CN115960008A - Synthesis method of imide derivative - Google Patents
Synthesis method of imide derivative Download PDFInfo
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- CN115960008A CN115960008A CN202111176363.7A CN202111176363A CN115960008A CN 115960008 A CN115960008 A CN 115960008A CN 202111176363 A CN202111176363 A CN 202111176363A CN 115960008 A CN115960008 A CN 115960008A
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- 150000003949 imides Chemical class 0.000 title claims abstract description 27
- 238000001308 synthesis method Methods 0.000 title description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- 238000000034 method Methods 0.000 claims abstract description 50
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 20
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 12
- 125000000524 functional group Chemical group 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 10
- 238000000605 extraction Methods 0.000 claims abstract description 10
- 238000005406 washing Methods 0.000 claims abstract description 10
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 7
- 230000018044 dehydration Effects 0.000 claims abstract description 5
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 4
- 238000004821 distillation Methods 0.000 claims abstract description 3
- 150000005826 halohydrocarbons Chemical class 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims abstract description 3
- 238000000926 separation method Methods 0.000 claims abstract description 3
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 19
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 16
- 239000012024 dehydrating agents Substances 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 9
- 150000004945 aromatic hydrocarbons Chemical group 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 238000004448 titration Methods 0.000 claims description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 2
- 239000001099 ammonium carbonate Substances 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 235000013877 carbamide Nutrition 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 claims 1
- 239000012450 pharmaceutical intermediate Substances 0.000 claims 1
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 22
- -1 amine compound Chemical class 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000012224 working solution Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- SJEBAWHUJDUKQK-UHFFFAOYSA-N 2-ethylanthraquinone Chemical compound C1=CC=C2C(=O)C3=CC(CC)=CC=C3C(=O)C2=C1 SJEBAWHUJDUKQK-UHFFFAOYSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000005086 pumping Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 2
- YZWKKMVJZFACSU-UHFFFAOYSA-N 1-bromopentane Chemical compound CCCCCBr YZWKKMVJZFACSU-UHFFFAOYSA-N 0.000 description 2
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000002862 amidating effect Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000007068 beta-elimination reaction Methods 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
- 239000013064 chemical raw material Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000005691 oxidative coupling reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000005622 photoelectricity Effects 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 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 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing imide derivatives, which comprises the following steps: (1) Dissolving carboxylic acid A and carboxylic acid B in an organic solvent, performing intermolecular dehydration reaction, separating a dehydration agent A after the reaction is finished, and then performing extraction separation to obtain inorganic extraction liquid and organic raffinate containing anhydride C; (2) Reacting the organic raffinate containing the anhydride C obtained in the step (1) with an ammonia source at low temperature, then reacting at high temperature, and separating an inorganic phase after the reaction is finished to obtain an organic solution containing imide D; (3) Adding a proper amount of halohydrocarbon into the organic solution containing the imide D to carry out nucleophilic substitution reaction, washing and extracting after the reaction is finished to obtain an organic extraction phase, removing the solvent by reduced pressure distillation, and drying to obtain the imide derivative product. The method has the advantages of mild reaction conditions, safety, environmental protection, high reaction yield, low cost, flexible regulation and control of functional groups of imide derivative molecules according to use characteristics, and wide application range.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a method for synthesizing an imide derivative.
Background
The imide derivative has the characteristics of rigid conjugated skeleton structure, controllable functional groups in molecules, electron deficiency and the like, and is widely applied to the fields of medicine synthesis, organic photoelectricity, molecular catalysis, chemical synthesis and the like.
The construction of C-N bond by direct oxidative coupling between C-H bond and N-H bond is a commonly used method in the prior art, and the NH nucleophile mainly used in the method is an amine compound or a specific amide (such as picolinamide or primary amide, etc.. WangLong et al (chem. Eur.j.2008, 14, 10722-10726) amidating an aldehyde compound under the condition of NBS/Cu catalytic system with an amide compound and the aldehyde compound as raw materials to prepare an imide derivative, wherein the reaction formula is as follows:
CN104788336B also takes amide compounds and aldehyde compounds as raw materials, and realizes the above reaction under the condition of iron salt/auxiliary agent compound catalytic system, so as to prepare the imide derivative.
