CN104356139B - Synthetic method of nitidine chloride - Google Patents
Synthetic method of nitidine chloride Download PDFInfo
- Publication number
- CN104356139B CN104356139B CN201410676737.5A CN201410676737A CN104356139B CN 104356139 B CN104356139 B CN 104356139B CN 201410676737 A CN201410676737 A CN 201410676737A CN 104356139 B CN104356139 B CN 104356139B
- Authority
- CN
- China
- Prior art keywords
- synthetic method
- organic solvent
- solvent
- chloride
- conditions
- 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.)
- Expired - Fee Related
Links
- 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 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 28
- 239000003960 organic solvent Substances 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 239000011780 sodium chloride Substances 0.000 claims abstract description 14
- -1 lithium aluminum hydride Chemical compound 0.000 claims abstract description 13
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000376 reactant 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
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000009467 reduction Effects 0.000 claims abstract description 8
- 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 7
- GPVDHNVGGIAOQT-UHFFFAOYSA-N Veratric acid Natural products COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000012298 atmosphere Substances 0.000 claims abstract description 7
- 230000018044 dehydration Effects 0.000 claims abstract description 6
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 6
- 239000012280 lithium aluminium hydride Substances 0.000 claims abstract description 6
- 230000011987 methylation Effects 0.000 claims abstract description 6
- 238000007069 methylation reaction Methods 0.000 claims abstract description 6
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 235000002639 sodium chloride Nutrition 0.000 claims description 13
- 229960002668 sodium chloride Drugs 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 10
- 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
- 238000001556 precipitation Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- FCVHBUFELUXTLR-UHFFFAOYSA-N [Li].[AlH3] Chemical class [Li].[AlH3] FCVHBUFELUXTLR-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
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- 239000003513 alkali Substances 0.000 claims 1
- 230000001681 protective effect Effects 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 238000004440 column chromatography Methods 0.000 abstract description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000741 silica gel Substances 0.000 abstract description 2
- 229910002027 silica gel Inorganic materials 0.000 abstract description 2
- 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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 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
- 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
- 239000000463 material Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000001914 filtration Methods 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
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 150000001408 amides Chemical class 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
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000013558 reference substance Substances 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
- 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
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002156 mixing Methods 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
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 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 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000699670 Mus sp. Species 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
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 1
- 206010034811 Pharyngeal cancer Diseases 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 241000949456 Zanthoxylum Species 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
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical group CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000032839 leukemia Diseases 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
- 229910052756 noble gas Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 238000006349 photocyclization reaction Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 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
- 150000005337 veratric acids Chemical class 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 pharmaceutical technology field, be specifically related to the synthetic method of a kind of nitidine chloride.
Background technology
Nitidine chloride (Nitidine Chloride, NC), structure as shown in following formula I, for yellow or
Pistac acicular crystal.Nitidine chloride is to extract in the dry root by Rutaceae xanthoxylum Radix Zanthoxyli
A kind of benzene a pair of horses going side by side [c] phenanthridine alkaloid alkaloid, to LEWIS pulmonary carcinoma, human nasal pharyngeal cancer, hepatocarcinoma, chronic
Granulocyte leukemia all has inhibitory action, also effective to mice Emhorn water cancer, hepatic ascites, therefore NC tool
There is good anti-tumor activity, there is the biggest development and application values.
