CN115650918A - Preparation process of high-purity low-impurity 10-methoxyiminostilbene - Google Patents
Preparation process of high-purity low-impurity 10-methoxyiminostilbene Download PDFInfo
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- CN115650918A CN115650918A CN202211473593.4A CN202211473593A CN115650918A CN 115650918 A CN115650918 A CN 115650918A CN 202211473593 A CN202211473593 A CN 202211473593A CN 115650918 A CN115650918 A CN 115650918A
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- ZKHZWXLOSIGIGZ-UHFFFAOYSA-N 5-methoxy-11h-benzo[b][1]benzazepine Chemical compound COC1=CC2=CC=CC=C2NC2=CC=CC=C12 ZKHZWXLOSIGIGZ-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000012535 impurity Substances 0.000 title claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 26
- -1 2-benzyl amino benzyl cyanide Chemical compound 0.000 claims abstract description 21
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 14
- 230000009471 action Effects 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 238000007069 methylation reaction Methods 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000011230 binding agent Substances 0.000 claims abstract description 8
- 150000008359 benzonitriles Chemical class 0.000 claims abstract description 7
- 230000003197 catalytic effect Effects 0.000 claims abstract description 6
- 238000006482 condensation reaction Methods 0.000 claims abstract description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 6
- 238000007327 hydrogenolysis reaction Methods 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 230000011987 methylation Effects 0.000 claims abstract description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 230000008569 process Effects 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 28
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 14
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 13
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- BXIPSZXSJGYTBO-UHFFFAOYSA-N 2-[2-(benzylamino)phenyl]acetonitrile Chemical compound N#CCC1=CC=CC=C1NCC1=CC=CC=C1 BXIPSZXSJGYTBO-UHFFFAOYSA-N 0.000 claims description 7
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 7
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000005489 Bromoxynil Substances 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical group 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000012022 methylating agents Substances 0.000 claims description 3
- NHWQMJMIYICNBP-UHFFFAOYSA-N 2-chlorobenzonitrile Chemical compound ClC1=CC=CC=C1C#N NHWQMJMIYICNBP-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims description 2
- 229910000020 calcium bicarbonate Inorganic materials 0.000 claims description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 2
- 229940102396 methyl bromide Drugs 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 8
- 238000006243 chemical reaction Methods 0.000 abstract description 18
- 239000002994 raw material Substances 0.000 abstract description 8
- 239000007791 liquid phase Substances 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 238000001914 filtration Methods 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 238000005406 washing Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 229910001220 stainless steel Inorganic materials 0.000 description 10
- 239000010935 stainless steel Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000004821 distillation Methods 0.000 description 8
- 239000012071 phase Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 229960001816 oxcarbazepine Drugs 0.000 description 4
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- AFMPMSCZPVNPEM-UHFFFAOYSA-N 2-bromobenzonitrile Chemical compound BrC1=CC=CC=C1C#N AFMPMSCZPVNPEM-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- PLAZTCDQAHEYBI-UHFFFAOYSA-N 2-nitrotoluene Chemical compound CC1=CC=CC=C1[N+]([O-])=O PLAZTCDQAHEYBI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- ODCATTUUPYWMMI-DHZHZOJOSA-N (e)-3-(4-aminophenyl)-1-phenylprop-2-en-1-one Chemical compound C1=CC(N)=CC=C1\C=C\C(=O)C1=CC=CC=C1 ODCATTUUPYWMMI-DHZHZOJOSA-N 0.000 description 1
- PXWYZLWEKCMTEZ-UHFFFAOYSA-N 1-ethyl-2-nitrobenzene Chemical compound CCC1=CC=CC=C1[N+]([O-])=O PXWYZLWEKCMTEZ-UHFFFAOYSA-N 0.000 description 1
- ZSMRRZONCYIFNB-UHFFFAOYSA-N 6,11-dihydro-5h-benzo[b][1]benzazepine Chemical compound C1CC2=CC=CC=C2NC2=CC=CC=C12 ZSMRRZONCYIFNB-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- DBUMSTYCMHUGMT-UHFFFAOYSA-N OP(O)(=O)OP(=O)(O)O.NC1=C(C=CC=C1)CC Chemical compound OP(O)(=O)OP(=O)(O)O.NC1=C(C=CC=C1)CC DBUMSTYCMHUGMT-UHFFFAOYSA-N 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000003403 chloroformylation reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000006198 methoxylation reaction Methods 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 239000000126 substance 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
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The application discloses a preparation process of high-purity low-impurity 10-methoxyiminostilbene, which comprises the following steps: s1: adding 2-benzyl amino benzyl cyanide, an acid-binding agent and 2-halogenated benzonitrile into a solvent A to prepare a compound I through substitution reaction; s2: in a solvent B, under the action of alkali 1, carrying out intramolecular condensation reaction on a compound I, then carrying out hydrolysis reaction, and acidifying with hydrochloric acid to obtain a compound II; s3: in a solvent C, under the action of alkali 2, carrying out methylation reaction on a compound II and a methylation reagent to obtain a compound III; s4: in a solvent D, under the action of a hydrogenation catalyst, the compound III is subjected to catalytic hydrogenolysis reaction to remove benzyl to obtain the 10-methoxy iminostilbene. The 10-methoxy iminostilbene prepared by the preparation process has high purity and low impurity content; the preparation process conditions are easy to realize, the operation is simple, convenient and safe, the reaction conditions are mild, the process flow is short, and the post-treatment is simple; the raw materials are cheap and easy to obtain, and the cost is low.
