CN116514723A - Synthesis method of 5, 6-2-chloro-1-ethyl-1H-benzimidazole-2-one (DCEBIO) - Google Patents
Synthesis method of 5, 6-2-chloro-1-ethyl-1H-benzimidazole-2-one (DCEBIO) Download PDFInfo
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- CN116514723A CN116514723A CN202310285507.5A CN202310285507A CN116514723A CN 116514723 A CN116514723 A CN 116514723A CN 202310285507 A CN202310285507 A CN 202310285507A CN 116514723 A CN116514723 A CN 116514723A
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 6
- LKHRMULASXZCLG-UHFFFAOYSA-N DCEBIO Chemical compound ClC1=C(Cl)C=C2NC(=O)N(CC)C2=C1 LKHRMULASXZCLG-UHFFFAOYSA-N 0.000 title claims 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 20
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000000047 product Substances 0.000 claims abstract description 16
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- 239000012043 crude product Substances 0.000 claims abstract description 12
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 10
- FXOCDIKCKFOUDE-UHFFFAOYSA-N 1,2-dichloro-4-fluoro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Cl)=C(Cl)C=C1F FXOCDIKCKFOUDE-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 12
- 239000003638 chemical reducing agent Substances 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 239000007790 solid phase Substances 0.000 claims description 6
- 239000011701 zinc Substances 0.000 claims description 6
- 229910052725 zinc Inorganic materials 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 abstract description 8
- 239000012362 glacial acetic acid Substances 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 4
- 238000001953 recrystallisation Methods 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
- 230000008569 process Effects 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 108091006146 Channels Proteins 0.000 description 2
- 108091008611 Protein Kinase B Proteins 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- -1 chloro-1-ethyl-1H-benzimidazol-2-one Chemical compound 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- YGSFNCRAZOCNDJ-UHFFFAOYSA-N propan-2-one Chemical compound CC(C)=O.CC(C)=O YGSFNCRAZOCNDJ-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- CXUCKELNYMZTRT-UHFFFAOYSA-N 1-Ethyl-2-benzimidazolinone Chemical class C1=CC=C2NC(=O)N(CC)C2=C1 CXUCKELNYMZTRT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 102000005765 Proto-Oncogene Proteins c-akt Human genes 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000005303 weighing Methods 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
- C07D235/26—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
- C07C209/10—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to carbon atoms of six-membered aromatic rings or from amines having nitrogen atoms bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
- C07C209/325—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups reduction by other means than indicated in C07C209/34 or C07C209/36
-
- 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
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
- Y02E60/30—Hydrogen technology
- Y02E60/50—Fuel cells
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of 5, 6-2-chloro-1-ethyl-1H-benzimidazole-2 ketone (DCEBIO). 1, 2-dichloro-4-fluoro-5-nitrobenzene which is cheap and easy to obtain in industry is used as a raw material, ethylamine, CDI, zinc powder, methanol, ethanol, acetonitrile, glacial acetic acid and other conventional reagents are used as auxiliary materials, and a crude product is synthesized through 3-step reaction; and purifying the product by recrystallization. The total yield of the final reaction was 69% and the synthetic product HPLC purity was 99.8%.
Description
Technical Field
The invention relates to a practical synthesis method of 5, 6-2-chloro-1-ethyl-1H-benzimidazole-2-ketone (DCEBIO), belonging to the technical field of synthesis of development and application of organic medical intermediates.
Background
DCEBIO (Compound name: 5,6-2 chloro-1-ethyl-1H-benzimidazol-2-one) is a derivative of 1-EBIO, which is a Cl secreted by T84 colon cells - The strong activator of the formula (I) not only can be used for researching the effect of potassium ion channels in various physiological functions, but also has wide application prospect in the field of biological medicines. For example, DCEBIO is activated by hIK1K + Channel and activation of the apex Cl - Conduction to stimulate Cl - Is applicable to Cl - Secretion related scientific or medical fields. DCEBIO can activate IKCa channel, mitROS, protein kinase B (Akt), mTOR and other pathways to increase muscle mass, and has a potential in treating muscle wasting diseases.
