CN117105779A - Preparation method of 5-bromo-2-formylbenzoic acid methyl ester - Google Patents
Preparation method of 5-bromo-2-formylbenzoic acid methyl ester Download PDFInfo
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- CN117105779A CN117105779A CN202310901084.5A CN202310901084A CN117105779A CN 117105779 A CN117105779 A CN 117105779A CN 202310901084 A CN202310901084 A CN 202310901084A CN 117105779 A CN117105779 A CN 117105779A
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- ZYGJVCDDZZSSEE-UHFFFAOYSA-N methyl 5-bromo-2-formylbenzoate Chemical compound COC(=O)C1=CC(Br)=CC=C1C=O ZYGJVCDDZZSSEE-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 239000003960 organic solvent Substances 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 19
- 229940125782 compound 2 Drugs 0.000 claims abstract description 15
- 238000005893 bromination reaction Methods 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 229940125904 compound 1 Drugs 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 229940126214 compound 3 Drugs 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 17
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 15
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 14
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- FDCYLMYCHALQJR-UHFFFAOYSA-N methyl 5-bromo-2-methylbenzoate Chemical compound COC(=O)C1=CC(Br)=CC=C1C FDCYLMYCHALQJR-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 3
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000001263 FEMA 3042 Substances 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 238000005086 pumping Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 229940033123 tannic acid Drugs 0.000 claims description 2
- 235000015523 tannic acid Nutrition 0.000 claims description 2
- 229920002258 tannic acid Polymers 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims 1
- 229940095102 methyl benzoate Drugs 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 8
- 230000001590 oxidative effect Effects 0.000 abstract description 4
- 238000007039 two-step reaction Methods 0.000 abstract description 4
- 238000005904 alkaline hydrolysis reaction Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- -1 3-substituted benzofuranone (1 (3H) -isobenzofuranone) structures Chemical group 0.000 description 2
- HJXMNVQARNZTEE-UHFFFAOYSA-N Butylphthalide Chemical compound C1=CC=C2C(CCCC)OC(=O)C2=C1 HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- ADBQOKFPSDJLQB-UHFFFAOYSA-N methyl 5-bromo-2-(dibromomethyl)benzoate Chemical compound COC(=O)C1=CC(Br)=CC=C1C(Br)Br ADBQOKFPSDJLQB-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ACZGCWSMSTYWDQ-UHFFFAOYSA-N 3h-1-benzofuran-2-one Chemical group C1=CC=C2OC(=O)CC2=C1 ACZGCWSMSTYWDQ-UHFFFAOYSA-N 0.000 description 1
- BELKVKMBIAENSA-UHFFFAOYSA-N 6-bromo-3h-2-benzofuran-1-one Chemical compound BrC1=CC=C2COC(=O)C2=C1 BELKVKMBIAENSA-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 101000946926 Homo sapiens C-C chemokine receptor type 5 Proteins 0.000 description 1
- 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 1
- JZUTXVTYJDCMDU-MOPGFXCFSA-N Hydrastine Chemical compound CN1CCC2=CC=3OCOC=3C=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 JZUTXVTYJDCMDU-MOPGFXCFSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 102100023132 Transcription factor Jun Human genes 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000001387 apium graveolens Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003067 chemokine receptor CCR5 antagonist Substances 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000026502 entry into host cell Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 102000048160 human CCR5 Human genes 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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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 preparation method of 5-bromo-2-formylbenzoic acid methyl ester, which comprises the following specific processes: synthesizing a compound 2 by bromination reaction of a compound 3 of a reaction formula II; the compound 1 is synthesized by the hydrolysis reaction of the compound 2 in an alkaline organic solvent, and the specific synthetic route is as follows: the method has the advantages of simple operation, mild reaction conditions and low cost, the target product is obtained through bromination reaction and alkaline hydrolysis reaction, expensive oxidizing reagent is avoided in the reaction, and the two-step reaction has mild conditions, safety and easy control. The raw materials and reagents used in the reaction are all industrialThe industrial product can effectively reduce the production cost, and the organic solvent in the reaction can be recycled.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 5-bromo-2-formylbenzoic acid methyl ester.