Description
Technical Field
The application relates to the technical field of pharmaceutical chemistry and chemical engineering, in particular to a preparation process of high-purity low-impurity 10-methoxyiminostilbene.
Background
10-methoxyiminostilbene, having the english name 10-Methoxy Iminostilbene, also known as 10-Methoxy-5H-dibenzo [ b, f ] azepine, having CAS number 4698-11-7, having the molecular formula C15H13NO, is a yellowish to off-white crystal, is a chemical intermediate, and can be used for the preparation of the drug oxcarbazepine. Oxcarbazepine gradually becomes a global first-line broad-spectrum antiepileptic drug with unique antiepileptic mechanism and definite curative effect and safety, and has a wider market.
The method comprises the steps of condensing ortho-nitrotoluene under the action of formate and strong base to obtain 2,2 '-di (2-nitrophenyl) ethane, reducing and salifying phosphoric acid to obtain 2,2' -di (2-aminophenyl) ethane diphosphate, cyclizing at the high temperature of 260-300 ℃ to prepare 10,11-dihydro-5H-dibenzo [ b, f ] azepine, then performing acyl chlorination, bromination and elimination to obtain 5-chloroformyl stilbene imino group, and performing bromine addition, methoxylation, formamidization and hydrolysis demethylation to prepare oxcarbazepine. The method for preparing 10-methoxyiminostilbene from o-nitrotoluene has the advantages of complex operation, high cyclization reaction temperature, low yield, low product purity, complex purification and large amount of three wastes, and is not suitable for industrial production.
Chinese patent document CN101386595A, CN101423496A uses 5-chloroformyl-10,11-dibromoiminodibenzyl or 10,11-dibromoiminodibenzyl as raw material, and reacts with a methanol solution of potassium hydroxide or potassium methoxide to prepare 10-methoxy-5H-dibenzo [ b, f ] azepine crude product, the crude product is refined to obtain 10-methoxy-5H-dibenzo [ b, f ] azepine refined product, and the refined product is subjected to chloroformylation reaction, amidation reaction and hydrolysis reaction to prepare oxcarbazepine. The method takes 5-chloroformyl-10,11-dibromoiminodibenzyl or 10,11-dibromoiminodibenzyl as raw materials, and has the defects of high raw material price and high cost.
Due to the improvement of the requirements of raw material medicines, the quality requirements of key intermediates for preparing medicines are higher and higher, so that a preparation process of high-purity low-impurity 10-methoxyiminostilbene needs to be designed.
Disclosure of Invention
In order to solve at least one technical problem, the invention provides a preparation method which is easy to operate, mild in reaction conditions, high in purity and low in impurity, and provides a preparation process of high-purity and low-impurity 10-methoxyiminostilbene.