There is no report on the industrialized synthesis route of the compound in the literature at home and abroad.
Disclosure of Invention
The technical problems to be solved in the industrial synthesis of pharmaceutical intermediates include: (1) The initial raw materials of the reaction are relatively easy to obtain, and the cost is controllable; (2) The reaction condition is mild, green and environment-friendly is realized as much as possible, and byproducts are easy to treat; (3) the purification of the reaction product is simple; (4) the synthetic process route is suitable for process amplification.
In order to solve the problems in the prior art, the invention provides a synthesis method of 5, 6-2-chloro-1-ethyl-1H-benzimidazole-2 ketone (DCEBIO), which comprises the following steps:
s1: the initial raw material is 1, 2-dichloro-4-fluoro-5-nitrobenzene, and ethylamine aqueous solution and ethanol are added and fully stirred at room temperature;
s2: filtering the yellow solid separated out by the reaction in the step S1; discarding the liquid phase filtrate, and drying the solid phase filter cake to obtain a pure intermediate 1;
s3: dissolving the intermediate 1 in a solvent 1, adding a reducing agent into the solvent, cooling the reaction solution to 0-10 ℃ by using an ice bath, then dropwise adding acetic acid or ammonium chloride into the reaction solution, removing the ice bath after the addition is completed, and stirring the reaction solution at room temperature for more than 2 hours; filtering to remove insoluble white solid phase, concentrating filtrate, extracting with dichloromethane, washing organic phase with saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, and concentrating to obtain intermediate 2;
or: dissolving the intermediate 1 in a solvent 1, replacing a system by nitrogen, adding a reducing agent into the solvent, and replacing the system by nitrogen; then the gas in the system is replaced by hydrogen; the reaction was stirred under a hydrogen system for 2 hours, the reducing agent for the reaction was removed by filtration, the filtrate was concentrated, and the crude product was purified by column chromatography to give pure intermediate 2.
S4: dissolving the intermediate 2 in a solvent 2, adding a ring-closing reagent into the solvent, and stirring the reaction at 80 ℃ for more than 3 hours;
s5: evaporating the solvent 2, extracting with ethyl acetate, washing an organic phase with saturated sodium bicarbonate and 1.0N dilute hydrochloric acid respectively, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product; recrystallizing the crude product to obtain a pure product.
Preferably, in the step S1, the concentration of the ethylamine aqueous solution is 70% w/w, and the dosage ratio of the 1, 2-dichloro-4-fluoro-5-nitrobenzene to the 70% ethylamine aqueous solution is 0.5-0.8 g/mL.
Preferably, in step S1, the sufficient stirring is performed by using a stirrer with a rotation speed of not less than 1000 rotations per minute for 1 hour or more.
Preferably, in step S2, the drying refers to vacuum drying, and the drying temperature is not higher than 60 ℃ and the drying pressure is not higher than-0.1 megapascals (MPa).
Preferably, in step S2, the structural formula of the intermediate 1 is:
preferably, in the step S3, the reducing agent is zinc powder-acetic acid system, zinc powder-ammonium chloride system, iron powder-acetic acid system, and palladium carbon (5%) -H 2 Any of the systems.
Preferably, in step S3, the solvent 1 is any one of methanol and ethyl acetate.
More preferably, in step S3, the reducing agent is a zinc powder-acetic acid system, and the solvent 1 is methanol.
Preferably, in the step S3, the dosage ratio of the intermediate 1 to the solvent is 0.05-0.2 g/mL.
Preferably, in step S3, the structural formula of the intermediate 2 is:
preferably, in step S4, the ring-closing reagent is any one of a combination of N, N' -Carbonyldiimidazole (CDI), triethylamine and triphosgene.
Preferably, in step S4, the solvent 2 is any one of acetonitrile and acetone.
More preferably, in step S4, the ring-closing reagent is N, N' -Carbonyldiimidazole (CDI), and the solvent 2 is acetonitrile.
Preferably, in the step S4, the molar ratio of the intermediate 2 to the ring-closing reagent is 1:1.1-1:1.5.
