CN107400090A - A kind of synthetic method of benzimidizole derivatives - Google Patents
A kind of synthetic method of benzimidizole derivatives Download PDFInfo
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- CN107400090A CN107400090A CN201710814392.9A CN201710814392A CN107400090A CN 107400090 A CN107400090 A CN 107400090A CN 201710814392 A CN201710814392 A CN 201710814392A CN 107400090 A CN107400090 A CN 107400090A
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- Prior art keywords
- amino
- benzo
- mercapto
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 5
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 93
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- -1 2-nitrophenyl Chemical group 0.000 claims description 59
- 239000007787 solid Substances 0.000 claims description 54
- 238000003756 stirring Methods 0.000 claims description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 46
- 238000006243 chemical reaction Methods 0.000 claims description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- 238000001914 filtration Methods 0.000 claims description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 239000012065 filter cake Substances 0.000 claims description 32
- 238000001035 drying Methods 0.000 claims description 31
- 239000002994 raw material Substances 0.000 claims description 27
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- 238000004809 thin layer chromatography Methods 0.000 claims description 26
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 25
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 22
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 22
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 21
- ODINCKMPIJJUCX-UHFFFAOYSA-N Calcium oxide Chemical compound [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims description 16
- 239000000292 calcium oxide Substances 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 235000019260 propionic acid Nutrition 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 238000001308 synthesis method Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 7
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 7
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 7
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 5
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims description 5
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 1-chloro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 claims description 4
- DPJCXCZTLWNFOH-UHFFFAOYSA-N 2-nitroaniline Chemical compound NC1=CC=CC=C1[N+]([O-])=O DPJCXCZTLWNFOH-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002250 absorbent Substances 0.000 claims description 4
- 230000002745 absorbent Effects 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- IOLQWGVDEFWYNP-UHFFFAOYSA-N ethyl 2-bromo-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)Br IOLQWGVDEFWYNP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 235000014443 Pyrus communis Nutrition 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052789 astatine Inorganic materials 0.000 claims description 2
- RYXHOMYVWAEKHL-UHFFFAOYSA-N astatine atom Chemical compound [At] RYXHOMYVWAEKHL-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- PQUSVJVVRXWKDG-UHFFFAOYSA-N methyl 2-bromo-2-methylpropanoate Chemical compound COC(=O)C(C)(C)Br PQUSVJVVRXWKDG-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000001119 stannous chloride Substances 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 4
- 238000003786 synthesis reaction Methods 0.000 claims 4
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 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 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 230000001276 controlling effect Effects 0.000 description 19
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 7
- AIISNCGKIQZINV-UHFFFAOYSA-N [Na].CCC(O)=O Chemical compound [Na].CCC(O)=O AIISNCGKIQZINV-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940017219 methyl propionate Drugs 0.000 description 2
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 1
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
- 238000006964 Chan-Lam coupling reaction Methods 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000006887 Ullmann reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- LKKPNUDVOYAOBB-UHFFFAOYSA-N naphthalocyanine Chemical compound N1C(N=C2C3=CC4=CC=CC=C4C=C3C(N=C3C4=CC5=CC=CC=C5C=C4C(=N4)N3)=N2)=C(C=C2C(C=CC=C2)=C2)C2=C1N=C1C2=CC3=CC=CC=C3C=C2C4=N1 LKKPNUDVOYAOBB-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/28—Sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to field of medicaments, is related to a kind of derivative of benzimidazole and its synthetic method of officinal salt and purification process.Synthetic route of the present invention is as follows.
Description
The technical field is as follows:
the invention belongs to the field of medicines, and relates to a synthesis method and a purification method of benzimidazole derivatives and pharmaceutically acceptable salts thereof.
Background art:
benzimidazole derivatives, namely 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid and salts thereof, and synthetic methods of the compounds have been reported.
The key step 3 is as follows:
the nitro group at the ortho position of the reaction enhances the activity of fluorine, and strong alkali NaH is adopted to remove hydrogen on naphthylamine, so that the reaction can be smoothly carried out, but after the experiment is repeated, the reaction yield is low, the activity and the danger of the adopted NaH are high, the violent reaction and the heat release are difficult to control, and the amplification and the industrial production are difficult.
For the reaction of aromatic ammonia and halogenated aromatic ring, most documents report that palladium or copper is used as the core for metal catalytic coupling reaction, such as Ullmann reaction, Buchwald-Hartwig coupling reaction, Chan-Lam coupling reaction and the like, the catalyst used in the reaction is expensive, and the aftertreatment is difficult to remove, thereby seriously affecting the heavy metal index of the final product.
Therefore, we have conducted intensive research on the intermediate, and surprisingly found in the research process that a simpler and safer inorganic base such as NaOH is adopted, a proper water absorbent such as CaO is added, an intermediate with the same structure can be obtained without using a catalyst, the reaction yield is high, the post-treatment mode is simple and convenient, the reaction route is shortened, the cost is reduced, the reaction safety is obviously improved, and the intermediate is suitable for industrial scale-up production.
The invention content is as follows:
the invention aims to provide a synthesis method of benzimidazole derivatives represented by a formula (I) and pharmaceutically acceptable salts (II) thereof.
The synthetic method of the invention has the following synthetic route:
wherein,
R1when it is a halogen atom, R2Is amino；R1When it is amino, R2Is a halogen atom;
R3is a halogen atom or imidazole, preferably imidazole;
R4is a halogen atom, preferably Br;
R5is H or C1-3An alkyl group;
m is Na, K, Li, Ca or Mg, preferably Na;
the halogen comprises fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), mother of pear (Ts);
in the reaction process, the following reagents are respectively used:
the reagent used in step 1 is a mixture of inorganic bases and/or water absorbents or a mixture of bases.
The preferable reagent is one or more than one of NaOH, KOH, CaO or NaH.
The solvent used in step 1 is selected from: one or more of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, toluene, acetonitrile, dichloromethane and chloroform.
The reagent used in step 2 is a reducing agent selected from the group consisting of: hydrazine hydrate, palladium carbon/hydrogen, iron powder, zinc powder or stannous chloride.
The cyclization reagent used in the step 3 is N, N' -thiocarbonyl diimidazole or thiophosgene.
The solvent used in step 4 is acetonitrile.
The solvent used in step 5 is ethanol.
Specifically, the synthesis method of the benzimidazole derivatives represented by the formula (I) and the pharmaceutically acceptable salts (II) thereof comprises the following steps:
step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 2-nitroaniline, CaO, NaOH and N, N-dimethylacetamide into a three-necked flask, controlling the external temperature to be 0-150 ℃ under stirring, adding 4-bromo-1-naphthanenitrile, stirring and reacting for 1-48h, detecting no raw material residue by TLC (thin layer chromatography), stopping reaction, adding a proper amount of water, adjusting the pH value to be weakly acidic by using hydrochloric acid, filtering, and drying a filter cake to obtain a red solid.
Step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding 4- [ (2-nitrophenyl) amino ] naphthanenitrile into a mixture of ethanol and water, adding ferric chloride, controlling the external temperature to be 20-120 ℃, adding hydrazine hydrate, reacting for 1-24h, detecting by TLC that no raw material remains, stopping the reaction, adding a proper amount of water, stirring, filtering, drying a filter cake, and decoloring by using activated carbon to obtain a yellow solid.
And step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Adding 4- [ (2-aminophenyl) amino ] naphthanenitrile, N' -thiocarbonyl diimidazole and acetonitrile into a single-mouth bottle, controlling the external temperature to be 0-100 ℃, stirring and reacting for 1-24h, detecting by TLC (thin layer chromatography) until no raw material remains, adding a proper amount of water, filtering, and drying a filter cake to obtain a yellow solid.
And 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 4- (2-mercapto-1H-benzo [ d ] imidazole-1-yl) naphthanenitrile, potassium carbonate and water into acetonitrile, adding ethyl 2-bromoisobutyrate under stirring, controlling the external temperature to be 20-100 ℃, reacting for 1-24H, stopping reaction, filtering, concentrating filtrate, extracting with ethyl acetate and water, separating liquid, decoloring an ethyl acetate phase with activated carbon, concentrating to dryness, adding isopropanol for recrystallization, filtering, and drying a filter cake to obtain a light yellow solid.
And 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid (I)
Adding ethyl 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate into ethanol, adding a sodium hydroxide solution while stirring, controlling the temperature to be 0-80 ℃, reacting for 1-24H, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, adjusting the pH to subacidity by hydrochloric acid, concentrating the system to dryness, adding the residue into water, adjusting the pH to solid full dissolution by sodium hydroxide solution, adding hydrochloric acid to adjust the pH to subacidity, separating out a large amount of solid, filtering, and drying a filter cake to obtain a white solid.
Step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium (II)
Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid into ethanol, adding an equivalent amount of sodium hydroxide solution while stirring, controlling the temperature to be 0-80 ℃, reacting for 1-24H, separating out a large amount of solid in a system, filtering, and drying a filter cake to obtain a white solid.
Specifically, the synthesis method of the benzimidazole derivatives represented by the formula (I) and the pharmaceutically acceptable salts (II) thereof comprises the following steps:
step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 4-amino-1-naphthalocyanine, KOH and N-methylpyrrolidone into a three-necked bottle, controlling the external temperature to be 0-150 ℃ under stirring, adding o-chloronitrobenzene, stirring for reacting for 1-48h, detecting no raw material residue by TLC, stopping the reaction, adding a proper amount of water, regulating the pH value to be weak acid by using hydrochloric acid, filtering, and drying a filter cake to obtain a red solid.
Step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding iron powder into a saturated ammonium chloride solution, adding acetic acid, heating to 50-100 ℃, stirring, dissolving 4- [ (2-nitrophenyl) amino ] naphthanenitrile in ethanol, adding into an iron powder ammonium chloride system, controlling the external temperature to be 50-100 ℃, reacting for 1-24h, detecting by TLC that no raw material remains, stopping the reaction, cooling to room temperature, adding ethyl acetate, extracting, decoloring by using activated carbon, and concentrating to dryness to obtain a yellow solid.
And step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Dissolving 4- [ (2-aminophenyl) amino ] naphthalocyanide in ethyl acetate, adding thiophosgene and triethylamine, controlling the external temperature to be 0-100 ℃, stirring and reacting for 1-24h, detecting no raw material residue by TLC, adding water with the same volume for extraction, washing an ethyl acetate phase twice by water, separating liquid, and concentrating to dryness to obtain a yellow solid.
And 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 4- (2-mercapto-1H-benzo [ d ] imidazole-1-yl) naphthanenitrile, potassium carbonate and water into acetonitrile, adding 2-bromomethyl isobutyrate under stirring, controlling the external temperature to be 20-100 ℃, reacting for 1-24H, stopping reaction, filtering, concentrating filtrate, extracting with ethyl acetate and water, separating liquid, decoloring an ethyl acetate phase with activated carbon, concentrating to dryness, adding isopropanol for recrystallization, filtering, and drying a filter cake to obtain a light yellow solid.
And 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid
Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] methyl propionate into ethanol, adding a sodium hydroxide solution under stirring, controlling the temperature to be 0-80 ℃, reacting for 1-24H, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, adjusting the pH to subacidity by hydrochloric acid, concentrating the system to dryness, adding the residue into water, adjusting the pH to solid full dissolution by sodium hydroxide solution, adding hydrochloric acid to adjust the pH to subacidity, separating out a large amount of solid, filtering, and drying a filter cake to obtain a white solid.
Step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium salt
Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid into ethanol, adding a proper amount of potassium hydroxide solution while stirring, controlling the temperature to be 0-80 ℃, reacting for 1-24H, separating out a large amount of solid in a system, filtering, and drying a filter cake to obtain a white solid.
Compared with the existing method, the synthesis method of the invention has the following advantages:
1) the invention adopts simpler and safer inorganic alkali such as NaOH and the like, is matched with proper water absorbent such as CaO and the like, does not use catalyst, avoids using hazardous components such as NaH and the like, and improves the safety of the production process.
2) The NaH process is characterized in that each raw material reagent is added at a lower temperature and heated to a target temperature for reaction, so that the heat release phenomenon is serious and is difficult to control; the invention adopts the mixed alkali of NaOH and CaO, can effectively control the reaction heat release in a batch feeding mode, and greatly improves the safety of the production process.
3) Through research on a reaction mechanism, the NaH is found to react with a part of solvent at a higher temperature, so that the yield is reduced, and impurities are generated; the mixed alkali of NaOH and CaO adopted by the invention can have proper alkalinity and NaH water removal capacity, KOH has the function of drying an alkaline solvent, the effect of NaH in the system can be well replaced, the side reaction is avoided, the yield of the step is effectively improved, the pressure of subsequent purification is reduced, and the overall yield is improved.
Detailed description of the invention
The present invention is further illustrated by the following specific examples, which are not intended to be limiting, and the starting materials and reagents used in the examples are known compounds and commercially available.
Example 1
Step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 2-nitroaniline (45g), CaO (24g), NaOH (26g) and N, N-dimethylacetamide (250mL) into a three-necked flask, controlling the temperature to be 80-110 ℃ under stirring, adding 4-bromo-1-naphthacenitrile (50g) in batches, stirring for reacting for 5 hours, detecting by TLC (thin layer chromatography) that no raw material is left, stopping the reaction, adding 500mL of water, adjusting the pH to be 3-4 by using hydrochloric acid, filtering, and drying a filter cake to obtain 53g of red solid with the yield of 80%.
Step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding 4- [ (2-nitrophenyl) amino ] naphthalocyanine (50g) into a mixture of 250mL of ethanol and 85mL of water, adding ferric chloride, controlling the external temperature to be 70-90 ℃, adding 85% hydrazine hydrate (51g), reacting for 2h, detecting by TLC that no raw material remains, stopping the reaction, adding 170mL of water, stirring, filtering, drying a filter cake, and decolorizing with activated carbon to obtain 31.3g of yellow solid with the yield of 70%.
And step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Adding 4- [ (2-aminophenyl) amino ] naphthacenitrile (30g), N' -thiocarbonyldiimidazole (23g) and acetonitrile (90mL) into a single-mouth bottle, controlling the external temperature to be 50-90 ℃, stirring for reaction for 2h, detecting by TLC (thin layer chromatography) that no raw material remains, adding 90mL of water, filtering, drying a filter cake to obtain a yellow solid (33g) with the yield of 95 percent
And 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthanenitrile (30g), potassium carbonate (27.6g) and water (15mL) into acetonitrile (300mL), adding ethyl 2-bromoisobutyrate (29g) under stirring, controlling the external temperature to be 70-90 ℃, reacting for 3H, stopping the reaction, filtering, concentrating the filtrate, extracting with 300mL of ethyl acetate and 200mL of water, separating, decoloring the ethyl acetate phase with activated carbon, concentrating to be dry, adding isopropanol (90mL), recrystallizing, filtering, and drying the filter cake to obtain 37.2g of light yellow solid with the yield of 90%.
And 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid (I)
Reacting 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d [ ]]Imidazol-2-yl]Mercapto group]Adding ethyl propionate (35g) into 350mL of ethanol, adding 35mL of aqueous solution of sodium hydroxide (6.7g) under stirring at room temperature, reacting for 2-3 h, detecting by TLC that no raw material remains, stopping the reaction, adjusting the pH to 2-3 with hydrochloric acid, concentrating the system to dryness, adding the residue into water, adjusting the pH to 10 with 20% sodium hydroxide solution, fully dissolving the solid, adjusting the pH to 2-3 with hydrochloric acid, precipitating a large amount of solid, filtering, and drying the filter cake to obtain 27.7g of white solid with the yield of 85%. LC-MS: m/z 388.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：＝1.61(s,3H)，1.62(s,3H)，6.87(d,J＝8.4Hz,1H)，7.15-7.20(m,2H)，7.28-7.32(m,1H)，7.69-7.77(m,2H)，7.89-7.95(m,2H)，8.32(d,J＝8.4Hz,1H)，8.44(d,J＝7.6Hz,1H)，12.92(s,1H)。
Step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium (II)
Reacting 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d [ ]]Imidazol-2-yl]Mercapto group]Propionic acid (20g) was added to ethanol (200mL), 20mL of aqueous solution of sodium hydroxide (2.1g) was added with stirring at room temperature, reaction was carried out for 1h, a large amount of solid precipitated in the system, filtration was carried out, and the filter cake was dried to obtain 17g of white solid with a yield of 80%. LC-MS: m/z 388.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：＝1.61(s,3H)，1.62(s,3H)，6.87(d,J＝8.4Hz,1H)，7.15-7.20(m,2H)，7.28-7.32(m,1H)，7.69-7.77(m,2H)，7.89-7.95(m,2H)，8.32(d,J＝8.4Hz,1H)，8.44(d,J＝7.6Hz,1H)。
Example 2
Step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 4-amino-1-naphthanitrile (34g), KOH (11.3g) and N-methylpyrrolidone (350mL) into a three-necked bottle, controlling the external temperature to be 70-100 ℃ under stirring, dropwise adding o-chloronitrobenzene (32g), stirring for reacting for 3 hours, detecting by TLC (thin layer chromatography) that no raw material is left, stopping the reaction, adding 700mL of water, filtering, and drying a filter cake to obtain 46.7g of red solid with the yield of 70%.
Step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding iron powder (43g) into saturated ammonium chloride solution (500mL), adding acetic acid, heating to 70-100 ℃, stirring, dissolving 4- [ (2-nitrophenyl) amino ] naphthacenitrile (45g) in 100mL of ethanol, adding into an iron powder ammonium chloride system, controlling the external temperature to be 70-100 ℃, reacting for 3h, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, cooling to room temperature, adding 300mL of ethyl acetate for extraction, decoloring by using activated carbon, and concentrating to dryness to obtain 32g of yellow solid with the yield of 80%.
And step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Dissolving 4- [ (2-aminophenyl) amino ] naphthacenitrile (30g) in 300mL of ethyl acetate, adding thiophosgene (20g) and triethylamine (47g), stirring and reacting for 3h at room temperature, detecting by TLC that no raw material remains, adding 300mL of water for extraction, washing an ethyl acetate phase twice (200mL x 2) by using water, separating, and concentrating to dryness to obtain a yellow solid (26g) with the yield of 75%;
and 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 4- (2-mercapto-1H-benzo [ d ] imidazole-1-yl) naphthanenitrile (25g), potassium carbonate (23g) and water (12.5mL) into acetonitrile (250mL), adding methyl 2-bromoisobutyrate (24g) under stirring, controlling the external temperature to be 70-90 ℃, reacting for 3H, stopping the reaction, filtering, concentrating the filtrate, extracting with 300mL of ethyl acetate and 200mL of water, separating, decoloring the ethyl acetate phase with activated carbon, concentrating to be dry, adding isopropanol (75mL), recrystallizing, filtering, and drying the filter cake to obtain 30g of light yellow solid with the yield of 90%.
And 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid
Reacting 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d [ ]]Imidazol-2-yl]Mercapto group]Adding methyl propionate (30g) into 300mL of ethanol, adding 30mL of aqueous solution of sodium hydroxide (6g) under stirring at room temperature, reacting for 3h, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, adjusting the pH to 3-4 by hydrochloric acid, concentrating the system to dryness, adding the residue into water, adjusting the pH to 10 by 20% sodium hydroxide solution, fully dissolving the solid, adjusting the pH to 2-3 by adding hydrochloric acid, separating out a large amount of solid, filtering, and drying the filter cake to obtain 24.6g of white solid with the yield of 85%. LC-MS: m/z 388.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：＝1.60(s,3H)，1.62(s,3H)，6.88(d,J＝8.4Hz,1H)，7.14-7.20(m,2H)，7.27-7.33(m,1H)，7.69-7.78(m,2H)，7.89-7.94(m,2H)，8.33(d,J＝8.4Hz,1H)，8.43(d,J＝7.6Hz,1H)，12.91(s,1H)。
Step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium salt
Reacting 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d [ ]]Imidazol-2-yl]Mercapto group]Propionic acid (20g) was added to ethanol (200mL), 20mL of aqueous solution of sodium hydroxide (2.1g) was added with stirring at room temperature, reaction was carried out for 1h, a large amount of solid precipitated in the system, filtration was carried out, and the filter cake was dried to obtain 17g of white solid with a yield of 80%. LC-MS: m/z 388.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：＝1.60(s,3H)，1.62(s,3H)，6.88(d,J＝8.4Hz,1H)，7.14-7.20(m,2H)，7.27-7.33(m,1H)，7.69-7.78(m,2H)，7.89-7.94(m,2H)，8.33(d,J＝8.4Hz,1H)，8.43(d,J＝7.6Hz,1H)。
Example 3 screening experiments
Screening the alkali in the step 1 to obtain the preferable alkali of the process of the embodiment 1, namely NaOH + CaO mixed alkali; the preferred base for the process of example 2 is KOH.
The following are partial screening results:
example 4 comparative experiment
Claims (9)
1. A synthetic method of benzimidazole derivatives represented by formula (I) and pharmaceutically acceptable salts (II) thereof is characterized in that the synthetic route is as follows:
wherein,
R1when it is a halogen atom, R2Is amino; r1When it is amino, R2Is a halogen atom;
R3is a halogen atom or imidazole;
R4is a halogen atom;
R5is H or C1-3An alkyl group;
m is Na, K, Li, Ca or Mg;
the halogens include fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), mother of pear (Ts).
2. The synthesis method according to claim 1, characterized in that the following reagents are respectively used in the reaction process:
the reagent used in the step 1 is a mixture of inorganic base and/or water absorbent or a mixture of a plurality of bases;
the solvent used in step 1 is selected from: one or more of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, toluene, acetonitrile, dichloromethane and chloroform;
the reagent used in step 2 is a reducing agent selected from the group consisting of: one or more of hydrazine hydrate, palladium carbon/hydrogen, iron powder, zinc powder or stannous chloride;
the cyclization reagent used in the step 3 is N, N' -thiocarbonyl diimidazole or thiophosgene;
the solvent used in the step 4 is acetonitrile;
the solvent used in step 5 is ethanol.
3. The synthesis method according to claim 1, wherein the reagent used in step 1 is one or more of NaOH, KOH, CaO, NaOH or NaH.
4. The synthesis method according to claim 1, wherein the reagent used in step 1 is one or more of NaOH, KOH and CaO.
5. The synthesis method according to claim 1, wherein the reagent used in step 1 is NaOH, a mixture of CaO and CaO, or KOH.
6. The method of synthesis according to claim 1,
step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 2-nitroaniline, CaO, NaOH and N, N-dimethylacetamide into a three-necked flask, controlling the external temperature to be 0-150 ℃ under stirring, adding 4-bromo-1-naphthacenitrile, stirring for reacting for 1-48h, detecting no raw material residue by TLC (thin layer chromatography), stopping the reaction, adding a proper amount of water, adjusting the pH value to be weak acid by using hydrochloric acid, filtering, and drying a filter cake to obtain 4- [ (2-nitrophenyl) amino ] naphthacenitrile.
7. The method of synthesis according to claim 1,
step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 4-amino-1-naphthacenitrile, KOH and N-methylpyrrolidone into a three-necked bottle, controlling the external temperature to be 0-150 ℃ under stirring, adding o-chloronitrobenzene, stirring for reacting for 1-48h, detecting by TLC that no raw material remains, stopping the reaction, adding a proper amount of water, adjusting the pH to be weakly acidic by using hydrochloric acid, filtering, and drying a filter cake to obtain the 4- [ (2-nitrophenyl) amino ] naphthacenitrile.
8. The method of synthesis according to claim 1, comprising the steps of:
step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 2-nitroaniline (45g), CaO (24g), NaOH (26g) and N, N-dimethylacetamide (250mL) into a three-necked bottle, controlling the temperature to be 80-110 ℃ under stirring, adding 4-bromo-1-naphthanenitrile (50g) in batches, stirring for reacting for 5 hours, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, adding 500mL of water, adjusting the pH to be 3-4 by using hydrochloric acid, filtering, and drying a filter cake to obtain a red solid;
step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding 4- [ (2-nitrophenyl) amino ] naphthanenitrile (50g) into a mixture of 250mL of ethanol and 85mL of water, adding ferric chloride, controlling the external temperature to be 70-90 ℃, adding 85% hydrazine hydrate (51g), reacting for 2 hours, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, adding 170mL of water, stirring, filtering, drying a filter cake, and decolorizing with activated carbon to obtain a yellow solid;
and step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Adding 4- [ (2-aminophenyl) amino ] naphthanenitrile (30g), N' -thiocarbonyldiimidazole (23g) and acetonitrile (90mL) into a single-mouth bottle, controlling the external temperature to be 50-90 ℃, stirring for reacting for 2h, detecting by TLC (thin layer chromatography) until no raw material is left, adding 90mL of water, filtering, and drying a filter cake to obtain a yellow solid;
and 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 4- (2-mercapto-1H-benzo [ d ] imidazole-1-yl) naphthanenitrile (30g), potassium carbonate (27.6g) and water (15mL) into acetonitrile (300mL), adding ethyl 2-bromoisobutyrate (29g) under stirring, controlling the external temperature to be 70-90 ℃, reacting for 3H, stopping the reaction, filtering, concentrating the filtrate, extracting with 300mL of ethyl acetate and 200mL of water, separating, decoloring the ethyl acetate phase with active carbon, concentrating to dryness, adding isopropanol for recrystallization, filtering, and drying the filter cake to obtain a light yellow solid;
and 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid (I)
Adding ethyl 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate (35g) into 350mL of ethanol, adding 35mL of aqueous solution of sodium hydroxide (6.7g) under stirring at room temperature, reacting for 2-3H, detecting by TLC that no raw material remains, stopping the reaction, adjusting the pH to 2-3 with hydrochloric acid, concentrating the system to dryness, adding the remainder into water, adjusting the pH to 10 with 20% sodium hydroxide solution, fully dissolving the solid, adjusting the pH to 2-3 with hydrochloric acid, precipitating a large amount of solid, filtering, and drying the filter cake to obtain a white solid;
step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium (II)
Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid into ethanol, adding 20mL of aqueous solution of sodium hydroxide at room temperature under stirring, separating out a large amount of solid in the system, filtering, and drying a filter cake to obtain a white solid.
9. The method of synthesis according to claim 1, comprising the steps of:
step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 4-amino-1-naphthanitrile (34g), KOH (11.3g) and N-methylpyrrolidone (350mL) into a three-necked bottle, controlling the external temperature to be 70-100 ℃ under stirring, dropwise adding o-chloronitrobenzene (32g), stirring for reacting for 3 hours, detecting by TLC that no raw material remains, stopping the reaction, adding 700mL of water, filtering, and drying a filter cake to obtain a red solid;
step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding iron powder (43g) into saturated ammonium chloride solution (500mL), adding acetic acid, heating to 70-100 ℃, stirring, dissolving 4- [ (2-nitrophenyl) amino ] naphthacenitrile (45g) in 100mL of ethanol, adding into an iron powder ammonium chloride system, controlling the external temperature to be 70-100 ℃, reacting for 3h, detecting by TLC (thin layer chromatography) that no raw material remains, stopping reaction, cooling to room temperature, adding 300mL of ethyl acetate for extraction, decoloring by using activated carbon, and concentrating to dryness to obtain yellow solid;
and step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Dissolving 4- [ (2-aminophenyl) amino ] naphthacenitrile (30g) in 300mL of ethyl acetate, adding thiophosgene (20g) and triethylamine (47g), stirring and reacting for 3h at room temperature, detecting by TLC that no raw material remains, adding 300mL of water for extraction, washing an ethyl acetate phase twice (200mL of 2) by using water, separating, and concentrating to dryness to obtain a yellow solid;
and 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 4- (2-mercapto-1H-benzo [ d ] imidazole-1-yl) naphthanenitrile (25g), potassium carbonate (23g) and water (12.5mL) into acetonitrile (250mL), adding methyl 2-bromoisobutyrate (24g) under stirring, controlling the external temperature to be 70-90 ℃, reacting for 3H, stopping the reaction, filtering, concentrating the filtrate, extracting with 300mL of ethyl acetate and 200mL of water, separating, decoloring the ethyl acetate phase with active carbon, concentrating to dryness, adding isopropanol (75mL), recrystallizing, filtering, and drying the filter cake to obtain a light yellow solid;
and 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid
Adding methyl 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate (30g) into 300mL of ethanol, adding 30mL of aqueous solution of sodium hydroxide (6g) under stirring at room temperature, reacting for 3H, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, adjusting the pH to 3-4 with hydrochloric acid, concentrating the system to dryness, adding the remainder into water, adjusting the pH to 10 with 20% sodium hydroxide solution, fully dissolving the solid, adding hydrochloric acid to adjust the pH to 2-3, separating out a large amount of solid, filtering, and drying the filter cake to obtain a white solid;
step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium salt
Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid into ethanol, adding 20mL of aqueous solution of sodium hydroxide at room temperature under stirring, separating out a large amount of solid in the system, filtering, and drying a filter cake to obtain a white solid.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110577494A (en) * | 2018-06-07 | 2019-12-17 | 华润赛科药业有限责任公司 | Polymorphic substance of benzimidazole derivative and preparation method and application thereof |
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| WO2010090300A1 (en) * | 2009-02-03 | 2010-08-12 | 日本ケミファ株式会社 | Diazepinedione derivatives |
| CN105601571A (en) * | 2015-12-22 | 2016-05-25 | 华润赛科药业有限责任公司 | Benzimidazole derivatives as well as preparation method and application thereof |
| CN105713029A (en) * | 2016-03-02 | 2016-06-29 | 吉林奥来德光电材料股份有限公司 | Compound with heterocyclic ligand and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010090300A1 (en) * | 2009-02-03 | 2010-08-12 | 日本ケミファ株式会社 | Diazepinedione derivatives |
| CN105601571A (en) * | 2015-12-22 | 2016-05-25 | 华润赛科药业有限责任公司 | Benzimidazole derivatives as well as preparation method and application thereof |
| CN105713029A (en) * | 2016-03-02 | 2016-06-29 | 吉林奥来德光电材料股份有限公司 | Compound with heterocyclic ligand and preparation method and application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110577494A (en) * | 2018-06-07 | 2019-12-17 | 华润赛科药业有限责任公司 | Polymorphic substance of benzimidazole derivative and preparation method and application thereof |
| CN110577494B (en) * | 2018-06-07 | 2021-07-16 | 华润赛科药业有限责任公司 | Polymorphic substance of benzimidazole derivative and preparation method and application thereof |
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