The application provides a preparation process of high-purity low-impurity 10-methoxyiminostilbene, which comprises the following steps:
s1: adding 2-benzyl amino benzyl cyanide, an acid-binding agent and 2-halogenated benzonitrile into a solvent A to prepare a compound I, namely N-benzyl-N-2' -cyanophenyl-2-amino benzyl cyanide through substitution reaction;
s2: in a solvent B, under the action of alkali 1, carrying out intramolecular condensation reaction on a compound I, then carrying out hydrolysis reaction, and acidifying with hydrochloric acid to obtain a compound II, namely 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo [ B, f ] azepine;
s3: in a solvent C, under the action of alkali 2, carrying out methylation reaction on a compound II and a methylation reagent to obtain a compound III, namely 5-benzyl-10-methoxyiminostilbene;
s4: in a solvent D, under the action of a hydrogenation catalyst, the compound III is subjected to catalytic hydrogenolysis reaction to remove benzyl to obtain the 10-methoxy iminostilbene.
Optionally, in step S1, the solvent a is one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, toluene, or chlorobenzene; the mass ratio of the solvent A to the 2-benzyl amino benzyl cyanide is (4-16) to 1.
Optionally, in step S1, the acid-binding agent is an inorganic base or an organic base, the inorganic base is one of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or calcium bicarbonate, and the organic base is one of triethylamine, tripropylamine, triisopropylamine or tri-n-butylamine; the molar ratio of the acid-binding agent to the 2-benzyl amino benzyl cyanide is (1.0-1.5): 1.
Optionally, in step S1, the 2-halogenated benzonitrile is one of 2-bromobenzonitrile or 2-chlorobenzonitrile; the molar ratio of the 2-halogenated benzonitrile to the 2-benzylaminophenylacetonitrile is (1.0-1.3): 1.
Optionally, in the step S1, the substitution reaction temperature is 90 to 110 ℃.
Optionally, in step S2, the solvent B is one of tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, N-dimethylformamide, or chlorobenzene; the mass ratio of the solvent B to the compound I is (4-12) to 1.
Optionally, in step S2, the base 1 is one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium hydride; the molar ratio of the base 1 to the compound I is (1.0-1.5): 1.
Optionally, in the step S2, the temperature of the intramolecular condensation reaction is 30 to 90 ℃; the hydrolysis reaction temperature is 40-80 ℃.
Optionally, in the step S2, the hydrochloric acid is acidified to a system pH of 2 to 2.5 by using a hydrochloric acid with a mass concentration of 30 to 35%.
Optionally, in step S3, the solvent C is one of tetrahydrofuran, methanol, ethanol, N-dimethylformamide, or toluene; the mass ratio of the solvent C to the compound II is (8-20) to 1.
Optionally, in step S3, the alkali 2 is one of potassium carbonate, sodium hydroxide, or potassium hydroxide; the molar ratio of the alkali 2 to the compound II is (1.0-1.8): 1.
Optionally, in step S3, the methylating agent is one of dimethyl carbonate, dimethyl sulfate, methyl bromide or methyl iodide; the molar ratio of the methylating agent to the compound II is (1.5-2.2) to 1; the methylation reaction temperature is 70-100 ℃.
Optionally, in step S4, the solvent D is one of tetrahydrofuran, methanol, ethanol, or isopropanol; the mass ratio of the solvent D to the compound III is (5-12) to 1.
Optionally, in step S4, the hydrogenation catalyst is one of palladium carbon or raney nickel; the mass of the palladium-carbon catalyst is 1-6% of that of the compound III, and the mass of the Raney nickel catalyst is 10-18% of that of the compound III.
Optionally, in step S4, the catalytic hydrogenolysis reaction temperature is 30-60 ℃, and the hydrogen pressure is 0.2-0.4MPa.
In summary, the invention includes at least one of the following beneficial technical effects:
1. the prepared 10-methoxy iminostilbene has high purity and low impurity;
2. the preparation process conditions are easy to realize, the operation is simple, convenient and safe, the reaction conditions are mild, the process flow is short, and the post-treatment is simple;
3. the raw materials are cheap and easy to obtain, the cost is low, the generation amount of three wastes is small, and the environment is protected.
Detailed Description
The present application will be described in further detail with reference to examples.
Unless otherwise indicated, the raw materials and equipment used in the present invention are conventional in the art (conventional commercial products) and are commercially available.
