthesis method of a local anesthetic bupivacaine impurity is characterized in that ketoxime obtained by reacting 2-cyclohexenone with hydroxylamine hydrochloride, namely a compound i, wherein the compound i is catalyzed by an acidic medium to produce a seven-membered ring, namely a compound ii, and the compound ii is finally condensed with onium salt formed by 1, 3-dimethyl iodobenzene and benzene to obtain bupivacaine impurity C; the specific synthetic route is as follows:
2. the synthesis method according to claim 1, comprising the steps of:
step one, adding 2-cyclohexenone into a reaction container I, wherein the mass ratio of the 2-cyclohexenone to the hydroxylamine hydrochloride is 10:7.88, and the ratio of the volume mL of the solvent I to the mass g of the 2-cyclohexenone is 10:1; after the addition, carrying out reaction at 60-78 ℃; the reaction is carried out until the raw materials are completely converted, the reaction is cooled to room temperature, the first solvent is removed by decompression concentration, and brown oily matter is obtained, namely the compound i is directly thrown into the next step without purification;
step two, adding an acidic medium into the reaction vessel two, and heating to 100-120 ℃; slowly adding the compound i into the reaction container II at the speed of 2-3 drops for 1 second, reacting at 100-120 ℃ until the reaction of the raw materials is finished, cooling the reactant to below 15 ℃, pouring the cooled reactant into a reaction container III containing ice water equivalent to 50 times of the mass of the compound i, slowly dropwise adding a saturated potassium carbonate aqueous solution into the reaction container III at the speed of 2-3 drops for 1 second, controlling the temperature in the dropwise adding process to be not more than 30 ℃, dropwise adding the solution to the pH=7, extracting six times by using dichloromethane DCM equivalent to 50 times of the mass of the compound i after quenching, merging organic phases, drying, concentrating to obtain a yellow oily compound ii, and directly using the yellow oily compound ii in the next step without purification;
step three, adding 1, 3-dimethyl iodobenzene and dichloromethane DCM into a reaction vessel four, wherein the ratio of the volume mL of the dichloromethane DCM to the mass g of the 1, 3-dimethyl iodobenzene is 100:13.35; stirring at room temperature, protecting with nitrogen, and adding m-chloroperoxybenzoic acid mCPBA into a reaction container IV, wherein the mass ratio of the m-chloroperoxybenzoic acid mCPBA to the 1, 3-dimethyl iodobenzene is 12.85:13.35; stirring until the mixture is dissolved; then dropwise adding benzene into a reaction vessel IV, wherein the mass ratio of benzene to 1, 3-dimethyl iodobenzene is 4.94:13.35, stirring at 20-50 ℃ for at least 30min, cooling to 0-10 ℃, and slowly dropwise adding the trifluoromethanesulfonic acid TFOH into a reaction vessel four by using a constant pressure dropping funnel at the speed of 1 second and 2-3 drops, wherein the mass ratio of the trifluoromethanesulfonic acid TFOH to the 1, 3-dimethyl iodobenzene is 17.27:13.35; stirring after dripping until the raw materials are completely reacted, concentrating dichloromethane DCM under reduced pressure to obtain concentrated solution, adding small polar solvent with the mass volume of 5-10 times of the concentrated solution for recrystallization, and stirring at 0-10 ℃ for crystallization; suction filtering, and separating and purifying the filter cake by an automatic column passing machine to obtain a compound iii;
step four, sequentially adding a compound iii, a compound ii, a base and N, N-dimethylformamide DMF, wherein the mass ratio of the compound ii to the base is 5.74 to a reaction vessel five: 4.19:2.82; the ratio of the volume mL of N, N-dimethylformamide DMF to the mass g of compound iii is 180:5.74; stirring at room temperature, after nitrogen is replaced for at least 3 times, transferring a reaction vessel five into an oil bath, heating and stirring, starting timing reaction when the internal temperature of the reaction vessel five reaches 100 ℃, reacting for 4 hours, detecting by a sampling point plate, taking out the reaction vessel five after the raw materials react completely, concentrating under reduced pressure to remove N, N-dimethylformamide DMF to obtain a concentrate, adding ethyl acetate EA into the concentrate for dilution, adding 1.67 times of the amount of the ethyl acetate EA into the concentrate, washing and separating the concentrate by using a saturated sodium chloride aqueous solution after dilution, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating the organic phase, adding a weak polar solvent into the concentrated organic phase for pulping, adding 1/6 of the amount of the ethyl acetate EA into the concentrated organic phase, leaching by using the weak polar solvent, obtaining a filter cake, and drying a filter cake to obtain a product;
the small polar solvent is isopropyl ether or methyl tertiary butyl ether;
the weak polar solvent is methyl tertiary butyl ether or isopropyl ether.
3. The method according to claim 2, wherein in the fourth step, the base is one of potassium tert-butoxide, sodium hydride and potassium hydroxide.
4. The method of claim 2, wherein the first solvent is absolute ethanol.
5. The synthetic method according to claim 1 or 2, characterized in that the acidic medium is polyphosphoric acid PPA or phosphorus pentachloride.