Preferably, in step S5, the pure product has the structural formula:
meanwhile, the HPLC purity of the pure product reaches 99.8 percent.
In summary, a preferred reaction equation of the present invention is as follows:
the invention has the following beneficial effects:
1. the adopted raw materials and auxiliary materials are all commonly and easily available compounds in industry, are easy to obtain and have low cost;
2. the reaction conditions of each link of the process are mild, the post-treatment is simple, the conversion rate is high, the environment is protected, the safety is realized, and the process production and the amplification are convenient.
3. The purification process is simple. Purification can be completed through a recrystallization process, and the final product with higher HPLC purity is obtained.
In summary, the invention solves the problems in the prior art, adopts cheap and easily available 1, 2-dichloro-4-fluoro-5-nitrobenzene as raw materials, ethylamine, CDI, zinc powder, methanol, ethanol, acetonitrile, glacial acetic acid and other conventional reagents as auxiliary materials, and synthesizes crude products through 3-step reaction. And purifying the product by recrystallization. The total yield of the reaction was 69% and the HPLC purity was 99.8%. A good technical effect is achieved.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of intermediate 1
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of intermediate 2
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO)
FIG. 4 is a LC-MS diagram of 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO)
Detailed Description
The present invention is described in more detail and more fully below by way of examples. The examples described below are not all embodiments of the present patent, but are provided only in part to illustrate the inventive concepts of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present invention without the exercise of inventive faculty, are intended to fall within the scope of protection of the present patent.
Example 1
A method for synthesizing 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO), which comprises the following steps:
s1: the clean reaction vessel was taken, 240 milliliters (mL) of absolute ethanol was added, 24 grams (i.e., 114 millimoles) of 1, 2-dichloro-4-fluoro-5-nitrobenzene were accurately weighed and fully dissolved in absolute ethanol, followed by 36mL of 70% w/w aqueous ethylamine solution, and added to the reaction vessel. Stirring was carried out at room temperature for 1 hour using a stirrer rotating at not less than 1000 revolutions per minute, during which time a yellow solid precipitated. ( And (3) injection: the room temperature in the embodiment of the invention is the temperature range of 20-30 ℃. The following is the same as )
S2: stopping stirring, filtering, and discarding the filtrate to obtain a yellow filter cake, and leaching the yellow filter cake with ethanol. Placing the leached filter cake in a vacuum drying oven, drying at a temperature not higher than 60 ℃ and a drying pressure not higher than-0.1 megapascal (MPa), and vacuum drying for 5 hours under reduced pressure to obtain the pure intermediate 1. 25.0 g was weighed, the purity was 98% and the yield was calculated to be 93%.
HPLC (UV 214): 98% purity;1H NMR (DMSO-d 6): delta 8.22 (s, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 3.44-3.36 (m, 2H), 1.20 (t, 3H). See fig. 1.
S3: a clean reaction vessel was additionally charged with 140 ml of methanol, 14 g (59.8 mmol) of intermediate 1 were dissolved in methanol, followed by accurate weighing of 18.2 g (280 mmol) of zinc powder and charging into the reaction vessel. The temperature of the reaction vessel was cooled to 0 to 10℃with an ice bath, and 14 ml (245 mmol) of glacial acetic acid was added dropwise thereto. And removing the ice bath after the dripping is completed. The reaction was completed by stirring at room temperature for 2 hours. Filtering to remove white solid phase, collecting filtrate, concentrating the filtrate with rotary evaporator at a temperature of not higher than 50deg.C and a pressure of about-0.1 megapascal (MPa). The residue was extracted with 200 ml of dichloromethane and 200 ml of saturated sodium bicarbonate solution, and the dichloromethane phase was further washed with 100ml of 1.0N diluted hydrochloric acid. The methylene chloride phase was taken, poured into about 10g of anhydrous sodium sulfate and stirred with a glass rod until the solution became clear and transparent, the solid was filtered off, and then concentrated using a rotary evaporator at a temperature of not more than 50℃and a pressure of about-0.1 megapascals (MPa) to give intermediate 2. The weight was 11.9 g, the purity was 93%, and the yield was 98.4% calculated.