The application designs a preparation process of high-purity low-impurity 10-methoxyiminostilbene, which comprises the following steps:
s1: adding 2-benzyl amino benzyl cyanide, an acid-binding agent and 2-halogenated benzonitrile into a solvent A to prepare a compound I, namely N-benzyl-N-2' -cyanophenyl-2-amino benzyl cyanide through substitution reaction;
s2: in a solvent B, under the action of alkali 1, carrying out intramolecular condensation reaction on a compound I, then carrying out hydrolysis reaction, and acidifying with hydrochloric acid to obtain a compound II, namely 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo [ B, f ] azepine;
s3: in a solvent C, under the action of alkali 2, carrying out methylation reaction on a compound II and a methylation reagent to obtain a compound III, namely 5-benzyl-10-methoxyiminostilbene;
s4: in a solvent D, under the action of a hydrogenation catalyst, the compound III is subjected to catalytic hydrogenolysis reaction to remove benzyl to obtain the 10-methoxy iminostilbene.
The 10-methoxy iminostilbene prepared by the preparation process has high purity and low impurity content; the preparation process conditions are easy to realize, the operation is simple, convenient and safe, the reaction conditions are mild, the process flow is short, and the post-treatment is simple.
Examples
Example 1
S1: into a 500ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 120g of N, N-dimethylformamide, 30g (0.148 mol) of 2-benzylaminophenylacetonitrile, 35.1g (0.192 mol) of 2-bromoxynil, 30.6g (0.222 mol) of potassium carbonate, and the reaction was stirred at 105 to 110 ℃ for 5 hours. Cooling to 20-25 deg.C, filtering, washing filter cake with 30gN, N-dimethyl formamide, combining filtrates, and vacuum distilling to recover solvent. 135g of isopropyl ether was added to the residue to conduct recrystallization, yielding 38.9g N-benzyl-N-2' -cyanophenyl-2-aminophenylacetonitrile, 90.7% yield and 99.2% liquid phase purity.
S2: into a 500ml four port flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel were charged 100g of 2-methyltetrahydrofuran, 10.2g (0.15 mol) of sodium ethoxide. A mixture of 32.3g (0.1 mol) of N-benzyl-N-2' -cyanophenyl-2-aminophenylacetonitrile and 30g of 2-methyltetrahydrofuran is added dropwise at a temperature of between 50 and 55 ℃, and the mixture is stirred and reacted for 4 hours at a temperature of between 80 and 85 ℃ after the dropwise addition. Cooling to 20-25 deg.C, adding 250g water, stirring at 75-80 deg.C for hydrolysis reaction for 3H, demixing, washing the water layer with 20g dichloromethane once, acidifying the obtained water phase with 35wt% hydrochloric acid to obtain pH of 2.0-2.5, filtering, drying to obtain 26.8g 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo [ b, f ] azepine with yield of 89.8% and liquid phase purity of 99.3%.
S3: into a 500ml stainless steel autoclave were charged 100g of methanol, 12.5g (0.042 mol) of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo [ b, f ] azepine, 8.32g (0.092 mol) of dimethyl carbonate, and 10.3g (0.075 mol) of potassium carbonate. The pressure kettle is sealed, the temperature is raised, and the stirring reaction is carried out for 4 hours at the temperature of 95-100 ℃. Cooling to 20-25 deg.C, filtering, washing filter cake with 20g methanol, combining filtrates, and recovering solvent by reduced pressure distillation. The residue was recrystallized from 50g of isopropyl ether and dried to give 11.96g of 5-benzyl-10-methoxyiminostilbene in 91.5% yield and 99.1% liquid-phase purity.
S4: 50g of methanol, 10g (0.032 mol) of 5-benzyl-10-methoxyiminostilbene and 0.6g of 5wt% palladium-carbon catalyst were added to a 100ml stainless steel autoclave. After the nitrogen is replaced for three times, hydrogen is introduced, the pressure of the hydrogen is kept at 0.3-0.4MPa, and the reaction is carried out for 5 hours at the temperature of 55-60 ℃. The nitrogen is replaced for three times, the palladium-carbon is recovered by filtration, and the filtrate is concentrated and dried to obtain 6.67g of 10-methoxyiminostilbene, the yield is 93.6 percent, and the purity of the liquid phase is 99.4 percent.