Background
Chiral 3-substituted benzofuranone (1 (3H) -isobenzofuranone) structures are of great interest due to their wide presence in natural products with potent and potential biological activity. For example: 3-butylphthalide is a Chinese medicinal component extracted from celery seed oil, is being subjected to phase II clinical trials in China, is likely to be used for treating stroke, has an anticonvulsant effect, increases anesthesia duration, and shows an anti-cerebral ischemia effect; fuscindarin is a potent human CCR5 antagonist that is effective in preventing HIV entry into host cells; (-) -Hydrastine is active against opioid receptors, while it has anti-paclitaxel resistant human ovarian cancer activity through c-Jun kinase-mediated apoptosis, and is in phase I clinical trials; verstatin and alcytoterosine E, (-) -rubiginone-H are antibacterial and/or antibiotic agents.
The active medicine molecules all contain benzofuranone structures, and the 5-bromo-2-formylbenzoic acid methyl ester is a key intermediate for preparing 3-substituted benzofuranone, and meanwhile, the 5-bromo-2-formylbenzoic acid methyl ester is a common basic raw material in organic synthesis, and has very important roles in the fields of pesticides, medicines and the like, so that a method for developing and synthesizing the 5-bromo-2-formylbenzoic acid methyl ester is very important. At present, the preparation method of the 5-bromo-2-formylbenzoic acid methyl ester mainly comprises the following steps:
(1) The preparation of formula Scheme 1 is disclosed in US20190127358 A1:
the reaction yield of the step is lower than 26%, and the expensive N-methylmorpholine oxide is used as an oxidant in the reaction, so that the production cost is greatly increased, and the danger in the oxidation reaction process is higher, so that the method is not suitable for industrial production.
(2) The preparation of formula Scheme 2 is disclosed in CN113527313 a:
the yield of the reaction in the step is 78%, but the silver nitrate reagent with high price is used in the reaction in the step, and the production cost is increased, so that the method is not suitable for industrial production.
(3) The preparation of formula Scheme 3 is disclosed in literature Organic Letters 2014,16,6366-6369:
the yield of the two steps is 70%, the process of the first step is difficult to control, the price of the raw material 6-bromophthalide is high, and the reaction uses the virulent dimethyl sulfate, and the preparation process is relatively complex, so that the method is not suitable for industrial production.
In view of the above, the existing synthesis method of methyl 5-bromo-2-formylbenzoate has high risk, uses expensive reagents or is not easy to control in the reaction process, and the like, which brings great inconvenience to industrial production, so that a method for preparing methyl 5-bromo-2-formylbenzoate with simple operation, mild reaction conditions and low cost is needed.
Disclosure of Invention
The invention solves the technical problem of providing a preparation method of 5-bromo-2-formylbenzoic acid methyl ester, which has the advantages of simple operation, mild reaction conditions and low cost.
The invention adopts the following technical scheme to solve the technical problems, and is characterized by comprising the following specific processes:
(1) Compound 2 is synthesized by bromination reaction of compound 3 of the reaction formula II, and the specific synthetic route is as follows:
(2) The compound 1 is synthesized by the hydrolysis reaction of the compound 2 in an alkaline organic solvent, and the specific synthetic route is as follows:
the alkaline organic solvent is one of triethanolamine, triethylamine, pyridine, ethylenediamine, morpholine, N-methylmorpholine, piperidine, cyclohexylamine, isopropylamine or tetrahydropyrrole.
The preparation method of the 5-bromo-2-formylbenzoic acid methyl ester is characterized by comprising the following specific steps:
step S1: adding methyl 5-bromo-2-methylbenzoate 3 into a reaction bottle, adding an organic solvent, heating, stirring and heating to reflux, adding N-bromosuccinimide (NBS) and Azodiisobutyronitrile (AIBN) into the reaction bottle in batches after mixing, cooling to room temperature after the reaction is finished, steaming to recover carbon tetrachloride, adding saturated sodium sulfite into the residual solid in the round-bottomed flask for washing, extracting with dichloromethane for three times, merging organic phases, drying by anhydrous sodium sulfate solid, and spin-drying the organic solvent to obtain methyl 5-bromo-2- (dibromomethyl) benzoate;
step S2: adding the product compound 2 obtained in the step S1 into a reaction bottle, adding an alkaline organic solvent, stirring for reaction, monitoring by TLC until the raw materials are completely reacted, filtering, washing the solid by the organic solvent, vacuum pumping the filtrate to dry the organic solvent, dissolving the rest solid by ethyl acetate, washing by a dilute acid solution, merging water phases, extracting by ethyl acetate, and merging organic phases; drying the anhydrous sodium sulfate solid, and spin-drying ethyl acetate to obtain the compound 1, namely 5-bromo-2-formylbenzoic acid methyl ester.