At present, NC is content only up to 0.2%～0.3% in Radix Zanthoxyli root bark, stem or leaf, carries from plant
Take is relatively costly, the most difficult for further transformation and optimization, also counteracts that the application of NC, therefore
Nitidine chloride is carried out complete synthesis extremely urgent.(Tetra lett, the 1974,26:2269-such as Kessar
2270.) with 2-bromo-4,5-dimethoxy Benzenecarbonyl chloride. and 2,3-methylenedioxy group naphthylamines is raw material, synthesizing amide,
Through lamp and high pressure mercury cyclization formed Fourth Ring amide, then through reduction, dehydrogenation, methylating to obtain Radix Zanthoxyli
Alkali salt, concrete synthetic route is as follows:
In above-mentioned synthetic method, raw material 2-bromo-4,5-dimethoxy Benzenecarbonyl chloride. is non-conventional raw material, needs
Will be with 3,4-dimethoxybenzoic acid or vanillin are Material synthesis, complex operation, and side reaction is many, reaction
In relate to Photocyclization, be unfavorable for industrialized production；Wherein with 3,4-dimethoxybenzoic acid as raw material
Time, yield is only 6.12% (US2013/253222), and needs 6 steps altogether with vanillin for raw material reaction
Just can complete, gross production rate the highest (J Org Chem, 1942,7:354,355).
Summary of the invention
The technical problem to be solved in the present invention is to provide the synthetic method of a kind of new nitidine chloride.Should
Method synthetic route is the simplest, and the yield of target product is higher.
The method of the invention is with 3, and 4-dimethoxybenzoic acid is initiation material, enters by following synthetic route
Row synthesis:
The synthetic method of nitidine chloride of the present invention, specifically includes following steps:
1) taking 3,4-dimethoxybenzoic acid is dissolved in the first organic solvent, adds thionyl chloride and reacts,
Reactant is evaporated off solvent, obtains intermediate 1 (acyl chlorides)；
2) after being dissolved with the first organic solvent by intermediate 1, addition 3,4-methylenedioxy group naphthylamines, take through nucleophilic
Generation reaction obtains intermediate 2 (amide)；
3) take intermediate 2 to be dissolved in the first organic solvent, add boron trifluoride diethyl etherate and two (trifluoroacetyl oxygen
Base) iodobenzene (the most double (trifluoroacetyl epoxide) iodobenzene, be abbreviated as PIFA) reacts, and reactant removes solvent,
Silica gel column chromatography on gained residue, obtains intermediate 3 (oxyterihanine)；
4) take intermediate 3 to be dissolved in the second organic solvent, hydrogenated aluminum lithium reduction under the conditions of atmosphere protection,
Dehydration and dimethyl sulfate methylation of ester, again through sodium chloride process, i.e. obtain target product nitidine chloride.
Above-mentioned synthetic method, the first described organic solvent is usually dichloromethane or chloroform, and described first
The consumption of organic solvent is advisable can dissolve the raw material participating in reaction；The second described organic solvent is usual
For anhydrous tetrahydro furan, absolute ether or absolute methanol, the consumption of described second organic solvent is with can be molten
The raw material solving participation reaction is advisable.
The step 1 of above-mentioned synthetic method) in, the mol ratio of 3,4-dimethoxybenzoic acids and thionyl chloride is
Stoichiometric proportion, usually 1:2～5；The reaction of described 3,4-dimethoxybenzoic acid and thionyl chloride is led to
Often carrying out under the conditions of 20～80 DEG C, reaction preferably employs the mode of heating or backflow and carries out, and whether reaction
Thin layer chromatography tracing detection can be used completely, under above-mentioned qualifications, react to take around completely 12～
48h。
The step 2 of above-mentioned synthetic method) in, nucleophilic substitution is preferably carried out under the conditions of 0～10 DEG C.
This step specifically includes: after being dissolved with the first organic solvent by intermediate 1, adds 3,4-under the conditions of 0～10 DEG C
(pyridine or triethylamine are used as acid binding agent, its consumption and existing skill for methylenedioxy group naphthylamines and pyridine or triethylamine
Art is identical), react under the conditions of above-mentioned and (react and can use thin layer chromatography tracing detection the most completely, upper
Stating under qualifications, reaction is to taking around 24～48h completely), course of reaction there is white solid separate out,
Sucking filtration, washs (generally using absolute methanol, dehydrated alcohol or acetonitrile to wash), i.e. obtains intermediate 2.
In order to improve the purity of intermediate 2 further, it is also possible to by intermediate 2 absolute methanol obtained, nothing
Water-ethanol or acetonitrile carry out recrystallization.In this step, intermediate 1 and 3,4-methylenedioxy group naphthylamines mol ratio
It is preferably 1～2:1.Too violent for avoiding reacting, preferably will enter 3,4-methylenedioxy group naphthylamines is dividedly in some parts.
The step 3 of above-mentioned synthetic method) in, intermediate 2, boron trifluoride diethyl etherate and two (trifluoroacetyl epoxides)
The mol ratio of iodobenzene is preferably 1:0.5～1:1～2, more preferably 1:0.6:1.3；Above-mentioned reaction is excellent
Choosing is to carry out under the conditions of 10～60 DEG C, and reaction can use thin layer chromatography tracing detection, the most completely upper
Stating under qualifications, reaction is to taking around 1～5h completely.In this step, silica gel on gained residue
During column chromatography, the most molten with the mixing being made up of the petroleum ether that volume ratio is 2～10:1 and ethyl acetate
Agent eluting, more preferably uses the mixing being made up of the petroleum ether that volume ratio is 2～6:1 and ethyl acetate molten
Agent eluting；Eluent solvent evaporated, obtains intermediate 3.
The step 4 of above-mentioned synthetic method) in, the mol ratio of described intermediate 3 and lithium aluminium hydride reduction is usually 1:
3～5, described addition lithium aluminium hydride reduction carries out reducing and follow-up processed is all 20～50 DEG C of conditions
Under carry out.Specifically, after intermediate 3 is dissolved in the second organic solvent, add under the conditions of atmosphere protection
Entering lithium aluminium hydride reduction to reduce under the conditions of 20～50 DEG C, reaction terminates (to react and can use thin layer the most completely
Chromatography tracing detection) afterwards gained reactant generally take off with the hydrochloric acid hydrochloric acid of 10～30% (the HCl content be)
Water processes, and then filters, filtrate dilute, has yellow mercury oxide (to be the product after dehydration, i.e. dihydro
Nitidine) separate out, collect yellow mercury oxide as the methylated raw material of next step dimethyl sulfate.
The step 4 of above-mentioned synthetic method) in, described dimethyl sulfate methylation of ester be by hydrogenated aluminum lithium reduce,
Product (the most above-mentioned yellow mercury oxide Dihydronitidine) after dehydration be dissolved in by Nitrobenzol and dimethylbenzene with 50～
The solvent of the percent by volume composition of 100%:0～50% (preferably by Nitrobenzol and dimethylbenzene with 70～
The percent by volume composition of 100%:0～30%) in, under the conditions of 150～200 DEG C, reaction (is reacted the completeest
Entirely can use thin layer chromatography tracing detection), add ether or oxolane after reactant cooling, have brown color
Precipitation, isolates precipitation, obtains sulphation nitidine, as next step sodium chloride process former
Material.The consumption of described dimethyl sulfate is preferably 2～5 times of the amount of intermediate 3 material.In this step,
Described atmosphere protection is typically in nitrogen or other noble gas such as atmosphere protection such as argon or helium condition
Under carry out.
The step 4 of above-mentioned synthetic method) in, it is by through dimethyl sulfate methylation of ester that described sodium chloride processes
Product (i.e. sulphation nitidine) react with sodium-chloride water solution (reaction generally at 20～40 DEG C, preferably
To carry out at ambient temperature, the time of reaction be Precipitation completely, usually 3～20min),
There is pale yellow precipitate to separate out, collect this pale yellow precipitate, be nitidine chloride.Wherein said chlorination
The consumption of sodium is usually 5～20 times of the amount of intermediate 3 material, after determining the consumption of sodium chloride,
With water, sodium chloride dissolving i.e. being obtained sodium-chloride water solution, the concentration of described sodium-chloride water solution is the most especially
Be particular about, it is common that be configured to 5～the sodium-chloride water solution of 20% (quality).
Compared with prior art, the inventive method is with 3, and 4-dimethoxybenzoic acid is initiation material, synthesis
Route is the simplest, and the yield of target product is higher, and total recovery is up to more than 27%.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail, to be more fully understood that the present invention's
Content, but the present invention is not limited to following example.