Example 2
S1: into a 500ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 120g of N, N-dimethylformamide, 15g (0.076 mol) of 2-benzylaminophenylacetonitrile, 16.9g (0.091 mol) of 2-bromobenzonitrile and 14.6g (0.106 mol) of potassium carbonate, and the reaction was stirred at 100 to 105 ℃ for 5 hours. Cooling to 20-25 deg.C, filtering, washing the filter cake with 20gN, N-dimethyl formamide, combining filtrates, and vacuum distilling to recover solvent. 70g of isopropyl ether was added to the residue for recrystallization to give 19.7g N-benzyl-N-2' -cyanophenyl-2-aminophenylacetonitrile in 91.2% yield and 99.3% liquid phase purity.
S2: into a 500ml four port flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel were charged 100g of 2-methyltetrahydrofuran, 6.4g (0.094 mol) of sodium ethoxide. A mixture of 21.7g (0.067 mol) of N-benzyl-N-2' -cyanophenyl-2-aminophenylacetonitrile and 30g of 2-methyltetrahydrofuran is added dropwise at a temperature of between 50 and 55 ℃ and stirred for reaction for 3.5 hours at a temperature of between 75 and 80 ℃ after the dropwise addition. Cooling to 20-25 deg.C, adding 200g water, stirring at 70-75 deg.C for hydrolysis reaction for 3H, layering, washing the water layer with 20g dichloromethane once, acidifying the obtained water phase with 35wt% hydrochloric acid to obtain pH of 2.0-2.5, filtering, and drying to obtain 18.1g 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo [ b, f ] azepine with yield of 90.7% and liquid phase purity of 99.4%.
S3: into a 500ml stainless steel autoclave were charged 100g of methanol, 8.3g (0.028 mol) of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo [ b, f ] azepine, 5g (0.056 mol) of dimethyl carbonate, and 6.1g (0.044 mol) of potassium carbonate. The pressure kettle is sealed, the temperature is raised, and the stirring reaction is carried out for 3.5h at the temperature of 90-95 ℃. Cooling to 20-25 deg.C, filtering, washing filter cake with 20g methanol, combining filtrates, and recovering solvent by reduced pressure distillation. The residue was recrystallized from 35g of isopropyl ether and dried to give 7.94g of 5-benzyl-10-methoxyiminostilbene with a yield of 92.3% and a liquid phase purity of 99.2%.
S4: 50g of methanol, 7.2g (0.023 mol) of 5-benzyl-10-methoxyiminostilbene and 0.36g of 5wt% palladium-carbon catalyst are added into a 100ml stainless steel pressure kettle. After the nitrogen is replaced for three times, hydrogen is introduced, the pressure of the hydrogen is kept at 0.3-0.4MPa, and the reaction is carried out for 5 hours at the temperature of 50-55 ℃. Replacing nitrogen for three times, filtering and recovering palladium carbon, concentrating the filtrate, and drying to obtain 4.81g 10-methoxy iminostilbene with the yield of 93.8 percent and the liquid phase purity of 99.5 percent.
Example 3
S1: to a 500ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were added 120g of N, N-dimethylformamide, 12g (0.061 mol) of 2-benzylaminophenylacetonitrile, 13.5g (0.073 mol) of 2-bromoxynil and 10.9g (0.079 mol) of potassium carbonate, and the reaction was stirred at 95 to 100 ℃ for 4 hours. Cooling to 20-25 deg.C, filtering, washing filter cake with 15gN, N-dimethylformamide, combining filtrates, and recovering solvent by reduced pressure distillation. 55g of isopropyl ether was added to the residue to conduct recrystallization, thereby obtaining 16.2g N-benzyl-N-2' -cyanophenyl-2-aminophenylacetonitrile with a yield of 91.4% and a liquid phase purity of 99.5%.
S2: into a 500ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel were charged 100g of 2-methyltetrahydrofuran, 4.4g (0.065 mol) of sodium ethoxide. A mixture of 16.3g (0.05 mol) of N-benzyl-N-2' -cyanophenyl-2-aminophenylacetonitrile and 30g of 2-methyltetrahydrofuran is added dropwise at a temperature of between 50 and 55 ℃, and the mixture is stirred and reacted for 3.5 hours at a temperature of between 70 and 75 ℃ after the dropwise addition. Cooling to 20-25 deg.C, adding 200g water, stirring at 65-70 deg.C for hydrolysis reaction for 3H, demixing, washing the water layer with 20g dichloromethane once, acidifying the obtained water phase with 35wt% hydrochloric acid to obtain pH of 2.0-2.5, filtering, drying to obtain 13.8g 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo [ b, f ] azepine with yield of 91.8% and liquid phase purity of 99.5%.
S3: into a 500ml stainless steel autoclave were charged 100g of methanol, 7.2g (0.024 mol) of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo [ b, f ] azepine, 3.87g (0.043 mol) of dimethyl carbonate, and 4.97g (0.036 mol) of potassium carbonate. The pressure kettle is sealed, the temperature is increased, and the stirring reaction is carried out for 3.5h at the temperature of 85-90 ℃. Cooling to 20-25 deg.C, filtering, washing filter cake with 20g methanol, combining filtrates, and recovering solvent by reduced pressure distillation. The residue was recrystallized from 30g of isopropyl ether and dried to give 6.93g of 5-benzyl-10-methoxyiminostilbene with a yield of 93.1% and a liquid phase purity of 99.4%.
S4: 50g of methanol, 6.26g (0.02 mol) of 5-benzyl-10-methoxyiminostilbene and 0.25g of 5wt% palladium on carbon catalyst were charged into a 100ml stainless steel autoclave. After nitrogen replacement for three times, introducing hydrogen, keeping the hydrogen pressure at 0.2-0.3MPa, and reacting for 4 hours at 45-50 ℃. Replacing nitrogen for three times, filtering and recovering palladium carbon, concentrating the filtrate, and drying to obtain 4.21g10-methoxyiminostilbene with the yield of 94.1 percent and the liquid phase purity of 99.6 percent.
Example 4
S1: into a 500ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 120g of N, N-dimethylformamide, 10g (0.045 mol) of 2-benzylaminophenylacetonitrile, 10.0g (0.054 mol) of 2-bromobenzonitrile, 7.45g (0.054 mol) of potassium carbonate, and the reaction was stirred at 95 to 100 ℃ for 5 hours. Cooling to 20-25 deg.C, filtering, washing filter cake with 15gN, N-dimethylformamide, combining filtrates, and recovering solvent by reduced pressure distillation. To the residue was added 45g of isopropyl ether for recrystallization to give 13.1g N-benzyl-N-2' -cyanophenyl-2-aminophenylacetonitrile in 91.2% yield and 99.4% liquid phase purity.
S2: into a 500ml four port flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel were charged 100g of 2-methyltetrahydrofuran, 3.25g (0.048 mol) of sodium ethoxide. At the temperature of 50-55 ℃, a mixture of 13g (0.04 mol) of N-benzyl-N-2' -cyanophenyl-2-aminobenzonitrile and 30g of 2-methyltetrahydrofuran is dripped, and the mixture is stirred and reacted for 4 hours at the temperature of 55-60 ℃ after the dripping is finished. Cooling to 20-25 ℃, adding 200g of water, stirring at 55-60 ℃ for hydrolysis reaction for 3H, demixing, washing the water layer with 20g of dichloromethane once, using 35wt% hydrochloric acid to acidify the obtained water phase to obtain a pH value of 2.0-2.5, filtering and drying to obtain 10.9g of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo [ b, f ] azepine, wherein the yield is 91.5% and the purity of the liquid phase is 99.5%.
S3: into a 500ml stainless steel autoclave were charged 100g of methanol, 6.0g (0.02 mol) of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo [ b, f ] azepine, 3.06g (0.034 mol) of dimethyl carbonate, and 3.31g (0.024 mol) of potassium carbonate. The pressure kettle is sealed, the temperature is increased, and the stirring reaction is carried out for 4 hours at the temperature of 80-85 ℃. Cooling to 20-25 deg.C, filtering, washing filter cake with 20g methanol, combining filtrates, and recovering solvent by reduced pressure distillation. The residue was recrystallized from 25g of isopropyl ether and dried to give 5.78g of 5-benzyl-10-methoxyiminostilbene in a yield of 92.7% and a liquid phase purity of 99.6%.