LC-MS(UV214):205，207(M+H) + ,93％purity； 1 H NMR (400 MHz, dmso) delta 6.64 (s, 1H), 6.40 (s, 1H), 5.01 (s, 2H), 4.84 (t, 1H), 3.05-2.95 (m, 2H), 1.18 (t, 3H) (see FIG. 2).
S4: another clean reaction vessel was taken, 120 ml of acetonitrile was added, 11.5 g (56 mmol) of intermediate 2 was precisely weighed and dissolved in acetonitrile, and 11 g (67.9 mmol) of N, N' -Carbonyldiimidazole (CDI) was added at a time; heating to 80+/-10 ℃ and stirring for 3 hours.
S5: removing acetonitrile by rotary evaporation, extracting with 250 ml ethyl acetate at a temperature of not higher than 50deg.C and a pressure of about-0.1 megapascal (MPa); the extracted organic phase is washed successively with 100ml of saturated sodium bicarbonate solution and then with 100ml of 1.0N diluted hydrochloric acid. The organic phase is washed with dilute hydrochloric acid to remove alkaline substances remaining in the organic phase, the concentration of the alkaline substances is not more than 2.0N, and the product is damaged by hydrochloric acid with too high concentration to reduce the yield. The organic phase is taken, about 12 g of anhydrous sodium sulfate is poured into the solution, the solution is stirred by a glass rod until the solution is clear and transparent, the solid phase is discarded after filtration, the filtrate is concentrated by a rotary evaporator at the temperature of not higher than 50 ℃ and the pressure of about-0.1 megapascal (MPa), and a solid crude product is obtained. To the crude product was added 50 ml of acetonitrile followed by 0.5 g of activated carbon, heated to 60 ℃ and refluxed for 1 hour, and filtered while hot. Standing the filtrate for 12 hours, and naturally cooling to fully separate out crystals. And (5) filtering, discarding the filtrate, and decompressing and vacuum drying the filter cake to obtain a final product. The final product weighed 9.6 g, measured 99.96% purity, calculated as 74% yield (calculated as 69% total reaction yield of S1-S5).
LC-MS(UV214):231.1(M+H) + ,99.96％purity；HPLC(UV 214):99.88％purity； 1 HNMR (DMSO-d 6) δ11.22 (s, 1H), 7.47 (s, 1H), 7.15 (s, 1H), 3.77-3.82 (m, 2H), 1.14 (t, 3H). See fig. 3.
Examples 2 to 5
The procedure of examples 2 to 5 was the same as in example 1, except that a reducing agent, a solvent, etc. were used, and specific information and data are shown in Table 1.
In particular, step S3 of example 2 is: 1.0 g of intermediate 1 (4.27 mmol) was accurately weighed into 10 ml of methanol, the system was replaced with nitrogen, 100 mg of palladium on carbon (5%) was added, and the system was replaced with nitrogen. The gas in the system is then replaced with hydrogen gas by a hydrogen gas source. The reaction was stirred under a hydrogen system for 2 hours. TLC monitored complete conversion of starting material. The reaction solution is directly taken and monitored by LC-MS, most of the products are byproducts of which the-Cl atoms are removed, and the column chromatography method can not completely separate the products and impurities, so that the reaction fails.
In particular, step S3 of example 3 is: 1.0 g of intermediate 1 (4.27 mmol) was accurately weighed into 10 ml of ethyl acetate, the system was replaced with nitrogen, 100 mg of palladium on carbon (5%) was added, and the system was replaced with nitrogen. The gas in the system is then replaced with hydrogen gas by a hydrogen gas source. The reaction was stirred under a hydrogen system for 2 hours. TLC monitored complete conversion of starting material. The palladium carbon used for the reaction is removed by filtration, the filtrate is concentrated at a temperature of not higher than 50 ℃ and a pressure of about-0.1 megapascal (MPa). The crude product was purified by column chromatography to give 820 mg (95% yield) of pure product.
