CN104356139A - Synthetic method of nitidine chloride - Google Patents
Synthetic method of nitidine chloride Download PDFInfo
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- CN104356139A CN104356139A CN201410676737.5A CN201410676737A CN104356139A CN 104356139 A CN104356139 A CN 104356139A CN 201410676737 A CN201410676737 A CN 201410676737A CN 104356139 A CN104356139 A CN 104356139A
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 26
- QLDAACVSUMUMOR-UHFFFAOYSA-M 2,3-dimethoxy-12-methyl-[1,3]benzodioxolo[5,6-c]phenanthridin-12-ium;chloride Chemical compound [Cl-].C1=C2C3=[N+](C)C=C4C=C(OC)C(OC)=CC4=C3C=CC2=CC2=C1OCO2 QLDAACVSUMUMOR-UHFFFAOYSA-M 0.000 title claims abstract description 18
- 239000003960 organic solvent Substances 0.000 claims abstract description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 14
- -1 lithium aluminum hydride Chemical compound 0.000 claims abstract description 13
- 239000000376 reactant Substances 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 11
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims abstract description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 10
- DAUAQNGYDSHRET-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC DAUAQNGYDSHRET-UHFFFAOYSA-N 0.000 claims abstract description 9
- GPVDHNVGGIAOQT-UHFFFAOYSA-N Veratric acid Natural products COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000012280 lithium aluminium hydride Substances 0.000 claims abstract description 9
- 239000011780 sodium chloride Substances 0.000 claims abstract description 7
- 239000012298 atmosphere Substances 0.000 claims abstract description 6
- 230000018044 dehydration Effects 0.000 claims abstract description 6
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 6
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000011987 methylation Effects 0.000 claims abstract description 5
- 238000007069 methylation reaction Methods 0.000 claims abstract description 5
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- KKMPSGJPCCJYRV-UHFFFAOYSA-N Nitidine Chemical compound C1=C2C3=[N+](C)C=C4C=C(OC)C(OC)=CC4=C3C=CC2=CC2=C1OCO2 KKMPSGJPCCJYRV-UHFFFAOYSA-N 0.000 claims description 10
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 10
- 238000001556 precipitation Methods 0.000 claims description 9
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 7
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 5
- 230000019635 sulfation Effects 0.000 claims description 5
- 238000005670 sulfation reaction Methods 0.000 claims description 5
- SNOFKGQEUYMNCE-UHFFFAOYSA-N 2,2,2-trifluoro-1-$l^{1}-oxidanylethanone Chemical compound [O]C(=O)C(F)(F)F SNOFKGQEUYMNCE-UHFFFAOYSA-N 0.000 claims description 4
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 238000004440 column chromatography Methods 0.000 abstract description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract 1
- WSEYRYIQSMUYMG-UHFFFAOYSA-N [3-iodo-2-(2,2,2-trifluoroacetyl)oxyphenyl] 2,2,2-trifluoroacetate Chemical compound FC(F)(F)C(=O)OC1=CC=CC(I)=C1OC(=O)C(F)(F)F WSEYRYIQSMUYMG-UHFFFAOYSA-N 0.000 abstract 1
- YSWKDHRWQYCLMP-UHFFFAOYSA-N benzo[g][1,3]benzodioxol-5-amine Chemical compound C1OC=2C=C(C3=CC=CC=C3C2O1)N YSWKDHRWQYCLMP-UHFFFAOYSA-N 0.000 abstract 1
- 238000001704 evaporation Methods 0.000 abstract 1
- 239000000741 silica gel Substances 0.000 abstract 1
- 229910002027 silica gel Inorganic materials 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 28
- 239000002994 raw material Substances 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- MTVOSXTZNVKGIF-UHFFFAOYSA-N 2,3-dimethoxy-12-methyl-13h-[1,3]benzodioxolo[5,6-c]phenanthridine Chemical compound C1=C2C(N(C)CC=3C=C(C(=CC=33)OC)OC)=C3C=CC2=CC2=C1OCO2 MTVOSXTZNVKGIF-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229910000474 mercury oxide Inorganic materials 0.000 description 4
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000012797 qualification Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PEZNEXFPRSOYPL-UHFFFAOYSA-N (bis(trifluoroacetoxy)iodo)benzene Chemical compound FC(F)(F)C(=O)OI(OC(=O)C(F)(F)F)C1=CC=CC=C1 PEZNEXFPRSOYPL-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QADMMVWIMLEMOU-UHFFFAOYSA-N 2-bromo-4,5-dimethoxybenzoyl chloride Chemical compound COC1=CC(Br)=C(C(Cl)=O)C=C1OC QADMMVWIMLEMOU-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 240000003248 Zanthoxylum nitidum Species 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 2