6. The method of claim 2, wherein the saturated sodium chloride is washed and separated at least 4 times; the amount of saturated sodium chloride used is the same as the amount of the weak polar solvent used for beating each time.
7. The method of synthesis according to claim 2, wherein the automatic column passing model number: biotage Iso-1LSV, column: welflash SiO 2 II, 120g Flash Column,40-63. Mu.m; max pressure 200psi, wet loading diluent is a mixed solvent of dichloromethane DCM and methanol MeOH, whichDCM of (iv): meoh=30: 1, eluting solvent: a: dichloromethane DCM, B: methanol, elution flow rate: 140mL/min,254nm, elution method: A/B,0% -0%3CV,0% -2%2CV,2% -2%3CV,2% -3%3CV,3% -3%5CV,3% -4%3CV,4% -4%5CV,4% -5%3CV, 100 mL/bottle of automatic sample collection, and collection of eluent of 3% -4%3CV and 4% -4%5CV for concentration.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211084359.2A CN115557892B (en) | 2022-09-06 | 2022-09-06 | Synthesis method of bupivacaine impurity serving as local anesthetic |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211084359.2A CN115557892B (en) | 2022-09-06 | 2022-09-06 | Synthesis method of bupivacaine impurity serving as local anesthetic |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115557892A CN115557892A (en) | 2023-01-03 |
CN115557892B true CN115557892B (en) | 2024-03-12 |
Family
ID=84739783
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211084359.2A Active CN115557892B (en) | 2022-09-06 | 2022-09-06 | Synthesis method of bupivacaine impurity serving as local anesthetic |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115557892B (en) |
-
2022
- 2022-09-06 CN CN202211084359.2A patent/CN115557892B/en active Active
Non-Patent Citations (6)
Title |
---|
Lucchetti Nicola.Sterically Congested 2,6-Disubstituted Anilines from Direct C-N Bond Formation at an Iodine(III) Center.Angewandte Chemie, International Edition.2016,第55卷(第42期),13335-13339. * |
Mueller Alexander.Synthesis of (3R,4R)-3-amino-4-hydroxyhexahydroazepine, the chiral constituent of the antibiotic ophiocordin.Liebigs Annalen der Chemie.1993,651-655. * |
Regiospecific N-Arylation of Aliphatic Amines under Mild and Metal-Free Reaction Conditions;Purkait Nibadita,等;Angewandte Chemie International Edition;第57卷(第35期);11427-11431 * |
Transition metal-free N-arylation of amino acid esters with diaryliodonium salts;Kervefors Gabriella,等;Chemistry - A European Journal;第27卷(第18期);5790-5795 * |
Transition-Metal-Free N-Arylation of Pyrazoles with Diaryliodonium Salts;Gonda Zsombor,等;Chemistry - A European Journal;第21卷(第47期);16801-16806 * |
国家药典委员会.中国人民共和国药典 2020年版 二部.中国医药科技出版社,2020,(第2020版),665-666. * |
Also Published As
Publication number | Publication date |
---|---|
CN115557892A (en) | 2023-01-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3386945A1 (en) | Solid forms of (2r,4s)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2- -methylpentanoic acid ethyl ester, its salts and a preparation method | |
CA2954276C (en) | Process for the preparation of 4-alkoxy-3-hydroxypicolinic acids | |
EP1136470B1 (en) | Process for the preparation of a piperazine derivative | |
JP2005507900A (en) | Citalopram manufacturing method | |
CN115557892B (en) | Synthesis method of bupivacaine impurity serving as local anesthetic | |
CN112679498B (en) | Quaternary ammonium sulfonate compound and preparation method and application thereof | |
IE59396B1 (en) | Process for the preparation of 2-alkoxy-n-(1-azabicyclo(2.2.2)octan-3-yl)amino-benzamides | |
CN111039852A (en) | N-ethylpyridine methylamine hydrochloride crystal, preparation process and application thereof in preparation of tropicamide | |
JP2022515070A (en) | Amide derivative impurities and their use | |
CN115960059A (en) | Method for synthesizing furosemide impurity D with high yield and high purity | |
CN111747926B (en) | Improved synthetic process method of topiramate free base | |
CN112110879B (en) | Preparation method of sulcardine free alkali | |
CN111732586B (en) | Crystal form of alkynyl-containing compound salt, preparation method and application | |
CN110818678B (en) | Method for preparing cyclohexane derivative | |
SI21850A (en) | Salts of olanzapin and their transformation into free base of olanzapin | |
US6545149B2 (en) | Synthesis and crystallization of piperazine ring-containing compounds | |
CN113072514A (en) | Preparation method of cycleanine and intermediate thereof | |
CN114957288B (en) | Synthesis method of tetramisole hydrochloride | |
CN111943979B (en) | Ifosfamide intermediate, preparation method and application thereof | |
CN114085209B (en) | Method for purifying loratadine key intermediate | |
CN116947691B (en) | Preparation method of fluvoxamine maleate | |
CN114075153B (en) | Preparation method of voathixetine impurity | |
CN117903138A (en) | Preparation method and application of larotinib | |
JPH0411544B2 (en) | ||
CN117327021A (en) | Method for removing sticky impurities in hexahydropyridazine synthesis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |