CN111793033A - Preparation method of plinabulin intermediate imidazole formaldehyde compound - Google Patents
Preparation method of plinabulin intermediate imidazole formaldehyde compound Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 58
- -1 imidazole formaldehyde compound Chemical class 0.000 title claims description 46
- UNRCMCRRFYFGFX-TYPNBTCFSA-N plinabulin Chemical compound N1C=NC(\C=C/2C(NC(=C\C=3C=CC=CC=3)/C(=O)N\2)=O)=C1C(C)(C)C UNRCMCRRFYFGFX-TYPNBTCFSA-N 0.000 title description 13
- 229950011498 plinabulin Drugs 0.000 title description 13
- 238000000034 method Methods 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 74
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- 239000003153 chemical reaction reagent Substances 0.000 claims description 34
- 238000010438 heat treatment Methods 0.000 claims description 26
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical group NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 22
- 239000003960 organic solvent Substances 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical group O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 239000007800 oxidant agent Substances 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 9
- 238000007254 oxidation reaction Methods 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 238000007031 hydroxymethylation reaction Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 8
- 229920002866 paraformaldehyde Polymers 0.000 claims description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 239000011630 iodine Chemical group 0.000 claims description 4
- 229910052740 iodine Chemical group 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 235000019256 formaldehyde Nutrition 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- RBZVCMKUEIDTSC-UHFFFAOYSA-N formaldehyde;1h-imidazole Chemical class O=C.C1=CNC=N1 RBZVCMKUEIDTSC-UHFFFAOYSA-N 0.000 abstract description 23
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 230000007797 corrosion Effects 0.000 abstract description 3
- 238000005260 corrosion Methods 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 8
- FSTXHTKEZGSDNN-UHFFFAOYSA-N 5-tert-butyl-1h-imidazole-4-carbaldehyde Chemical compound CC(C)(C)C=1N=CNC=1C=O FSTXHTKEZGSDNN-UHFFFAOYSA-N 0.000 description 7
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- 238000005457 optimization Methods 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- SAIRZMWXVJEBMO-UHFFFAOYSA-N 1-bromo-3,3-dimethylbutan-2-one Chemical compound CC(C)(C)C(=O)CBr SAIRZMWXVJEBMO-UHFFFAOYSA-N 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 238000000108 ultra-filtration Methods 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000010865 sewage Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 210000000612 antigen-presenting cell Anatomy 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- VUYNTIDSHCJIKF-UHFFFAOYSA-N ethyl 4,4-dimethyl-3-oxopentanoate Chemical compound CCOC(=O)CC(=O)C(C)(C)C VUYNTIDSHCJIKF-UHFFFAOYSA-N 0.000 description 2
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical group CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 description 1
- 101150084229 ATXN1 gene Proteins 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 229940122429 Tubulin inhibitor Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000004041 dendritic cell maturation Effects 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000012803 optimization experiment Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical compound O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 201000003624 spinocerebellar ataxia type 1 Diseases 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
Abstract
The invention discloses a preparation method of imidazole formaldehydes, which reduces operation danger level and production cost by optimizing and improving a preparation route method, optimizing reaction conditions and improving a post-treatment and purification method; the requirement on the corrosion resistance grade of reaction container equipment is low, the operation safety is good, and the post-treatment is green and environment-friendly; the preparation method has the advantages of simple operation of each step, safe and feasible solvent and process conditions, realization of environment-friendly and green production and wide application prospect.
Description
Technical Field
The invention relates to the technical field of synthesis of drug intermediates, in particular to a preparation method of a plinabulin intermediate imidazole formaldehyde compound.
Background
Plinabulin (Plinabulin) is a diketopiperazine tubulin inhibitor synthesized by structure-activity relationship research on the basis of a natural product phenyl inhibitor structure separated from marine aspergillus pyrosus.
The structure is as follows:
plinabulin is a brand new small molecule differential immunity and stem cell regulator as an anti-tumor candidate drug. The clinical three-phase study of plinabulin in combination with docetaxel for treating non-small cell lung cancer and preventing severe neutropenia caused by chemotherapy has been completed currently. The long-lasting anticancer effect of plinabulin is associated with its use as a potent inducer of Antigen Presenting Cells (APCs) by activating dendritic cell maturation and T cell activation. The CIN data of plinabulin underscores its ability to increase the number of mouse hematopoietic stem/progenitor cells (HSPCs) or lineage-/cKit +/Sca1+ (LSK) cells. The effect on HSPCs may explain why plinabulin can not only treat CIN, but also ameliorate thrombocytopenia resulting from chemotherapy, increasing circulating CD34+ cells.
The key intermediate for synthesizing the plinabulin, namely 5-tert-butyl-1H-imidazole-4-formaldehyde, has a molecular formula as follows: c8H12N2O, english name: 5- (Tert-butyl) -1H-imidazole-4-carbaldehyde, the formula of which is shown as follows:
in the prior art, in the preparation method of 5-tert-butyl-1H-imidazole-4-formaldehyde, WO2004054498 document uses ethyl 4, 4-dimethyl-3-oxopentanoate as a starting material, and performs chlorination of sulfonyl chloride, cyclization of formamide, reduction of lithium aluminum hydride and oxidation of manganese dioxide to obtain an intermediate 5-tert-butyl-1H-imidazole-4-formaldehyde, and the preparation method has the following route;
according to the preparation method, a large amount of corrosive and polluting sulfonyl chloride reagent is used in the first step, so that corrosion damage is caused to reaction container equipment, a large amount of corrosive sewage is generated in post-treatment, and the preparation method is not beneficial to green and environment-friendly industrial production; the hazardous reagent lithium aluminum hydride is used for reduction reaction, so that the personal risk of operators is high; the formamide is adopted for the ring closure reaction, so that the yield is low, the cost is high, and the industrial popularization is not facilitated.
Document J.Med.chem.2012,55,1056-1071. taking ethyl isocyanate as a starting material, closing a ring by pivalic anhydride, formamide exchange, lithium aluminum hydride reduction and manganese dioxide oxidation to obtain an intermediate 5-tert-butyl-1H-imidazole-4-formaldehyde, wherein the preparation method route is shown as follows;
the raw material of the preparation method, namely the ethyl isocyanate, is high in price and large in smell, and is used as a starting raw material in a large amount, so that the cost is not reduced, the smell is large, the environment is polluted, and the environmental protection is not facilitated; in the process, a large amount of lithium aluminum hydride hazardous reagents are used, so that the industrial risk is high, and the industrial production is not facilitated.
In conclusion, the preparation method of the 5-tert-butyl-1H-imidazole-4-formaldehyde product disclosed by the prior art has the advantages that in the preparation process, a dangerous reagent lithium aluminum hydride is used for carbonyl reduction, so that the operation danger is high, the safety is poor, and the safety level and the production cost of the production are improved; the raw materials are corrosive, polluting or smelly reagents, a large amount of the reagents are used, the corrosive damage is caused to a reaction container, a large amount of corrosive and smelly sewage is generated by post-treatment, the green and environment-friendly industrial production cannot be realized, and the industrial popularization and application are not facilitated.
Therefore, the technical personnel in the field are dedicated to develop a preparation method of imidazole formaldehydes, aiming at solving the problem of the defects of 5-tert-butyl-1H-imidazole-4-formaldehyde product compounds in the prior art in the synthesis method.
Disclosure of Invention
The technical problem to be solved by the invention is that in the prior art, the preparation method of the 5-tert-butyl-1H-imidazole-4-formaldehyde compound has the disadvantages of using dangerous, corrosive and smelly reagents, low yield, poor safety and unsuitability for industrial scale-up production and industrial application.
In order to achieve the purpose, the invention provides a preparation method of an imidazole formaldehyde compound, the structure of the imidazole formaldehyde compound is shown as the following formula A,
the preparation method of the imidazole formaldehydes compound has the following route I:
route I:
wherein R is selected from C1-C10 alkyl and C1-C14 alkylaryl; x is selected from chlorine, bromine and iodine;
the specific operation steps are as follows:
step 1, mixing a compound A-0 with a ring closing reagent, heating to 140-; adding water into the reaction solution for quenching, adjusting the pH value to 10-12, adding an organic solvent for extraction, washing an organic phase, drying, filtering, concentrating and removing the organic solvent to obtain a compound A-1;
step 2, heating the compound A-1 and a hydroxymethylation reagent in the presence of alkali and an alcohol solvent to 55-90 ℃ for reaction for 20-30 hours, and performing post-treatment to obtain a compound A-2;
step 3, carrying out oxidation reaction on the compound A-2 and an oxidant in an organic solvent, and carrying out post-treatment to obtain an imidazole formaldehyde compound (formula A);
further, R is C1-C10 alkyl;
further, R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;
further, X is bromine or iodine;
further, in the step 1, the ring closing reagent is formamide or formamidine acetate;
further, in the step 1, the organic solvent is one of dichloromethane, chloroform and ethyl acetate;
further, in the step 1, the molar ratio of the compound A-0 to the ring closing reagent is 1: 1-1: 10;
further, in the step 2, the hydroxymethyl reagent is one of paraformaldehyde and a formaldehyde aqueous solution;
further, in the step 2, the alkali is one or more of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide;
further, in the step 2, the alcohol solvent is one or more of methanol, ethanol, isopropanol and n-butanol;
further, in the step 2, the weight ratio of the compound A-1 to the hydroxymethylation reagent is 1: 1-4: 1;
further, in the step 2, the weight-volume (g: ml) ratio of the compound A-1 to the alcohol solvent is 1: 2-1: 20;
further, in the step 2, the molar ratio of the compound A-1 to the alkali is 1: 1-1: 4;
further, in the step 3, the oxidizing agent is manganese dioxide;
further, in the step 3, the organic solvent is one or more of dichloromethane, acetone and chloroform;
further, in the step 3, the molar ratio of the compound A-2 to the oxidant is 1: 2-1: 8;
further, in the step 3, the weight-to-volume (g: ml) ratio of the compound A-2 to the organic solvent is 1: 5-1: 20;
further, in the step 3, the reaction temperature of the oxidation reaction is 15-80 ℃, and the reaction time is 10-20 hours;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes compound, in the step 1, the molar ratio of the compound A-0 to the ring closing reagent is 1: 2;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes compound, in the step 1, the molar ratio of the compound A-0 to the ring closing reagent is 1: 5;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes compound, in the step 1, the molar ratio of the compound A-0 to the ring closing reagent is 1: 8;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes compound, in the step 1, the molar ratio of the compound A-0 to the ring closing reagent is 1: 10;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes compound, in the step 1, the heating temperature is 150-160 ℃;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes compound, in the step 1, the heating temperature is 140-150 ℃;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes compound, in the step 1, the heating temperature is 160-180 ℃;
according to a preferred embodiment of the method for preparing imidazole formaldehydes, in the step 2, the weight ratio of the compound A-1 to the hydroxymethylation reagent is 1: 1;
according to a preferred embodiment of the method for preparing imidazole formaldehydes, in step 2, the weight ratio of the compound A-1 to the hydroxymethylation reagent is 2: 1;
according to a preferred embodiment of the method for preparing imidazole formaldehydes, in step 2, the weight ratio of the compound A-1 to the hydroxymethylation reagent is 4: 1;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes, in the step 2, the weight-to-volume (g: ml) ratio of the compound A-1 to the alcohol solvent is 1: 2;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes, in the step 2, the weight-to-volume (g: ml) ratio of the compound A-1 to the alcohol solvent is 1: 5;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes, in the step 2, the weight-to-volume (g: ml) ratio of the compound A-1 to the alcohol solvent is 1: 10;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes, in the step 2, the weight-to-volume (g: ml) ratio of the compound A-1 to the alcohol solvent is 1: 20;
according to a preferred embodiment of the method for preparing imidazole formaldehydes, in step 2, the molar ratio of compound a-1 to base is 1: 1;
according to a preferred embodiment of the method for preparing imidazole formaldehydes, in step 2, the molar ratio of compound a-1 to base is 1: 2;
according to a preferred embodiment of the method for preparing imidazole formaldehydes, in step 2, the molar ratio of compound a-1 to base is 1: 4;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes compound, in the step 2, the heating temperature is 55-65 ℃;
according to a preferred embodiment of the method for preparing imidazole formaldehydes, in step 2, the heating temperature is 65-75 ℃;
according to a preferred embodiment of the method for preparing imidazole formaldehydes, in step 2, the heating temperature is 75-90 ℃;
according to a preferred embodiment of the method for preparing imidazole formaldehydes, in step 3, the molar ratio of compound a-2 to the oxidizing agent is 1: 2;
according to a preferred embodiment of the method for preparing imidazole formaldehydes, in step 3, the molar ratio of compound a-2 to the oxidizing agent is 1: 4;
according to a preferred embodiment of the method for preparing imidazole formaldehydes, in step 3, the molar ratio of compound a-2 to the oxidizing agent is 1: 5;
according to a preferred embodiment of the method for preparing imidazole formaldehydes, in step 3, the molar ratio of compound a-2 to the oxidant is 1: 8;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes, in the step 3, the weight-to-volume (g: ml) ratio of the compound a-2 to the organic solvent is 1: 5;
according to a preferred embodiment of the method for preparing imidazole formaldehydes, in step 3, the weight-to-volume (g: ml) ratio of compound a-2 to organic solvent is 1: 10;
according to a preferred embodiment of the preparation method of the imidazole formaldehydes, in the step 3, the weight-to-volume (g: ml) ratio of the compound a-2 to the organic solvent is 1: 20;
the technical parameter characteristics in the above preparation method of the present invention can be combined at will.
In the above operations, the post-treatment includes, but is not limited to, stirring, liquid or solid transferring, water washing, alkali washing, acid washing, PH adjusting, filtering, ultrafiltration, circulating ultrafiltration, suction filtration, dilution, concentration, drying, recrystallization, freeze-drying, or the like, or one or more of stirring, liquid or solid transferring, water washing, alkali washing, acid washing, PH adjusting, filtering, ultrafiltration, circulating ultrafiltration, suction filtration, dilution, concentration, drying, recrystallization, freeze-drying, and the like.
Compared with the prior art, the preparation method of the imidazole formaldehydes compound has the following beneficial effects:
the preparation method of the imidazole formaldehydes compound optimizes and improves the operation method of the preparation route, adopts safe and pollution-free cheap raw material compounds, and prepares the imidazole formaldehydes compound through three steps of reactions of ring closing, hydroxymethylation and oxidation, the whole route does not use corrosive reagents, the operation condition is mild, the operation difficulty is reduced, the requirement on the corrosion resistance of reaction container equipment is low, the operation safety is good, and the potential threat level of the life hazard to production front-line staff is reduced; the post-treatment does not generate corrosive and polluting sewage, is green and environment-friendly, and is beneficial to the amplification production and the industrialized popularization; the reduction reaction of a dangerous reagent lithium aluminum hydride is avoided, the personal safety threat to operators is reduced, and the safety level and the production cost of production are reduced; the use of reagents with large odor is avoided, the pollution to the atmospheric environment is reduced, and the application of green and environment-friendly industrial production is facilitated;
the preparation method of the imidazole formaldehydes compound has the advantages of short route steps, high yield, reduced preparation cost, mild conditions and high safety, and is favorable for application of large-scale production.
Detailed Description
All of the features disclosed in this specification, or all of the steps in any method or process so disclosed, may be combined in any combination, except combinations of features and/or steps that are mutually exclusive.
Any feature disclosed in this specification may be replaced by alternative features serving equivalent or similar purposes, unless expressly stated otherwise. That is, unless expressly stated otherwise, each feature is only an example of a generic series of equivalent or similar features.
The following will further describe the preparation method of the imidazole formaldehydes compound of the present invention in detail.
According to an exemplary embodiment of the present invention, the method for preparing imidazole formaldehydes,
the imidazole formaldehydes compound has a structure shown as the following formula Aa,
the preparation method of the imidazole formaldehydes compound has the following route Ia:
route Ia:
in the preparation method of the imidazole formaldehydes compound, in the step 1,
the ring closing reagent is formamide;
the organic solvent is dichloromethane;
the heating temperature is 150-160 ℃;
in the preparation method of the imidazole formaldehydes compound, in the step 2,
the hydroxymethyl reagent is paraformaldehyde;
the alkali is potassium carbonate;
the alcohol solvent is isopropanol;
the heating temperature is 65-75 ℃;
in the preparation method of the imidazole formaldehydes compound, in the step 3,
the oxidant is manganese dioxide;
the organic solvent is dichloromethane;
the reaction temperature of the oxidation reaction is 40-50 ℃;
the preparation method of the imidazole formaldehydes compound comprises the following specific operations in the step 1:
mixing the compound Aa-0 with formamide, heating to 150-; cooling the reaction liquid, adding water for quenching, adding a sodium hydroxide aqueous solution to adjust the pH value to 10, adding dichloromethane for extraction, washing an organic phase, drying, filtering, and concentrating to remove an organic solvent to obtain a compound Aa-1;
the preparation method of the imidazole formaldehydes compound comprises the following specific operations in the step 2:
feeding and mixing the compound Aa-1, paraformaldehyde, potassium carbonate and isopropanol, heating the reaction solution to 65-75 ℃ for reacting for 22-24 hours, filtering the reaction solution, and concentrating the filtrate to obtain a compound Aa-2;
the preparation method of the imidazole formaldehydes compound comprises the following specific operations in the step 3:
feeding and mixing a compound Aa-2, manganese dioxide and dichloromethane, heating reaction liquid to 40-50 ℃ for reacting for 16-18 hours, and sequentially filtering, concentrating, dissolving, recrystallizing and drying the reaction liquid to obtain a 5-tert-butyl-1H-imidazole-4-formaldehyde compound (formula Aa);
the yield of each step of the preparation method of the plinabulin intermediate 5-tert-butyl-1H-imidazole-4-formaldehyde compound (formula Aa) is more than 70%.
The preparation of the Plinabulin intermediate imidazole formaldehydes of the present invention is further illustrated below by taking 5-tert-butyl-1H-imidazole-4-carbaldehyde compound (formula Aa) as an example.
Example 1 preparation of Compound Aa-1
Adding 30g of 1-bromo-3, 3-dimethyl-2-butanone (compound Aa-0) and 60g of formamide into a reaction bottle, heating to 160 ℃ after the addition is finished, and stirring for reaction for 5-7 h; after the reaction mixture was cooled to room temperature, 180ml of water was added, followed by addition of an aqueous sodium hydroxide solution to adjust the pH to 10, followed by addition of dichloromethane for extraction and liquid separation, and the combined organic phases were dried, filtered, and concentrated to obtain compound Aa-1(15.0g, yield 72%).
Example 2 preparation of Compound Aa-2
Adding 13g of compound Aa-1, 6.3g of paraformaldehyde, 29g of potassium carbonate and 130mL of isopropanol into a reaction bottle in sequence, heating the reaction solution to 65-75 ℃ after the addition is finished, and stirring for reaction for 22-24 h; the reaction mixture was cooled to room temperature, and then filtered and concentrated to remove isopropanol, thereby obtaining compound Aa-2(11.8g, yield 73%).