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 2
- 235000012141 vanillin Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VJAXYZXLBFEJEG-UHFFFAOYSA-N Oxyterihanine Natural products C1=C2OCOC2=CC2=C(N(C)C(=O)C3=C4C=C(C(=C3)O)OC)C4=CC=C21 VJAXYZXLBFEJEG-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 150000005002 naphthylamines Chemical class 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 238000006349 photocyclization reaction Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- FQZYTYWMLGAPFJ-OQKDUQJOSA-N tamoxifen citrate Chemical compound [H+].[H+].[H+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 FQZYTYWMLGAPFJ-OQKDUQJOSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic method of nitidine chloride. The synthetic method comprises the following steps: 1) dissolving 3,4-dimethoxybenzoic acid in a first organic solvent, adding thionyl chloride to react, evaporating out the solvent from reactants to obtain an intermediate 1; 2) dissolving the intermediate 1 by use of the first organic solvent, adding 3,4-methylenedioxy naphthylamine, and performing nucleophilic substitution reaction to obtain an intermediate 2; 3) dissolving the intermediate 2 in the first organic solvent, adding boron trifluoride diethyl etherate and di(trifluoroacetoxyl) iodobenzene to react, removing the solvent from the reactants, performing column chromatography on obtained residues on silica gel to obtain an intermediate 3; 4) dissolving the intermediate 3 in a second organic solvent, and performing lithium aluminum hydride reduction, dehydration and dimethyl sulfate methylation under an atmosphere protection condition, and then treating with sodium chloride to obtain the target product nitidine chloride. The synthetic method disclosed by the invention is relatively simple in synthesis route and relatively high in yield of the target product and the yield is higher than 27%.
Description
Technical field
The present invention relates to medical art, be specifically related to a kind of synthetic method of nitidine chloride.
Background technology
Nitidine chloride (Nitidine Chloride, NC), structure, as shown in following formula I, is yellow or pistac needle crystal.Nitidine chloride is by a kind of benzene a pair of horses going side by side [c] phenanthridine alkaloid alkaloid extracted in the dry root of Rutaceae xanthoxylum Shinyleaf Pricklyash Root, all restraining effect is had to LEWIS lung cancer, human body nasopharyngeal carcinoma, liver cancer, chronic myelocytic leukemia, also effective to mouse Emhorn water cancer, hepatic ascites, therefore NC has good anti-tumor activity, there is very large development and application values.
At present, NC content in two sides crown skin, stem or leaf only reaches 0.2% ~ 0.3%, and the cost extracted from plant is higher, comparatively difficult for further transformation and optimization, also counteracts that the application of NC, therefore carries out complete synthesis extremely urgent to nitidine chloride.(the Tetra lett such as Kessar, 1974,26:2269-2270.) with 2-bromo-4,5-dimethoxy-benzoyl chloride and 2,3-methylenedioxy group naphthylamines is raw material, and synthesizing amide circularizes into the acid amides at Fourth Ring through lamp and high pressure mercury, again through reduction, dehydrogenation, methylating to obtain Shinyleaf Pricklyash Root alkali salt, concrete synthetic route is as follows:
In above-mentioned synthetic method, raw material 2-bromo-4,5-dimethoxy Benzoyl chloride is non-common raw material, and need with 3,4-dimethoxybenzoic acid or vanillin food grade,1000.000000ine mesh for Material synthesis, complex operation, side reaction is many, relates to Photocyclization in reaction, is unfavorable for suitability for industrialized production; When being wherein raw material with 3,4-dimethoxybenzoic acid, output is only 6.12% (US2013/253222), and is that raw material reaction needs 6 steps just can complete altogether with vanillin food grade,1000.000000ine mesh, overall yield not high (J Org Chem, 1942,7:354,355).
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of synthetic method of new nitidine chloride.The method synthetic route is more simple, and the yield of target product is higher.