Yongjun et al (Synthesis of amides by Palladium-Catalyzed C-H catalysis of Aldehydes with Secondary Amides. Chemistry, 2013, 19 (3): 1129-33) synthesize a Secondary imide compound under the catalysis of noble metal Palladium, using N-substituted N-aromatic-2-carboxamide and an aldehyde compound as raw materials, and have the following reaction formula:
at present, the synthesis of imide derivatives is mainly based on aldehyde-amidation synthesis, the synthetic process route
The following technical characteristics mainly exist: (1) The economic cost of reactants and catalyst raw materials is high, and the economic practicability of the technical route is influenced; (2) The conversion rate of the amidation reaction of the aldehyde substance is relatively low, which leads to the low product yield of the imide derivative, and if the yield is improved, the reaction needs to be carried out under the harsh reaction condition, which further influences the industrial scale production of the process(ii) a (3) Since the amide reactant raw material is relatively less in species, C 3 The above alpha-unsaturated aldehydes generally exist in a mixed manner, the purity of raw materials is relatively low, the functional groups of imide derivative molecules are difficult to flexibly regulate and control, and the application range is narrow.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthesis method of an imide derivative. The method has the advantages of mild reaction conditions, safety, environmental protection, high reaction yield, low cost, flexible regulation and control of functional groups of imide derivative molecules according to the use characteristics, and wide application range.
The synthesis method of the imide derivative comprises the following steps: (1) Dissolving carboxylic acid A and carboxylic acid B in an organic solvent, performing intermolecular dehydration reaction under the conditions of a catalyst A, a dehydrating agent A and high temperature, separating the dehydrating agent A after the reaction is finished, and then performing extraction separation to obtain inorganic extraction liquid and organic raffinate containing anhydride C; (2) Under the action of a catalyst B and a dehydrating agent B, reacting the organic raffinate containing the anhydride C obtained in the step (1) with an ammonia source at a low temperature for a period of time, then reacting at a high temperature for a period of time, and separating an inorganic phase after the reaction is finished to obtain an organic solution containing the imide D; (3) Adding a proper amount of halohydrocarbon into an organic solution containing the imide D, carrying out nucleophilic substitution reaction under the condition of weak base or strong base, washing and extracting after the reaction is finished to obtain an organic extraction phase, carrying out reduced pressure distillation to remove the solvent, and drying to obtain the imide derivative product.
In the method of the present invention, the step (1) is to form a polymeric acid anhydride C having a different structural functional group by intermolecular dehydration of a carboxylic acid A and a carboxylic acid B having a different or the same structural functional group.
In the method of the present invention, the intermolecular dehydration reaction formula described in step (1) is as follows:
in the method of the present invention, the carboxyl group in the step (1)Acid A (R) 1 COOH) and carboxylic acid B (R) 2 COOH) in which R 1 Is one of furan, aromatic hydrocarbon substituent, benzyl or alkane substituent; r 2 The functional group is one of furan, aromatic hydrocarbon substituent, benzyl or alkane substituent, wherein the furan, aromatic hydrocarbon substituent, benzyl or alkane substituent can further contain one or more functional groups of alkyl, alkoxy and ester groups.
In the method, the organic solvent in the step (1) is selected from one or more of dimethylbenzene, trimethylbenzene, chlorobenzene, N-Dimethylformamide (DMF), ethyl acetate or pyridine and the like; the ratio of the organic solvent to the carboxylic acid is 2 to 10 mL/g, preferably 3 to 6mL/g.
In the method, the catalyst A in the step (1) is aqueous solution of sodium methoxide and ferric salt, the molar concentrations of the sodium methoxide and the ferric salt are respectively 0.01 to 5mol/L and 0.1 to 10 mol/L, and the dehydrating agent A is P 2 O 5 ；
In the method of the present invention, the carboxylic acid A in the step (1): carboxylic acid B: catalyst A: the mole ratio of the dehydrating agent A is 1:1:0.15 to 0.5:0.5 to 5.
In the method of the invention, the dehydration reaction conditions in the step (1) are as follows: reacting for 18 to 25 hours under the conditions of normal pressure and 40 to 80 ℃. And (2) selecting silica gel of 300 to 400 meshes by a layer-by-layer analysis method (ethyl acetate: n-hexane = 2) in the reaction process, and tracking and monitoring the reaction process of the target product by TCL. And after the reaction is finished, washing the reaction mixture for 3 times by using deionized water, extracting by using dichloromethane to obtain an organic extraction phase, distilling under reduced pressure to remove the solvent, and drying in an oven to obtain a target product, namely a white solid.