Preferably, the organic solvent in step S1 is one of carbon tetrachloride, chlorobenzene or cyclohexane, preferably carbon tetrachloride.
Preferably, the mass ratio of the methyl 5-bromo-2-methylbenzoate 3, the N-bromosuccinimide and the azodiisobutyronitrile in the step S1 is 1:2-5:0.05-0.1.
Preferably, the reaction time in step S1 is 12 to 30 hours.
Preferably, the N-bromosuccinimide and the azodiisobutyronitrile in the step S1 are mixed and then added into a reaction bottle in 5-10 batches, and the interval time of each batch is 1-3 hours.
Preferably, the basic organic solvent in step S2 is morpholine.
Preferably, the mass ratio of the compound 2 to the alkaline organic solvent in the step S2 is 1:2-10.
Preferably, the reaction temperature in step S2 is 0 to 100℃and the reaction time is 12 to 24 hours.
Preferably, the dilute acid solution in step S2 is one of dilute sulfuric acid, dilute nitric acid, dilute hydrochloric acid, citric acid, tannic acid, acetic acid, formic acid or phosphoric acid, preferably dilute hydrochloric acid.
Preferably, the concentration of the dilute acid solution in the step S2 is 1-5 mol/L.
Compared with the prior art, the invention has the following advantages:
1) The target product is obtained through bromination reaction and alkaline hydrolysis reaction, expensive oxidizing reagent is avoided in the reaction, and the two-step reaction is mild in condition, safe and easy to control.
2) The raw materials and the reagents used in the reaction are industrial products, so that the production cost is effectively reduced, and the organic solvent in the reaction can be recycled.
3) The product after bromination reaction can be directly used for the next hydrolysis reaction without purification, and the post-treatment and operation of each step of reaction are simple, thus being applicable to industrial production.
4) The alkaline organic solvent has less hydrolysis reaction byproducts, high product yield and 86 percent of total yield of the two-step reaction.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of methyl 5-bromo-2-formylbenzoate prepared in example 1;
FIG. 2 is a high performance liquid chromatography of methyl 5-bromo-2-formylbenzoate prepared in example 1.
Detailed Description
The above-described matters of the present invention will be described in further detail by way of examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and all techniques realized based on the above-described matters of the present invention are within the scope of the present invention.
Example 1
To the reaction flask was added methyl 5-bromo-2-methylbenzoate (compound 3, 10 g), followed by 150mL of carbon tetrachloride, followed by heating and stirring to 80 ℃, and after mixing N-bromosuccinimide (NBS, 25 g) and azobisisobutyronitrile (AIBN, 0.8 g), 5 batches were added to the reaction flask, each batch being separated by 2 hours, the reaction was stirred for 24 hours at room temperature, cooled to room temperature and distilled to recover carbon tetrachloride, 250mL of saturated sodium sulfite was added to the remaining solids in the round bottom flask, followed by three extractions with dichloromethane (about 120mL each), the organic phases were combined, dried over anhydrous sodium sulfate solid, and dried over spin-on organic solvent to give compound 2 as a white solid, 5-bromo-2- (dibromomethyl) benzoate, 17g, which was used directly in the next step.
The product 5-bromo-2- (dibromomethyl) benzoic acid methyl ester (compound 2, 17 g) prepared above was added to a reaction flask, 85g of morpholine solvent was added, the temperature was raised to 50 ℃ and stirred for reaction, TLC was monitored until the starting material was reacted, filtration was carried out, the solid was washed with a small amount of morpholine, the filtrate was dried under reduced pressure to recover morpholine solvent, the remaining solid was dissolved with 50mL of ethyl acetate, 3M hydrochloric acid solution was washed (twice, 50mL each), the aqueous phases were combined and extracted with 30mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate solid, and recrystallized from a mixture of ethanol and petroleum ether to give compound 1 as a white solid, i.e., methyl 5-bromo-2-formylbenzoate, 9.1g, in 86% yield.
While the basic principles, principal features and advantages of the present invention have been described in the foregoing examples, it will be appreciated by those skilled in the art that the present invention is not limited by the foregoing examples, but is merely illustrative of the principles of the invention, and various changes and modifications can be made without departing from the scope of the invention, which is defined by the appended claims.