The method of the invention, is synthesized by following synthetic route for starting raw material with 3,4-dimethoxybenzoic acid:
The synthetic method of nitidine chloride of the present invention, specifically comprises the following steps:
1) get 3,4-dimethoxybenzoic acid to be dissolved in the first organic solvent, add thionyl chloride and react, reactant steams and desolventizes, and obtains intermediate 1 (acyl chlorides);
2) by intermediate 1 with adding 3,4-methylenedioxy group naphthylamines after the first organic solvent dissolution, nucleo philic substitution reaction obtains intermediate 2 (acid amides);
3) getting intermediate 2 is dissolved in the first organic solvent, add boron trifluoride diethyl etherate and two (trifluoroacetyl oxygen base) iodobenzene (i.e. two (trifluoroacetyl oxygen base) iodobenzene, be abbreviated as PIFA) react, reactant is except desolventizing, silica gel column chromatography on gained residue, obtains intermediate 3 (oxyterihanine);
4) getting intermediate 3 is dissolved in the second organic solvent, through lithium aluminium hydride reduction, dehydration and dimethyl sulfate methylation of ester, again through sodium-chlor process, namely obtain target product nitidine chloride under atmosphere protection condition.
Above-mentioned synthetic method, the first described organic solvent is generally methylene dichloride or chloroform, and the consumption of described first organic solvent is advisable can dissolve the raw material participating in reaction; The second described organic solvent is generally anhydrous tetrahydro furan, anhydrous diethyl ether or anhydrous methanol, and the consumption of described second organic solvent is advisable can dissolve the raw material participating in reaction.
The step 1 of above-mentioned synthetic method) in, the mol ratio of 3,4-dimethoxybenzoic acid and thionyl chloride is stoichiometric ratio, is generally 1:2 ~ 5; Described 3, the reaction of 4-dimethoxybenzoic acid and thionyl chloride is carried out usually under 20 ~ 80 DEG C of conditions, and reaction preferably adopts the mode of heating or backflow to carry out, and whether reaction can adopt thin-layer chromatography tracing detection completely, under above-mentioned qualifications, reaction is to completely approximately needing 12 ~ 48h.
The step 2 of above-mentioned synthetic method) in, nucleophilic substitution reaction preferably carries out under 0 ~ 10 DEG C of condition.This step specifically comprises: by intermediate 1 with after the first organic solvent dissolution, 3 are added under 0 ~ 10 DEG C of condition, (pyridine or triethylamine are used as acid binding agent for 4-methylenedioxy group naphthylamines and pyridine or triethylamine, its consumption is same as the prior art), under above-mentioned condition, react (whether reaction can adopt thin-layer chromatography tracing detection completely again, under above-mentioned qualifications, reaction is to completely approximately needing 24 ~ 48h), in reaction process, adularescent solid is separated out, suction filtration, washing (adopts anhydrous methanol usually, dehydrated alcohol or acetonitrile wash), namely intermediate 2 is obtained.In order to improve the purity of intermediate 2 further, intermediate 2 anhydrous methanol of acquisition, dehydrated alcohol or acetonitrile can also be carried out recrystallization.In this step, intermediate 1 and 3,4-methylenedioxy group naphthylamines mol ratio are preferably 1 ~ 2:1.For avoiding reaction too violent, preferably will enter 3,4-methylenedioxy group naphthylamines and adding in batches.
The step 3 of above-mentioned synthetic method) in, the mol ratio of intermediate 2, boron trifluoride diethyl etherate and two (trifluoroacetyl oxygen base) iodobenzene is preferably 1:0.5 ~ 1:1 ~ 2, is more preferably 1:0.6:1.3; Above-mentioned reaction is preferably carried out under 10 ~ 60 DEG C of conditions, and whether reaction can adopt thin-layer chromatography tracing detection completely, and under above-mentioned qualifications, reaction is to completely approximately needing 1 ~ 5h.In this step, on gained residue during silica gel column chromatography, preferably with being the mixed solvent wash-out that the sherwood oil of 2 ~ 10:1 and ethyl acetate form by volume ratio, more preferably adopting by volume ratio is the mixed solvent wash-out that the sherwood oil of 2 ~ 6:1 and ethyl acetate form; Elutriant solvent evaporated, obtains intermediate 3.