In the method, the catalyst B and the dehydrating agent B in the step (2) are mixed solutions of triethylamine and potassium carbonate, the molar concentrations of the catalyst B and the dehydrating agent B are respectively 0.01-2mol/L and 0.5-10 mol/L, and the molar ratio of the triethylamine to the potassium carbonate is 1:0.6 to 2.5.
In the method, the ammonia source in the step (2) is ammonia gas, ammonia water, ammonium bicarbonate, urea or the like, preferably ammonia gas or ammonia water, and the feeding molar ratio of the ammonia source to the acid anhydride C is 1.2-10: 1.
in the method, the pressure in the step (2) is 0.1 to 0.5MPa.
In the method of the invention, the low-temperature reaction conditions in the step (2) are as follows: reacting for 2 to 5 hours at the temperature of 25 to 50 ℃; the high-temperature reaction conditions are as follows: the reaction is carried out at 110 to 120 ℃ for 1 to 1.5 hours.
In the method, the step (2) is preferably carried out in a high-temperature reaction process under the vacuum dehydration condition, wherein the vacuum degree is-0.01 to-0.1 MPa.
In the step (2), the reaction is firstly carried out prehydrolysis reaction at a low temperature of 25-50 ℃, and ammonolysis reaction is carried out at a high temperature of 210-230 ℃ after a reaction substrate is activated in a catalytic system.
In the method of the present invention, the ammonolysis reaction formula in step (2) is as follows:
in the method of the present invention, in the step (2), preferably, the organic raffinate containing the acid anhydride C is added to the mixed solution of the catalyst B and the dehydrating agent B (triethylamine and potassium carbonate) in a batch manner or a slow titration manner, and the addition time is preferably 25 to 35 minutes.
In step (3) of the method of the present invention, the hydrogen halide produced by the nucleophilic substitution reaction (β -elimination reaction) is dissolved in an alkaline aqueous solution, and the target main product is dissolved in an organic solvent.
In the method of the present invention, the reaction equation in step (3) is as follows (with brominated alkanes as an example):
in the method of the present invention, the reaction conditions in step (3) are: reacting at 25 to 50 ℃ for 8 to 15 hours.
In the method of the present invention, the drying conditions in step (3) are: drying for 12 to 24 hours under the conditions of normal pressure and temperature of 120 to 140 ℃.
In the method of the present invention, the washing in step (3) is generally performed 2 to 4 times with deionized water.
In the method, the halogenated alkane in the step (3) is brominated alkane, chlorinated alkane and the like, preferably brominated alkane, and the molar ratio of the halogenated alkane to the carboxylic acid A is 1.2 to 1.5:1.
the method can prepare imide derivative products with different functional groups according to actual needs, and can be widely applied to the fields of drug intermediate synthesis, chemical raw material synthesis, photoelectric molecular catalysis and the like.
Detailed Description
The invention is further described below with reference to specific preferred examples, without thereby limiting the scope of protection of the invention. The percentage contents in the embodiment of the invention are all mass percentage contents.
Example 1
Taking the synthetic process of N-isoamyl 1-isopropyl-2-tert-butyl imide as an example
88.1g of t-butyric acid, 74.5g of propionic acid and 71 g of P were put into a 500 mL reaction vessel at a time 2 O 5 30mL of a mixture of sodium methoxide and iron salt (5.4 g of sodium methoxide and 9.1g of ferrous nitrate). Raising the temperature of the system to 50 ℃, reacting for 20 hours at constant temperature, finishing the reaction, and filtering out P 2 O 5 Powder, transferring the reaction solution into a separating funnel, fully washing the reaction solution for three times by using deionized water, and separating out an inorganic aqueous solution; returning the organic raffinate to the reaction kettle, adding a mixed solution of 45-50 wt% of potassium carbonate and triethylamine once, filling a mixed gas of ammonia and nitrogen into the reaction system, increasing the pressure to 0.25-0.3 MPa, reacting at 30 ℃ for 2 hours, increasing the temperature of the system to 120 ℃ for reacting for 1.5 hours, and separating an inorganic phase in the mixed solution after the system is cooled to room temperature; adding 165g of 1-bromopentane into the residual organic phase reaction liquid, reacting for 12 hours at 35 ℃, selecting silica gel of 300-400 meshes by a layer-by-layer analysis method (ethyl acetate: n-hexane =2,and after the reaction is finished, washing the reaction product with deionized water for 3 times, washing the product with dichloromethane, distilling the solvent under reduced pressure, and drying the product in an oven for 4 hours to finally obtain a white crystal product. The obtained product was confirmed to have an N-isopentyl-1-isopropyl-2-tert-butylimide structure by 1H NMR and MS spectroscopic analysis, and the yield was 95.6% (based on the starting carboxylic acid, the same applies hereinafter).