The invention discloses a preparation method of 5-bromo-2-formylbenzoic acid methyl ester, which comprises the following specific processes: synthesizing a compound 2 by bromination reaction of a compound 3 of a reaction formula II; the compound 1 is synthesized by the hydrolysis reaction of the compound 2 in an alkaline organic solvent, and the specific synthetic route is as follows:
the method has the advantages of simple operation, mild reaction conditions and low cost, the target product is obtained through bromination reaction and alkaline hydrolysis reaction, expensive oxidizing reagent is avoided in the reaction, and the two-step reaction has mild conditions, safety and easy control. The raw materials and the reagents used in the reaction are industrial products, so that the production cost is effectively reduced, and the organic solvent in the reaction can be recycled.
Claims (10)
1. A preparation method of 5-bromo-2-formylbenzoic acid methyl ester is characterized by comprising the following specific steps:
(1) Compound 2 is synthesized by bromination reaction of compound 3 of the reaction formula II, and the specific synthetic route is as follows:
(2) The compound 1 is synthesized by the hydrolysis reaction of the compound 2 in an alkaline organic solvent, and the specific synthetic route is as follows:
the alkaline organic solvent is one of triethanolamine, triethylamine, pyridine, ethylenediamine, morpholine, N-methylmorpholine, piperidine, cyclohexylamine, isopropylamine or tetrahydropyrrole.
2. The method for preparing the methyl 5-bromo-2-formylbenzoate according to claim 1, which is characterized by comprising the following specific steps:
step S1: adding 5-bromo-2-methyl benzoate 3 into a reaction bottle, adding an organic solvent, heating, stirring and heating to reflux, adding N-bromosuccinimide and azodiisobutyronitrile into the reaction bottle in batches after mixing, cooling to room temperature after the reaction is finished, steaming to recover carbon tetrachloride, adding saturated sodium sulfite into the residual solid in the round-bottomed flask for washing, extracting with dichloromethane for three times, merging organic phases, drying the anhydrous sodium sulfate solid, and spin-drying the organic solvent to obtain a compound 2, namely 5-bromo-2- (dibromomethyl) methyl benzoate;
step S2: adding the product compound 2 obtained in the step S1 into a reaction bottle, adding an alkaline organic solvent, stirring for reaction, monitoring by TLC until the raw materials are completely reacted, filtering, washing the solid by the organic solvent, vacuum pumping the filtrate to dry the organic solvent, dissolving the rest solid by ethyl acetate, washing by a dilute acid solution, merging water phases, extracting by ethyl acetate, and merging organic phases; drying the anhydrous sodium sulfate solid, and spin-drying ethyl acetate to obtain the compound 1, namely 5-bromo-2-formylbenzoic acid methyl ester.
3. The method for preparing methyl 5-bromo-2-formylbenzoate according to claim 2, wherein the organic solvent in step S1 is one of carbon tetrachloride, chlorobenzene or cyclohexane.
4. The method for preparing the methyl 5-bromo-2-formylbenzoate according to claim 2, wherein the mass ratio of the methyl 5-bromo-2-methylbenzoate 3, the N-bromosuccinimide to the azobisisobutyronitrile in the step S1 is 1:2-5:0.05-0.1.
5. The process for preparing methyl 5-bromo-2-formylbenzoate according to claim 2, characterized in that the reaction time in step S1 is 12 to 30 hours.
6. The method for preparing methyl 5-bromo-2-formylbenzoate according to claim 2, wherein in step S1, the N-bromosuccinimide and azobisisobutyronitrile are mixed and then added to the reaction flask in 5 to 10 batches, each batch being separated by 1 to 3 hours.
7. The method for preparing methyl 5-bromo-2-formylbenzoate according to claim 2, wherein the mass ratio of compound 2 to basic organic solvent in step S2 is 1:2-10.
8. The process for preparing methyl 5-bromo-2-formylbenzoate according to claim 2, wherein the reaction temperature in step S2 is 0 to 100 ℃ and the reaction time is 12 to 24 hours.
9. The method for preparing methyl 5-bromo-2-formylbenzoate according to claim 2, wherein the dilute acid solution in step S2 is one of dilute sulfuric acid, dilute nitric acid, dilute hydrochloric acid, citric acid, tannic acid, acetic acid, formic acid or phosphoric acid.
10. The method for producing methyl 5-bromo-2-formylbenzoate according to claim 2, characterized in that the concentration of said dilute acid solution in step S2 is 1 to 5mol/L.
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