S4: 50g of methanol, 5g (0.016 mol) of 5-benzyl-10-methoxyiminostilbene and 0.15g of 5wt% palladium carbon catalyst are added into a 100ml stainless steel pressure kettle. After nitrogen replacement for three times, introducing hydrogen, keeping the hydrogen pressure at 0.2-0.3MPa, and reacting for 5 hours at the temperature of 40-45 ℃. Replacing nitrogen for three times, filtering and recovering palladium carbon, concentrating the filtrate, and drying to obtain 3.32g of 10-methoxyiminostilbene with the yield of 93.4 percent and the liquid phase purity of 99.5 percent.
Example 5
S1: to a 500ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were charged 120g of N, N-dimethylformamide, 7.5g (0.034 mol) of 2-benzylaminophenylacetonitrile, 6.29g (0.034 mol) of 2-bromoxynil, 4.69g (0.034 mol) of potassium carbonate, and the reaction was stirred at 90 to 95 ℃ for 5 hours. Cooling to 20-25 deg.C, filtering, washing filter cake with 15gN, N-dimethylformamide, combining filtrates, and recovering solvent by reduced pressure distillation. 35g of isopropyl ether was added to the residue for recrystallization to give 10.1g N-benzyl-N-2' -cyanophenyl-2-aminophenylacetonitrile in 91.3% yield and 99.3% liquid phase purity.
S2: into a 500ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel were charged 100g of 2-methyltetrahydrofuran, 2.3g (0.034 mol) of sodium ethoxide. At the temperature of 40-45 ℃, a mixture of 10.8g (0.034 mol) of N-benzyl-N-2' -cyanophenyl-2-aminophenylacetonitrile and 30g of 2-methyltetrahydrofuran is dripped, and the mixture is stirred and reacted for 5 hours at the temperature of 40-45 ℃ after dripping. Cooling to 20-25 deg.C, adding 200g water, stirring at 45-50 deg.C for hydrolysis reaction for 4H, layering, washing the water layer with 20g dichloromethane once, acidifying the obtained water phase with 35wt% hydrochloric acid to obtain pH of 2.0-2.5, filtering, and drying to obtain 8.93g 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo [ b, f ] azepine with yield of 90.8% and liquid phase purity of 99.4%.
S3: into a 500ml stainless steel autoclave were charged 100g of methanol, 5.0g (0.017 mol) of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo [ b, f ] azepine, 2.34g (0.026 mol) of dimethyl carbonate, and 2.35g (0.017 mol) of potassium carbonate. The pressure kettle is sealed, the temperature is increased, and the reaction is carried out for 5 hours under the stirring at the temperature of 70-75 ℃. Cooling to 20-25 deg.C, filtering, washing filter cake with 20g methanol, combining filtrates, and recovering solvent by reduced pressure distillation. The residue was recrystallized from 25g of isopropyl ether and dried to obtain 4.76g of 5-benzyl-10-methoxyiminostilbene, the yield was 92.3%, and the liquid phase purity was 99.5%.
S4: 50g of methanol, 4.2g (0.013 mol) of 5-benzyl-10-methoxyiminostilbene and 0.05g of 5wt% palladium on carbon catalyst were placed in a 100ml stainless steel autoclave. After nitrogen replacement for three times, introducing hydrogen, keeping the hydrogen pressure at 0.2-0.3MPa, and reacting for 5 hours at the temperature of 30-35 ℃. Replacing nitrogen for three times, filtering and recovering palladium carbon, concentrating the filtrate, and drying to obtain 2.78g of 10-methoxyiminostilbene with the yield of 93.3 percent and the liquid phase purity of 99.3 percent.
In examples 1 to 5, the purity of the obtained 10-methoxyiminostilbene was high and the purity of the liquid phase was more than 99.3%. It can be found by analysis that the purity of 10-methoxyiminostilbene obtained by the preparation process described in example 3 is slightly higher than that of the other examples.
The method and the device are simple, convenient and safe to operate, mild in reaction conditions and multiple in selectivity. Most of the solvent and the palladium-carbon catalyst can be recycled, the raw materials are cheap and easy to obtain, the cost is low, the generation amount of three wastes is small, and the method is green and environment-friendly and is suitable for industrial production.
The above embodiments are preferred embodiments of the present application, and the protection scope of the present application is not limited by the above embodiments, so: all equivalent changes made according to the structure, shape and principle of the present application shall be covered by the protection scope of the present application.