Embodiment 1
1) synthesis of intermediate 1:
By 0.98g 3,4-dimethoxybenzoic acid (5.4mmol) thermosol in 40mL dichloromethane, then
Add 0.78mL SOCl2(10.8mmol) it is heated to reflux 4h at 40 DEG C.Solvent evaporated, obtains white solid
Body, is intermediate 1, productivity 100%.
2) synthesis of intermediate 2:
Take above-mentioned 1.12g intermediate 1 and be dissolved in 40mL dichloromethane, at 0 DEG C, be added thereto to 2.8mL
Pyridine and 1g 3,4-methylenedioxy group aniline (3,4-methylenedioxy group aniline are divided into 3 batches of additions in 10min),
24h is reacted under the conditions of 5 DEG C.Having white solid to separate out in course of reaction, sucking filtration, dehydrated alcohol is washed
Wash, obtain white needle-like crystals with dehydrated alcohol recrystallization the most again, be intermediate 2, productivity 47.5%,
Fusing point 235-236 DEG C.FAB-MS m/z:352([M+H]+)；1H NMR(DMSO-d6)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 ,-CH2),3.86(s,6H,-OCH3)；13C
NMR (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 dichloromethane, adds 0.56g PIFA solid and 0.1
ML boron trifluoride diethyl etherate, reacts 3h under the conditions of 10 DEG C.After reaction terminates, solvent is drained, with oil
Ether/ethyl acetate (volume ratio is 4:1) is that eluant carries out column chromatography for separation, and eluent solvent evaporated, in obtaining
Mesosome 3, productivity is 12%.m.p.235-236℃；1H NMR(CDCl3)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,-OCH3),2.53(s,3H,-CH3).
4) synthesis of nitidine chloride:
4.1) 0.1g intermediate 3 is dissolved in 10mL anhydrous tetrahydro furan, under nitrogen protection, adds 0.06g
LiAlH4, react 3h, after reaction terminates, reactant 2mol/L hydrochloric acid processed under room temperature condition,
Filter insoluble matter, in gained filtrate, add 10mL distilled water, have yellow mercury oxide to separate out, be dihydro
Nitidine, uses 95% ethyl alcohol recrystallization again by this precipitation, obtains yellow needle-like crystals 0.06g, productivity
60%；
4.2) take the above-mentioned yellow needle-like crystals of 0.06g to be placed in and be made up of 4mL Nitrobenzol and 2mL dimethylbenzene
In solvent, add the dimethyl sulfate of 200 μ L, react 7min under the conditions of 180 DEG C, after reactant cooling
Being added thereto to ether to there being brown color Precipitation, sucking filtration, filtering residue absolute methanol is recrystallized to give sulfur
Acidifying nitidine, productivity 70%；
4.3) take in the sodium chloride solution that 0.1mmol sulphation nitidine joins 5mL 8w/w%, room
Temperature stirring reaction 30min, has pale yellow precipitate to separate out, isolates this pale yellow precipitate and be target product
Nitidine chloride, productivity 80%,1H NMR(DMSO-d6) 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-CH2-O-,4.99(s,3H,N-CH3),4.29(s,3H,-OCH3),4.14(s,3H,-OCH3).
Fusing point 272～275 DEG C, basically identical with literature value 275～276 DEG C, by TLC method and reference substance (Shanghai
Chun You bio tech ltd) comparison is same compound (developing solvent: chloroform: methanol=9:1).
Embodiment 2
The method repeating embodiment 1, is only by revising as follows:
1, by step 1) in methylene chloride used be revised as chloroform, reaction condition is revised as 30 DEG C
Under the conditions of react 48h；
2, by step 2) in methylene chloride used be revised as chloroform, reaction condition is revised as 10 DEG C
Under the conditions of react 12h；
3, by step 3) in reaction condition be revised as 50 DEG C under the conditions of react 1h；
4, by step 4.1) in solvent anhydrous tetrahydro furan used be revised as absolute ether；By step 4.2)
In reaction condition be revised as 200 DEG C under the conditions of react 3min, simultaneously by step 4.2) in used by 4
The solvent of mL Nitrobenzol and 2mL dimethylbenzene composition is revised as 6mL Nitrobenzol.