Example 3 preparation of a Compound of formula Aa
Adding 10.0g of compound Aa-2, 22.6g of manganese dioxide and 100mL of dichloromethane into a reaction bottle, heating the reaction solution to 45-55 ℃ after the addition is finished, and stirring for reacting for 16-18 h; the reaction solution was cooled to room temperature and then filtered, the filtrate was concentrated to remove the solvent, then ethyl acetate and petroleum ether were added, heated to dissolve, cooled to filter, and the solid was dried to obtain the target compound 5-tert-butyl-1H-imidazole-4-carbaldehyde compound (formula Aa) (7.5g, yield 76%).
Test examples 4,
(1) In the case of other similar embodiments, the first and second electrodes are,
in the above example 1, formamide is replaced by formamidine acetate, potassium carbonate is added, the heating reaction temperature is adjusted to 140-; carrying out condition test optimization on example 1, and respectively preparing a compound Aa-1; the experimental preparation yield under each parallel optimization condition is 55-80%;
(2) in the case of other similar embodiments, the first and second electrodes are,
in example 2 above, paraformaldehyde was replaced with an aqueous formaldehyde solution, the heating reaction temperature was adjusted to 55 to 65 ℃ and 75 to 90 ℃, potassium carbonate was replaced with sodium carbonate and sodium hydroxide, respectively, the weight ratio of the compound Aa-1 to the methylolation reagent was adjusted to 1:1 and 5:1, respectively, the weight-to-volume (g: ml) ratio of the compound Aa-1 to the alcohol solvent was adjusted to 1:5 and 1:20, respectively, and the molar ratio of the compound Aa-1 to the base was adjusted to 1:1 and 1:4, respectively; the condition optimization experiment is carried out on the example 2, and the compound Aa-2 is prepared respectively; the experimental preparation yield under each parallel optimization condition is 20-80%;
(3) in the case of other similar implementations of the invention,
in example 3, the target compound of formula Aa was prepared by carrying out optimization of the conditions of example 3 by replacing methylene chloride with acetone, adjusting the heating temperature to 15 to 25 ℃, adjusting the molar ratios of the compound Aa-2 to the oxidizing agent to 1:2 and 1:5, respectively, and adjusting the weight-to-volume (g: ml) ratios of the compound Aa-2 to the organic solvent to 1:5 and 1:20, respectively; the experimental preparation yield under each parallel optimization condition is 46-85%; comparative examples 5,
The raw material compound Aa-0 of the ring closure reaction in the above example 1 is replaced by a compound obtained by chlorinating or brominating ethyl 4, 4-dimethyl-3-oxopentanoate, the ring closure reaction is carried out, and the post-treatment is carried out to obtain the Aa-1 compound with an ethyl acetate group, wherein the ring closure reaction yield is 26% by calculation; from the data, compared with the technical scheme disclosed by the prior art, the yield of 72% of the cyclization reaction in the technical scheme is greatly higher than that of the route disclosed by the prior art, so that the yield of the whole route is greatly improved, and the cost is reduced; is favorable for realizing industrialized production.
The preparation method has the advantages of simple and convenient operation of each step, easy purification, simple and convenient post-treatment, environmental protection, easy operation, safe and feasible solvent and conditions, contribution to environment-friendly green industrial scale-up production and wide application prospect.
The invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification and any novel method or process steps or any novel combination of features disclosed.