Claims (10)
1. A preparation process of high-purity low-impurity 10-methoxyiminostilbene is characterized by comprising the following steps:
s1: adding 2-benzyl amino benzyl cyanide, an acid-binding agent and 2-halogenated benzonitrile into a solvent A to prepare a compound I, namely N-benzyl-N-2' -cyanophenyl-2-amino benzyl cyanide through substitution reaction;
s2: in a solvent B, under the action of alkali 1, carrying out intramolecular condensation reaction on a compound I, then carrying out hydrolysis reaction, and acidifying with hydrochloric acid to obtain a compound II, namely 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo [ B, f ] azepine;
s3: in a solvent C, under the action of alkali 2, carrying out methylation reaction on a compound II and a methylation reagent to obtain a compound III, namely 5-benzyl-10-methoxyiminostilbene;
s4: in a solvent D, under the action of a hydrogenation catalyst, the compound III is subjected to catalytic hydrogenolysis reaction to remove benzyl to obtain the 10-methoxy iminostilbene.
2. The process of claim 1, wherein in step S1, the solvent a is one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, toluene, or chlorobenzene; the mass ratio of the solvent A to the 2-benzyl amino benzyl cyanide is (4-16) to 1.
3. The process for preparing 10-methoxyiminostilbene according to claim 1, wherein in step S1, the acid-binding agent is inorganic base or organic base, the inorganic base is one of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or calcium bicarbonate, and the organic base is one of triethylamine, tripropylamine, triisopropylamine or tri-n-butylamine; the molar ratio of the acid-binding agent to the 2-benzyl amino benzyl cyanide is (1.0-1.5): 1.
4. The process for preparing 10-methoxyiminostilbene according to claim 1, wherein in step S1, the 2-halobenzonitrile is one of 2-bromoxynil and 2-chlorobenzonitrile; the molar ratio of the 2-halogenated benzonitrile to the 2-benzylaminophenylacetonitrile is (1.0-1.3): 1.
5. The process for preparing 10-methoxyiminostilbene according to claim 1, wherein the substitution reaction temperature in step S1 is 90-110 ℃.
6. The process for preparing 10-methoxyiminostilbene according to claim 1, wherein in step S2:
the solvent B is one of tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, N-dimethylformamide or chlorobenzene; the mass ratio of the solvent B to the compound I is (4-12) to 1;
the alkali 1 is one of sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride; the molar ratio of the base 1 to the compound I is (1.0-1.5): 1.
7. The process for preparing 10-methoxyiminostilbene according to claim 1, wherein in the step S2, the temperature of intramolecular condensation reaction is 30 to 90 ℃; the hydrolysis reaction temperature is 40-80 ℃.
8. The process for preparing 10-methoxyiminostilbene according to claim 1, wherein in the step S2, the hydrochloric acid is acidified to a system pH of 2-2.5 by using 30-35% by mass hydrochloric acid.
9. The process for preparing 10-methoxyiminostilbene according to claim 1, wherein in step S3:
the solvent C is one of tetrahydrofuran, methanol, ethanol, N-dimethylformamide or toluene; the mass ratio of the solvent C to the compound II is (8-20) to 1;
the alkali 2 is one of potassium carbonate, sodium hydroxide or potassium hydroxide; the molar ratio of the alkali 2 to the compound II is (1.0-1.8) to 1;
the methylation reagent is one of dimethyl carbonate, dimethyl sulfate, methyl bromide or methyl iodide; the molar ratio of the methylating agent to the compound II is (1.5-2.2) to 1; the methylation reaction temperature is 70-100 ℃.
10. The process for preparing 10-methoxyiminostilbene according to claim 1, wherein in step S4:
the solvent D is one of tetrahydrofuran, methanol, ethanol or isopropanol; and the mass ratio of the solvent D to the compound III is (5-12) to 1;
the hydrogenation catalyst is one of palladium carbon or Raney nickel; the mass of the palladium-carbon catalyst is 1-6% of that of the compound III, and the mass of the Raney nickel catalyst is 10-18% of that of the compound III;
the catalytic hydrogenolysis reaction temperature is 30-60 ℃, and the hydrogen pressure is 0.2-0.4MPa.
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| WO2024109438A1 (en) * | 2022-11-23 | 2024-05-30 | 浙江华洋药业有限公司 | Preparation process of high-purity low-impurity 10-methoxyiminostilbene |
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