The end product productivity 22% that this enforcement prepares, fusing point 272～275 DEG C, with literature value 275-276 DEG C
Basically identical, it is sameization by TLC method and reference substance (Chun You bio tech ltd, Shanghai) comparison
Compound (developing solvent: chloroform: methanol=9:1).
Embodiment 3
The method repeating embodiment 1, is only by revising as follows:
1, by step 3) in the mixed solvent of eluting change to by the petroleum ether that volume ratio is 10:1 and second
Acetoacetic ester forms；
2, by step 3) in reaction condition be revised as 60 DEG C under the conditions of react 1h；
3, by step 4.2) in reaction condition be revised as 150 DEG C under the conditions of react 15min, and will wherein
Ether change to oxolane.
The end product productivity 20% that this enforcement prepares, fusing point 272～275 DEG C, with literature value 275-276 DEG C
Basically identical, it is sameization by TLC method and reference substance (Chun You bio tech ltd, Shanghai) comparison
Compound (developing solvent: chloroform: methanol=9:1).
Claims (10)
1. a synthetic method for nitidine chloride, comprises the following steps:
1) taking 3,4-dimethoxybenzoic acid is dissolved in the first organic solvent, adds thionyl chloride and carries out instead
Should, reactant is evaporated off solvent, obtains intermediate 1；
2) adding 3 after being dissolved with the first organic solvent by intermediate 1,4-methylenedioxy group naphthylamines, through nucleophilic
Substitution reaction obtains intermediate 2；
3) take intermediate 2 to be dissolved in the first organic solvent, add boron trifluoride diethyl etherate and two (trifluoroacetyls
Epoxide) iodobenzene reacts, and reactant removes solvent, silica gel column chromatography on gained residue, obtains
Intermediate 3；
4) take intermediate 3 to be dissolved in the second organic solvent, hydrogenated aluminum lithium reduction under the conditions of atmosphere protection,
Dehydration and dimethyl sulfate methylation of ester, again through sodium chloride process, i.e. obtain target product chlorination Radix Zanthoxyli
Alkali；Wherein, described atmosphere protection is for carry out under nitrogen or argon or helium protective condition；
Synthetic route is as follows:
Synthetic method the most according to claim 1, it is characterised in that: described first is organic
Solvent is dichloromethane or chloroform.
Synthetic method the most according to claim 1, it is characterised in that: step 1) in, reaction
Carry out under the conditions of 20～80 DEG C.
Synthetic method the most according to claim 1, it is characterised in that: step 2) in, nucleophilic
Substitution reaction is carried out under the conditions of 0～10 DEG C.
Synthetic method the most according to claim 1, it is characterised in that: step 3) in, reaction
Carry out under the conditions of 10～60 DEG C.
Synthetic method the most according to claim 1, it is characterised in that: step 3) in, gained
On residue during silica gel column chromatography, with by the petroleum ether that volume ratio is 2～10:1 and ethyl acetate group
The mixed solvent eluting become.
Synthetic method the most according to claim 1, it is characterised in that: described second is organic
Solvent is anhydrous tetrahydro furan, absolute ether or absolute methanol.
Synthetic method the most according to claim 1, it is characterised in that: step 4) in, add
Lithium aluminium hydride reduction carries out reducing, processed is to carry out under the conditions of 20～50 DEG C.
Synthetic method the most according to claim 1, it is characterised in that: step 4) in, described
Dimethyl sulfate methylation of ester be by hydrogenated aluminum lithium reduce, dehydration after product be dissolved in by Nitrobenzol and two
Toluene with 50～100%:0～50% percent by volume composition solvent in, at 150～200 DEG C of bars
React under part, add ether or oxolane after reactant cooling, have Precipitation, isolate precipitation,
Obtain sulphation nitidine.