1H NMR（500MHz，CDCl 3 ）δ=0.95~1.10（m，18H），2.07~2.17（m，1H），2.25~2.4（m，2H），2.5~2.55（m，2H），3.45~3.55（s，2H）；
MS[M+H] + ：241.3。
Example 2
Taking the synthetic process of N-tert-butyl di-tert-butyl imide as an example
176.2 g of t-butyric acid and 75 g of P were put into a 500 mL reaction vessel at a time 2 O 5 Heating the system temperature to 65 ℃ with 50mL of mixed solution of sodium methoxide and ferric salt (wherein the sodium methoxide is 6.8g, and the ferrous nitrate is 10 g), reacting for 20 hours at constant temperature, finishing the reaction, and filtering out P 2 O 5 Powder, transferring the reaction solution into a paging funnel, fully washing the reaction solution for three times by using deionized water, and separating out an inorganic aqueous solution; returning the organic raffinate to the reaction kettle, filling a mixed gas of ammonia and nitrogen into a reaction system, increasing the pressure to 0.25 to 0.3MPa, reacting for 2 hours at 35 ℃, pumping 50mL of a mixed solution of 45 to 50wt.% of potassium carbonate and triethylamine into the reaction system during the reaction, wherein the pumping time is 20 minutes, increasing the temperature of the system to 120 ℃, reacting for 1.5 hours, and separating an inorganic phase in the mixed solution after the system is cooled to room temperature; adding 165g of 1-bromobutane into the residual organic phase reaction liquid, reacting for 12 hours at 35 ℃, selecting silica gel of 300-400 meshes by a layer-by-layer analysis method (ethyl acetate: n-hexane =2: 1), tracking and monitoring the composition of raw materials and products in the reaction system by TCL, after the reaction is finished, washing the reaction product by deionized water for 3 times, and feeding the reaction liquid into the reaction liquid under the vacuum condition of-0.6 to-0.75 MPaVacuum dehydration is carried out, the product is washed by dichloromethane, the solvent is distilled under reduced pressure, and the product is dried in an oven for 4 hours to finally obtain white N-butyl di-tert-butyl imide crystals. 1H NMR and MS spectrum analysis of the obtained product prove that the product is N-butyl di-tert-butyl imide, and the total yield is 95.6%.
1H NMR（500MHz，CDCl 3 ）δ=0.9~1.0（m，18H），1.9~2.05（m，1H），2.05~2.15（m，2H），2.25~2.4（m，4H），3.4~3.45（s，2H）；
MS[M+H] + ：241.7。
Examples 3 to 5
The following examples were prepared as in example 2, except that the functional groups (R) for the different target products were different 1 、R 2 、R 3 ) The corresponding carboxylic acid and haloalkane starting materials are selected.
In the embodiment 3, tert-butyl acid, alkoxy propionic acid and bromobutane are selected as raw materials, in the embodiment 4, acetic acid, propionic ester and bromopentane are selected as raw materials, and in the embodiment 5, formic acid, benzoic acid and chloropropane are selected as raw materials.
Specific properties of the objective products of examples 1 to 5 are shown in Table 1, and evaluation results are shown in Table 2.
Example 6
225mL of C 9 Fully mixing aromatic hydrocarbon, 75mL of solvent to be detected (such as N-tertiary butyl di-tertiary butyl imide) and 45g of 2-ethyl anthraquinone to form working solution; 4.5g of hydrogenation catalyst is filled in a transparent visual fixed bed reactor, and the catalyst adopts a conventional palladium catalyst (Pd/Al) in the hydrogen peroxide industry 2 O 3 ) The particle diameter of the catalyst is 0.4 to 0.5mm, and the pore volume is 0.6 to 0.8cm 3 Per gram, the specific surface area is 150 to 180m 2 (ii) Pd content of 0.25 to 0.30wt.%.