TABLE 1 Experimental conditions and yield data Table for the Synthesis of intermediate 2
Note that: the reaction time is S3
Examples 6 to 8
The procedure of examples 6 to 8 was the same as that of example 1, except that the ring-closing reagent, the reaction temperature and the like were selected, and specific information and data are shown in Table 2.
In particular, step S4 of example 6 is: 1.0 g of intermediate 2 (4.9 mmol) was weighed out exactly, dissolved in 10 ml of acetone, stirred in an ice bath and 0.99 g of triethylamine (9.8 mmol) was added, and the reaction system was replaced with nitrogen. Subsequently, 5 ml (total triphosgene content 2.45 mmol, 0.73 g) of triphosgene acetone solution having a concentration of 0.49 mol/l was slowly added dropwise to the reaction, and the dropping time was controlled to about 15 minutes. After the completion of the dropwise addition, the reaction was further carried out under an ice bath for 6 hours. TLC monitored complete conversion of starting material. Saturated sodium bicarbonate ml was added to the reaction, and the reaction was quenched. The solvent is removed by a rotary evaporator at a temperature of not higher than 50deg.C and a pressure of about-0.1 megapascals (MPa). The residue was extracted with 100ml of dichloromethane and 100ml of deionized water. The dichloromethane phase was taken, poured into about 5 g of anhydrous sodium sulfate and stirred with a glass rod until the solution was clear and transparent, the solid was filtered off, followed by purification by column chromatography to give 0.64 g (57% yield) of the product.
In particular, step S4 of example 7 is: 1.0 g of intermediate 2 (4.9 mmol) was weighed out exactly, dissolved in 10 ml of acetone, stirred in an ice bath and 0.99 g of triethylamine (9.8 mmol) was added, and the reaction system was replaced with nitrogen. Subsequently, 5 ml (total triphosgene content 2.45 mmol, 0.73 g) of triphosgene acetone solution having a concentration of 0.49 mol/l was slowly added dropwise to the reaction, and the dropping time was controlled to about 15 minutes. The temperature is raised to 50 ℃ after the dripping, and the reaction time is 3 hours. TLC monitored complete conversion of starting material. To the reaction was added 5 ml of saturated sodium bicarbonate and the reaction was quenched. The solvent is removed by a rotary evaporator at a temperature of not higher than 50deg.C and a pressure of about-0.1 megapascals (MPa). The residue was extracted with 100ml of dichloromethane and 100ml of deionized water. The dichloromethane phase was taken, poured into about 5 g of anhydrous sodium sulfate and stirred with a glass rod until the solution was clear and transparent, the solid was filtered off, and then purified by column chromatography to give 0.56 g (51% yield) of the product.
TABLE 2 data sheet for different ring-closing reagents and reaction temperatures and final product yields
| Examples | Ring-closing reagent | Solvent(s) | Duration of the reaction | Reaction temperature | Reaction yield |
| 1 | CDI | Acetonitrile | 3 hours | 80℃ | 74％ |
| 6 | Triethylamine, triphosgene | Acetone (acetone) | For 6 hours | 0℃ | 57％ |
| 7 | Triethylamine, triphosgene | Acetone (acetone) | 3 hours | 50℃ | 51％ |
| 8 | CDI | Acetonitrile | 16 hours | 30℃ | N/A |
In summary, by adopting the technical scheme provided by the invention, 1, 2-dichloro-4-fluoro-5-nitrobenzene which is cheap and easy to obtain in industry can be used as a raw material, ethylamine, CDI, zinc powder, methanol, ethanol, acetonitrile, glacial acetic acid and other conventional reagents are used as auxiliary materials, a crude product is synthesized through 3 steps of reaction, and then the product is purified in a recrystallization way, so that higher total yield and HPLC purity are finally realized, and the method has good beneficial effects.
Finally, it should be noted that: the foregoing description is only of a preferred embodiment of the invention and is not intended to be limiting; although the present patent has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the present invention and equivalents may be substituted for elements thereof, and any modifications, equivalents, improvements and changes may be made without departing from the spirit and principles of the present invention.