The step 4 of above-mentioned synthetic method) in, the mol ratio of described intermediate 3 and lithium aluminum hydride is generally 1:3 ~ 5, described in add lithium aluminum hydride and carry out reducing and follow-up processed is all carry out under 20 ~ 50 DEG C of conditions.Particularly; intermediate 3 is being dissolved in after in the second organic solvent; add lithium aluminum hydride under atmosphere protection condition to reduce under 20 ~ 50 DEG C of conditions; reaction end (whether reaction can adopt thin-layer chromatography tracing detection completely) afterwards gained reactant uses hydrochloric acid (HCl content is the hydrochloric acid of 10 ~ 30%) to carry out processed usually; then filter; filtrate thin up; yellow mercury oxide is had (to be the product after dehydration; i.e. Dihydronitidine) separate out, collect yellow mercury oxide as the methylated raw material of next step methyl-sulfate.
The step 4 of above-mentioned synthetic method) in, described dimethyl sulfate methylation of ester is by through lithium aluminium hydride reduction, product (i.e. above-mentioned yellow mercury oxide Dihydronitidine) after dehydration is dissolved in the solvent (being preferably made up of with the volume percent of 70 ~ 100%:0 ~ 30% oil of mirbane and dimethylbenzene) be made up of with the volume percent of 50 ~ 100%:0 ~ 50% oil of mirbane and dimethylbenzene, react under 150 ~ 200 DEG C of conditions (whether reaction can adopt thin-layer chromatography tracing detection completely), ether or tetrahydrofuran (THF) is added after reactant cooling, there is brown color Precipitation, isolate precipitation, obtain sulfation nitidine, as the raw material of next step sodium-chlor process.The consumption of described methyl-sulfate is preferably 2 ~ 5 times of intermediate 3 amount of substance.In this step, described atmosphere protection normally carries out under nitrogen or other rare gas element are as the atmosphere protection such as argon gas or helium condition.
The step 4 of above-mentioned synthetic method) in, described sodium-chlor process (is reacted reacting through the methylated product of methyl-sulfate (i.e. sulfation nitidine) and sodium chloride aqueous solution usually at 20 ~ 40 DEG C, preferably carry out at ambient temperature, reaction time be Precipitation completely, be generally 3 ~ 20min), there is pale yellow precipitate to separate out, collect this pale yellow precipitate, be nitidine chloride.The consumption of wherein said sodium-chlor is generally 5 ~ 20 times of intermediate 3 amount of substance, after determining the consumption of sodium-chlor, with water, namely sodium-chlor dissolving is obtained sodium chloride aqueous solution, the concentration of described sodium chloride aqueous solution is not exquisite especially, is normally mixed with the sodium chloride aqueous solution of 5 ~ 20% (quality).
Compared with prior art, the inventive method is with 3,4-dimethoxybenzoic acid for starting raw material, and synthetic route is more simple, and the yield of target product is higher, and total recovery can reach more than 27%.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, and to understand content of the present invention better, but the present invention is not limited to following examples.
Embodiment 1
1) synthesis of intermediate 1:
By 0.98g 3,4-dimethoxybenzoic acid (5.4mmol) thermosol in 40mL methylene dichloride, then add 0.78mL SOCl
2(10.8mmol) reflux 4h at 40 DEG C.Solvent evaporated, obtains white solid, is intermediate 1, productive rate 100%.
2) synthesis of intermediate 2:
Get above-mentioned 1.12g intermediate 1 and be dissolved in 40mL methylene dichloride, add 2.8mL pyridine and 1g 3,4-methylenedioxy group aniline (3,4-methylenedioxy group aniline is divided into 3 batches and adds in 10min) at 0 DEG C wherein, then react 24h under 5 DEG C of conditions.In reaction process, adularescent solid is separated out, suction filtration, absolute ethanol washing, and then obtains white needle-like crystals with dehydrated alcohol recrystallization, is intermediate 2, productive rate 47.5%, fusing point 235-236 DEG C.FAB-MS m/z:352([M+H]
+)；
1H NMR(DMSO-d
6)δ:10.15(s,1H,NH),7.78-7.59(m,3H,ArH),7.37(dd,J＝5.4,1.2Hz,3H,ArH),7.20(s,1H,ArH),7.11(d,J＝8.5Hz,1H,ArH),6.14(s,2H,-CH
2),3.86(s,6H,-OCH
3)；
13CNMR(DMSO-d6,100MHz)，165.94,152.10,148.81,148.03,133.96,131.49,127.03,125.85,124.41,123.30,121.60,111.50,104.32,101.80,100.19,56.12.