Pumping the 2-ethyl anthraquinone working solution into a fixed bed reactor by adopting a metering pump, wherein the temperature is 55 ℃, the pressure is 0.25MPa, and the airspeed is 15h -1 Carrying out hydrogenation reaction on the working solution under the condition, detecting the flowing state of the working solution by laser tracking, and stopping the hydrogenation reaction when the working solution in a bed layer reaches a critical turbid state (namely the 2-ethyl anthraquinone reaction carrier reaches a precipitation critical state); in bedTaking out the 2-ethylanthraquinone working solution from the bottom of the layer, analyzing the composition of the working solution by high performance liquid chromatography, determining and analyzing the hydrogenation efficiency of the working solution by potassium permanganate titration, calculating the solubility of hydroanthraquinone in the solvent system (mixture of aromatic hydrocarbon and imide target product) by the hydrogenation efficiency under the condition that no obvious degradation product is detected in the result of high performance liquid chromatography, wherein the solubilities of the working solutions of different target products to the hydroanthraquinone are shown in Table 2
Comparative example 1
CN104788336B embodiment:
1mol of compound of formula (I) and 0.06 mol of FeCl are added into a mechanical stirring reaction kettle 2 Stirring and introducing nitrogen to maintain a nitrogen atmosphere, then adding 6L of solvent toluene into the system, and adding 3mol of the compound of the formula (II), 2.2mol of TBHP and a mass ratio of 1:0.4:0.2 of 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl, 1, 10-phenanthroline and I 2 O 5 Introducing nitrogen into the assistant mixture (the total mass is 10 g), sealing, heating to 50 ℃ for reaction for 14h, adding water for quenching after the reaction is finished, extracting by using diethyl ether, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating in vacuum, and purifying residues by using a silica gel column chromatography to obtain the compound shown in the formula (III), wherein the yield is 93.8%, and the purity is 98.9% (HPLC).
1HNMR( 400MHz ,CDCl 3 )δ=7 .62-7 .49(m ,5H ),3 .21(s ,3H ),2 .33(s ,3H )；
MS[M+H] + :177 .07。
TABLE 1 Properties of the target products of the examples
| Examples | R 1 | R 2 | R 3 | Appearance of the product | Yield of | Purity of |
| Example 1 | C 3 H 7 | C 4 H 9 | C 5 H 11 | White crystal | 95.6 | 98.2% |
| Example 2 | C 4 H 9 | C 4 H 9 | C 4 H 9 | White crystal | 96.7 | 99.3% |
| Example 3 | CH 3 | C 3 H 7 O- | C 4 H 9 | White crystal | 96.1 | 98.1% |
| Example 4 | C 2 H 5 | C 3 H 7 COO- | C 5 H 11 | White crystal | 95.9 | 99.5% |
| Example 5 | CH 3 | CH 3 C 6 H 5 - | C 3 H 7 | White crystal | 97.2 | 98.8% |
| Comparative example 1 | CH 3 | CH 3 | C 6 H 5 | White crystal | 93.8 | 98.9% |
Table 2 evaluation results of the products of examples
| Examples | R 1 | R 2 | R 3 | Solubility of 2-Ethylhydroanthraquinone | Water content |
| Example 1 | C 3 H 7 | C 4 H 9 | C 5 H 11 | 108.3 | 0.15wt% |
| Example 2 | C 4 H 9 | C 4 H 9 | C 4 H 9 | 116.5 | 0.13wt% |
| Example 3 | CH 3 | C 3 H 7 O- | C 4 H 9 | 83.8 | 0.15wt% |
| Example 4 | C 2 H 5 | C 3 H 7 COO- | C 5 H 11 | 97.9 | 0.19wt% |
| Example 5 | CH 3 | CH 3 C 6 H 5 - | C 3 H 7 | 86.7 | 0.17wt% |
| Comparative example 1 | CH 3 | CH 3 | C 6 H 5 | 75.4 | 0.24wt% |
Claims (19)
1. A method for synthesizing imide derivatives is characterized by comprising the following steps: (1) Dissolving carboxylic acid A and carboxylic acid B in an organic solvent, performing intermolecular dehydration reaction under the conditions of a catalyst A, a dehydrating agent A and high temperature, separating the dehydrating agent A after the reaction is finished, and then performing extraction separation to obtain inorganic extraction liquid and organic raffinate containing anhydride C; (2) Under the action of a catalyst B and a dehydrating agent B, reacting the organic raffinate containing the anhydride C obtained in the step (1) with an ammonia source at a low temperature for a period of time, then reacting at a high temperature for a period of time, and separating an inorganic phase after the reaction is finished to obtain an organic solution containing the imide D; (3) Adding a proper amount of halohydrocarbon into an organic solution containing the imide D, carrying out nucleophilic substitution reaction under the condition of weak base or strong base, washing and extracting after the reaction is finished to obtain an organic extraction phase, carrying out reduced pressure distillation to remove the solvent, and drying to obtain the imide derivative product.