Claims (13)
1. The synthesis method of the 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO) is characterized by comprising the following steps:
s1: the initial raw material is 1, 2-dichloro-4-fluoro-5-nitrobenzene, and ethylamine aqueous solution and ethanol are added and fully stirred at room temperature;
s2: filtering the yellow solid separated out by the reaction in the step S1; discarding the liquid phase filtrate, and drying the solid phase filter cake to obtain a pure intermediate 1;
s3: dissolving the intermediate 1 in a solvent 1, adding a reducing agent into the solvent, cooling the reaction solution to 0-10 ℃ by using an ice bath, then dropwise adding acetic acid or ammonium chloride into the reaction solution, removing the ice bath after the addition is completed, and stirring the reaction solution at room temperature for more than 2 hours; filtering to remove insoluble white solid phase, concentrating filtrate, extracting with dichloromethane, washing organic phase with saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, and concentrating to obtain intermediate 2;
or: dissolving the intermediate 1 in a solvent 1, replacing a system by nitrogen, adding a reducing agent into the solvent, and replacing the system by nitrogen; then the gas in the system is replaced by hydrogen; stirring the reaction for 2 hours under a hydrogen system, filtering to remove the reducing agent for the reaction, concentrating the filtrate, and purifying the crude product by column chromatography to obtain a pure intermediate 2;
s4: dissolving the intermediate 2 in a solvent 2, adding a ring-closing reagent into the solvent, and stirring the reaction at 80 ℃ for more than 3 hours;
s5: evaporating the solvent 2, extracting with ethyl acetate, washing an organic phase with saturated sodium bicarbonate and 1.0N dilute hydrochloric acid respectively, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product; recrystallizing the crude product to obtain a pure product.
2. The method for synthesizing 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO) according to claim 1, wherein in the step S1, the concentration of the aqueous ethylamine solution is 70% w/w, and the dosage ratio of the 1, 2-dichloro-4-fluoro-5-nitrobenzene to the 70% aqueous ethylamine solution is 0.5-0.8 g/mL.
3. The method for synthesizing 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO) according to claim 1, wherein in step S1, the sufficient stirring means stirring for more than 1 hour by using a stirrer with a rotation speed of not less than 1000 revolutions per minute.
4. The method for synthesizing 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO) according to claim 1, wherein in step S2, the drying is vacuum drying, and the drying temperature is not higher than 60 ℃ and the drying pressure is not higher than-0.1 megapascal (MPa).
5. The method for synthesizing 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO) according to claim 1, wherein in step S2, the structural formula of the intermediate 1 is:
6. the method for synthesizing 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO) according to claim 1, wherein in step S3, the reducing agent is zinc powder-acetic acid system, zinc powder-ammonium chloride system, iron powder-acetic acid system, and palladium carbon (5%) -H 2 Any one of the systems; the solvent 1 is any one of methanol and ethyl acetate.
7. The method for synthesizing 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO) according to claim 1, wherein in step S3, the reducing agent is zinc powder-acetic acid system, and the solvent 1 is methanol.
8. The method for synthesizing 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO) according to claim 1, wherein in step S3, the ratio of the intermediate 1 to the solvent is 0.05-0.2 g/mL.
9. The method for synthesizing 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO) according to claim 1, wherein in step S3, the structural formula of the intermediate 2 is:
10. the method for synthesizing 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO) according to claim 1, wherein in step S4, the ring-closing reagent is any one of a combination of N, N' -Carbonyldiimidazole (CDI), triethylamine and triphosgene; the solvent 2 is any one of acetonitrile and acetone.
11. The method of claim 1, wherein in step S4, the ring-closing reagent is N, N' -Carbonyldiimidazole (CDI), and the solvent 2 is acetonitrile.
12. The method for synthesizing 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO) according to claim 1, wherein in the step S4, the molar ratio of the intermediate 2 to the ring-closing reagent is 1:1.1-1:1.5.
13. The method for synthesizing 5, 6-2-chloro-1-ethyl-1H-benzimidazol-2-one (DCEBIO) according to claim 1, wherein in step S5, the pure product has the structural formula:
meanwhile, the HPLC purity of the pure product reaches 99.8 percent.
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