Synthetic method the most according to claim 1, it is characterised in that: step 4) in, described
Sodium chloride process be will to react with sodium-chloride water solution through the methylated product of dimethyl sulfate, there have to be heavy
Precipitation goes out, and collects this precipitation, is nitidine chloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410676737.5A CN104356139B (en) | 2014-11-21 | 2014-11-21 | Synthetic method of nitidine chloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410676737.5A CN104356139B (en) | 2014-11-21 | 2014-11-21 | Synthetic method of nitidine chloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104356139A CN104356139A (en) | 2015-02-18 |
| CN104356139B true CN104356139B (en) | 2017-01-11 |
Family
ID=52523470
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410676737.5A Expired - Fee Related CN104356139B (en) | 2014-11-21 | 2014-11-21 | Synthetic method of nitidine chloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104356139B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369772B (en) * | 2018-12-19 | 2021-01-05 | 桂林理工大学 | Synthetic method and anti-tumor application of phenanthridine nitidine derivatives |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3912740A (en) * | 1974-02-28 | 1975-10-14 | Us Health | Method for the preparation of oxygenated benzo{8 c{9 phenanthridine compounds |
| JP2006143625A (en) * | 2004-11-17 | 2006-06-08 | Nippon Kayaku Co Ltd | METHOD FOR PRODUCING BENZO[c]PHENANTHRIDINE DERIVATIVE |
| CN102887904B (en) * | 2012-10-10 | 2015-01-14 | 广西师范大学 | 2,3-dioxyethyl-5-methyl-8,9-dimethoxy benzophenanthridine derivative, and preparation method and application thereof |
-
2014
- 2014-11-21 CN CN201410676737.5A patent/CN104356139B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN104356139A (en) | 2015-02-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8884021B2 (en) | Process for preparing racemic nicotine | |
| CN107513031B (en) | Preparation method of 2-oxo-1-pyrrolidine chiral derivative | |
| CN102584795A (en) | Preparing method of crizotinib | |
| CN103224473B (en) | Preparation method of triazine ring | |
| CN103772278A (en) | Important tetrahydroisoquinoline derivative midbody and synthesis method thereof | |
| CN102850325B (en) | Preparation method of Dabigatran etexilate key intermediate | |
| KR20090083455A (en) | Imatinib and their intermediates and preparation methods thereof | |
| CN111763170B (en) | Preparation method of flumatinib intermediate | |
| CN104926768A (en) | Moslosooflavone, isowogonin and norwogonin synthetic method | |
| CN104356139B (en) | Synthetic method of nitidine chloride | |
| CN105198821A (en) | Preparation method of Rociletinib | |
| CN103254183B (en) | Ah method is for the preparation method of Buddhist nun | |
| CN109721552B (en) | Preparation method of gefitinib | |
| CN105061467A (en) | Method for preparing pacritinib | |
| CN111138269B (en) | Process method for preparing 2-butanone acid sodium salt | |
| CN103396371A (en) | Preparation method of erlotinib hydrochloride crystal form A | |
| CN101880285B (en) | Method for synthetizing allyl-substituted camptothecin compound | |
| CN111995569B (en) | Preparation method of cyclin-dependent kinase inhibitor intermediate | |
| CN104163798A (en) | Synthesis method of 3-amino-8-trifluoromethyl quinoline | |
| CN101239947A (en) | The preparation method of aconitine | |
| CN117510471B (en) | A kind of synthetic method of abemaciclib | |
| US20160168161A1 (en) | Method for producing heterocyclic compound | |
| WO2020125581A1 (en) | Amide derivatives and preparation method for intermediates thereof | |
| CN115368219B (en) | Preparation method of FGFR inhibitor key intermediate | |
| CN110304986B (en) | Preparation method of 1-bromoadamantane |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170111 Termination date: 20191121 |