2. The method of claim 1, wherein: the intermolecular dehydration reaction formula of step (1) is as follows:
3. the method of claim 1, wherein: the carboxylic acid A in the step (1) has a molecular formula R 1 COOH) and carboxylic acids B of the formula R 2 COOH, wherein R 1 Is one of furan, aromatic hydrocarbon substituent, benzyl or alkane substituent; r is 2 Is one of furan, aromatic hydrocarbon substituent, benzyl or alkane substituent.
4. The method of claim 3, wherein: wherein the furan, arene substituent, benzyl or alkane substituent also contains one or more functional groups of alkyl, alkoxy and ester group.
5. The method of claim 1, wherein: the organic solvent in the step (1) is selected from one or more of dimethylbenzene, trimethylbenzene, chlorobenzene, N-dimethylformamide, ethyl acetate or pyridine.
6. The method of claim 1, wherein: the dosage ratio of the organic solvent to the carboxylic acid in the step (1) is 2-10 mL/g, preferably 3-6 mL/g.
7. The method of claim 1, wherein: the catalyst A in the step (1) isSodium methoxide and ferric salt aqueous solution, wherein the molar concentrations of the sodium methoxide and the ferric salt aqueous solution are respectively 0.01 to 5mol/L and 0.1 to 10 mol/L, and the dehydrating agent A is P 2 O 5 。
8. The method of claim 1, wherein: the carboxylic acid A in the step (1): carboxylic acid B: catalyst A: the mole ratio of the dehydrating agent A is 1:1:0.15 to 0.5:0.5 to 5.
9. The method of claim 1, wherein: the dehydration reaction conditions in the step (1) are as follows: reacting for 18 to 25 hours under the conditions of normal pressure and 40 to 80 ℃.
10. The method of claim 1, wherein: the catalyst B and the dehydrating agent B in the step (2) are mixed solutions of triethylamine and potassium carbonate, the molar concentrations of the catalyst B and the dehydrating agent B are respectively 0.01 to 2mol/L and 0.5 to 10 mol/L, and the molar ratio of the triethylamine to the potassium carbonate is 1:0.6 to 2.5.
11. The method of claim 1, wherein: the ammonia source in the step (2) is ammonia gas, ammonia water, ammonium bicarbonate or urea; the feeding molar ratio of the ammonia source to the acid anhydride C is 1.2 to 10:1.
12. the method of claim 1, wherein: the pressure in the step (2) is 0.1 to 0.5MPa.
13. The method of claim 1, wherein: the low-temperature reaction conditions in the step (2) are as follows: reacting for 2 to 5 hours at the temperature of 25 to 50 ℃; the high-temperature reaction conditions are as follows: reaction at 110 to 120 ℃ for 1 to 1.5 hours.
14. The method of claim 1, wherein: and (2) setting vacuum dehydration conditions in the high-temperature reaction process, wherein the vacuum degree is-0.01 to-0.1 MPa.
15. The method of claim 1, wherein: and (2) adding the organic raffinate containing the anhydride C into the mixed solution of the catalyst B and the dehydrating agent B in a batch feeding or slow titration mode, wherein the adding time is preferably 25 to 35 minutes.
16. The method of claim 1, wherein: the reaction conditions in the step (3) are as follows: reacting at 25 to 50 ℃ for 8 to 15 hours.
17. The method of claim 1, wherein: the drying conditions in the step (3) are as follows: drying for 12 to 24 hours under the conditions of normal pressure and temperature of 120 to 140 ℃.
18. The method of claim 1, wherein: the halogenated alkane in the step (3) is brominated alkane or chlorinated alkane, and the molar ratio of the halogenated alkane to the carboxylic acid A is 1.2 to 1.5:1.
19. an imide derivative product prepared by any one of the methods of claims 1-9, for use in synthesis of pharmaceutical intermediates, synthesis of chemical raw materials, and photoelectromolecular catalysis.
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