3) synthesis of intermediate 3:
1mmol intermediate 2 is dissolved in 60mL methylene dichloride, adds 0.56g PIFA solid and 0.1mL boron trifluoride diethyl etherate, under 10 DEG C of conditions, react 3h.After reaction terminates, drained by solvent, carry out column chromatography for separation, elutriant solvent evaporated with petrol ether/ethyl acetate (volume ratio is for 4:1) for eluent, obtain intermediate 3, productive rate is 12%.m.p.235-236℃；
1H NMR(CDCl
3)δ:8.37(s,1H,ArH),8.28(s,2H,ArH),8.14～7.98(m,2H,ArH),7.84(t,J＝7.4Hz,1H,ArH),7.66～7.53(m,4H,ArH),7.48(dd,J＝15.9,8.5Hz,2H,ArH),6.67(d,J＝2.1Hz,1H,ArH),3.84(s,3H,-OCH
3),2.53(s,3H,-CH
3).
4) synthesis of nitidine chloride:
4.1) 0.1g intermediate 3 is dissolved in 10mL anhydrous tetrahydro furan, under nitrogen protection, adds 0.06gLiAlH
43h is reacted under room temperature condition, after reaction terminates, reactant 2mol/L hydrochloric acid processed, filters insolubles, 10mL distilled water is added in gained filtrate, there is yellow mercury oxide to separate out, be Dihydronitidine, this precipitation is used 95% ethyl alcohol recrystallization again, obtain yellow needle-like crystals 0.06g, productive rate 60%;
4.2) get the above-mentioned yellow needle-like crystals of 0.06g and be placed in the solvent be made up of 4mL oil of mirbane and 2mL dimethylbenzene, add the methyl-sulfate of 200 μ L, 7min is reacted under 180 DEG C of conditions, ether is added wherein to there being brown color Precipitation after reactant cooling, suction filtration, filter residue anhydrous methanol recrystallization obtains sulfation nitidine, productive rate 70%;
4.3) getting 0.1mmol sulfation nitidine joins in the sodium chloride solution of 5mL 8w/w%, and stirring at room temperature reaction 30min, has pale yellow precipitate to separate out, isolate this pale yellow precipitate and be target product nitidine chloride, productive rate 80%,
1h NMR (DMSO-d
6) δ: 9.98 (s, 1H, CH=N), 8.68 (s, 1H, ArH), 8.62 (d, J=7.4Hz, 1H, ArH), 8.20 (d, J=7.4Hz, 1H, ArH), 8.18 (d, J=7.4Hz, ArH), 8.17 (d, J=8.5Hz, 2H, ArH), 7.54 (d, J=8.5Hz, 1H, ArH), 6.27 (s, 2H ,-O-CH
2-O-, 4.99 (s, 3H, N-CH
3), 4.29 (s, 3H ,-OCH
3), 4.14 (s, 3H ,-OCH
3). fusing point 272 ~ 275 DEG C, basically identical with literature value 275 ~ 276 DEG C, be same compound (developping agent: chloroform: methyl alcohol=9:1) by TLC method and reference substance (Chun You bio tech ltd, Shanghai) comparison.
Embodiment 2
Repeat the method for embodiment 1, just revise as follows:
1, by step 1) in methylene chloride used be revised as chloroform, react 48h under reaction conditions being revised as 30 DEG C of conditions;
2, by step 2) in methylene chloride used be revised as chloroform, react 12h under reaction conditions being revised as 10 DEG C of conditions;
3, by step 3) in reaction conditions be revised as 50 DEG C of conditions under react 1h;
4, by step 4.1) in solvent anhydrous tetrahydro furan used be revised as anhydrous diethyl ether; By step 4.2) in reaction conditions be revised as 200 DEG C of conditions under react 3min, simultaneously by step 4.2) in the used solvent be made up of 4mL oil of mirbane and 2mL dimethylbenzene be revised as 6mL oil of mirbane.
The final product productive rate 22% that this enforcement is obtained, fusing point 272 ~ 275 DEG C, basically identical with literature value 275-276 DEG C, be same compound (developping agent: chloroform: methyl alcohol=9:1) by TLC method and reference substance (Chun You bio tech ltd, Shanghai) comparison.