Claims (9)
1. A preparation method of imidazole formaldehydes compound is characterized in that the structure of the imidazole formaldehydes compound is shown as the following formula A,
the preparation method of the imidazole formaldehydes compound has the following route I:
route I:
wherein R is selected from C1-C10 alkyl and C1-C14 alkylaryl; x is selected from chlorine, bromine and iodine;
the specific operation steps are as follows:
step 1, mixing a compound A-0 with a ring closing reagent, heating to 140-; adding water into the reaction solution for quenching, adjusting the pH value to 10-12, adding an organic solvent for extraction, washing an organic phase, drying, filtering, concentrating and removing the organic solvent to obtain a compound A-1;
step 2, heating the compound A-1 and a hydroxymethylation reagent in the presence of alkali and an alcohol solvent to 55-90 ℃ for reaction for 20-30 hours, and performing post-treatment to obtain a compound A-2;
and 3, carrying out oxidation reaction on the compound A-2 and an oxidant in an organic solvent, and carrying out post-treatment to obtain the imidazole formaldehyde compound.
2. The method of claim 1,
r is C1-C10 alkyl;
and X is bromine or iodine.
3. The method according to claim 1, wherein, in the step 1,
the ring closing reagent is formamide or formamidine acetate;
the organic solvent is one of dichloromethane, chloroform and ethyl acetate;
the molar ratio of the compound A-0 to the ring closing reagent is 1: 1-1: 10.
4. The method according to claim 1, wherein, in the step 2,
the hydroxymethyl reagent is one of paraformaldehyde and a formaldehyde aqueous solution;
the alkali is one or more of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide;
the alcohol solvent is one or more of methanol, ethanol, isopropanol and n-butanol;
the weight ratio of the compound A-1 to the hydroxymethylation reagent is 1: 1-4: 1;
the weight-volume ratio of the compound A-1 to the alcohol solvent is 1: 2-1: 20;
the molar ratio of the compound A-1 to the base is 1: 1-1: 4.
5. The method according to claim 1, wherein, in the step 3,
the oxidant is manganese dioxide;
the organic solvent is one or more of dichloromethane, acetone and chloroform;
the molar ratio of the compound A-2 to the oxidant is 1: 2-1: 8;
the weight-volume ratio of the compound A-2 to the organic solvent is 1: 5-1: 20;
the reaction temperature of the oxidation reaction is 15-80 ℃, and the reaction time is 10-20 hours.
6. The method of claim 1,
the imidazole formaldehydes compound has a structure shown as the following formula Aa,
the preparation method of the imidazole formaldehydes compound has the following route Ia:
route Ia:
in the step 1, the step of processing the raw material,
the ring closing reagent is formamide;
the organic solvent is dichloromethane;
the heating temperature is 150-160 ℃;
in the step 2, in the step of processing,
the hydroxymethyl reagent is paraformaldehyde;
the alkali is potassium carbonate;
the alcohol solvent is isopropanol;
the heating temperature is 65-75 ℃;
in the step 3, the step of processing the image,
the oxidant is manganese dioxide;
the organic solvent is dichloromethane;
the reaction temperature of the oxidation reaction is 40-50 ℃.
7. The method of claim 6,
the step 1 is specifically operated as follows:
mixing the compound Aa-0 with formamide, heating to 150-; cooling the reaction liquid, adding water for quenching, adding sodium hydroxide aqueous solution to adjust the pH value to 10, adding dichloromethane for extraction, washing an organic phase, drying, filtering, and concentrating to remove an organic solvent to obtain a compound Aa-1.
8. The method of claim 6,
the step 2 specifically comprises the following operations:
and (3) mixing the compound Aa-1, paraformaldehyde, potassium carbonate and isopropanol, heating the reaction solution to 65-75 ℃ for reacting for 22-24 hours, filtering the reaction solution, and concentrating the filtrate to obtain the compound Aa-2.
9. The method of claim 6,
the step 3 is specifically operated as follows:
and (3) feeding and mixing the compound Aa-2, manganese dioxide and dichloromethane, heating the reaction solution to 40-50 ℃ for reacting for 16-18 hours, and sequentially filtering, concentrating, dissolving, recrystallizing and drying the reaction solution to obtain the 5-tert-butyl-1H-imidazole-4-formaldehyde compound.
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