Embodiment 3
Repeat the method for embodiment 1, just revise as follows:
1, by step 3) in the mixed solvent of wash-out to change to by volume ratio be that the sherwood oil of 10:1 and ethyl acetate form;
2, by step 3) in reaction conditions be revised as 60 DEG C of conditions under react 1h;
3, by step 4.2) in reaction conditions be revised as 150 DEG C of conditions under react 15min, and ether is wherein changed to tetrahydrofuran (THF).
The final product productive rate 20% that this enforcement is obtained, fusing point 272 ~ 275 DEG C, basically identical with literature value 275-276 DEG C, be same compound (developping agent: chloroform: methyl alcohol=9:1) by TLC method and reference substance (Chun You bio tech ltd, Shanghai) comparison.
Claims (10)
1. a synthetic method for nitidine chloride, comprises the following steps:
1) get 3,4-dimethoxybenzoic acid to be dissolved in the first organic solvent, add thionyl chloride and react, reactant steams and desolventizes, and obtains intermediate 1;
2) by intermediate 1 with adding 3,4-methylenedioxy group naphthylamines after the first organic solvent dissolution, nucleo philic substitution reaction obtains intermediate 2;
3) get intermediate 2 to be dissolved in the first organic solvent, add boron trifluoride diethyl etherate and two (trifluoroacetyl oxygen base) iodobenzene and react, reactant is except desolventizing, and silica gel column chromatography on gained residue, obtains intermediate 3;
4) getting intermediate 3 is dissolved in the second organic solvent, through lithium aluminium hydride reduction, dehydration and dimethyl sulfate methylation of ester, again through sodium-chlor process, namely obtain target product nitidine chloride under atmosphere protection condition.
2. synthetic method according to claim 1, is characterized in that: the first described organic solvent is methylene dichloride or chloroform.
3. synthetic method according to claim 1, is characterized in that: step 1) in, react and carry out under 20 ~ 80 DEG C of conditions.
4. synthetic method according to claim 1, is characterized in that: step 2) in, nucleophilic substitution reaction carries out under 0 ~ 10 DEG C of condition.
5. synthetic method according to claim 1, is characterized in that: step 3) in, react and carry out under 10 ~ 60 DEG C of conditions.
6. synthetic method according to claim 1, is characterized in that: step 3) in, on gained residue during silica gel column chromatography, with by volume ratio being the mixed solvent wash-out that the sherwood oil of 2 ~ 10:1 and ethyl acetate form.
7. synthetic method according to claim 1, is characterized in that: the second described organic solvent is anhydrous tetrahydro furan, anhydrous diethyl ether or anhydrous methanol.
8. synthetic method according to claim 1, is characterized in that: step 4) in, add that lithium aluminum hydride carries out reducing, processed is carried out under 20 ~ 50 DEG C of conditions.
9. synthetic method according to claim 1, it is characterized in that: step 4) in, described dimethyl sulfate methylation of ester is dissolved in the solvent be made up of with the volume percent of 50 ~ 100%:0 ~ 50% oil of mirbane and dimethylbenzene by the product after lithium aluminium hydride reduction, dehydration, react under 150 ~ 200 DEG C of conditions, ether or tetrahydrofuran (THF) is added after reactant cooling, there is Precipitation, isolate precipitation, obtain sulfation nitidine.
10. synthetic method according to claim 1, is characterized in that: step 4) in, described sodium-chlor process is reacted through the methylated product of methyl-sulfate and sodium chloride aqueous solution, has Precipitation, collect this precipitation, be nitidine chloride.
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| CN109369772A (en) * | 2018-12-19 | 2019-02-22 | 桂林理工大学 | Synthesis method and antitumor application of a kind of phenanthridine derivatives |
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| CN101061121A (en) * | 2004-11-17 | 2007-10-24 | 日本化药株式会社 | Method for producing benzo[c]phenanthridine derivative |
| CN102887904A (en) * | 2012-10-10 | 2013-01-23 | 广西师范大学 | 2,3-dioxyethyl-5-methyl-8,9-dimethoxy benzophenanthridine derivative, and preparation method and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369772A (en) * | 2018-12-19 | 2019-02-22 | 桂林理工大学 | Synthesis method and antitumor application of a kind of phenanthridine derivatives |
| CN109369772B (en) * | 2018-12-19 | 2021-01-05 | 桂林理工大学 | Synthetic method and anti-tumor application of phenanthridine nitidine derivatives |
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