CN114163316A - Method for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde - Google Patents
Method for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 27
- BXRSZURBBUMBLU-UHFFFAOYSA-N 4-bromo-2-methoxy-5-(trifluoromethyl)benzaldehyde Chemical compound BrC1=CC(=C(C=O)C=C1C(F)(F)F)OC BXRSZURBBUMBLU-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 239000002994 raw material Substances 0.000 claims abstract description 17
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 20
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 17
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 15
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 14
- 238000005893 bromination reaction Methods 0.000 claims description 12
- 238000006192 iodination reaction Methods 0.000 claims description 11
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical group [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical group BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000006198 methoxylation reaction Methods 0.000 claims description 8
- 238000006396 nitration reaction Methods 0.000 claims description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 7
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 7
- 229910017604 nitric acid Inorganic materials 0.000 claims description 7
- 230000009471 action Effects 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 6
- 238000007037 hydroformylation reaction Methods 0.000 claims description 5
- 230000002083 iodinating effect Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 239000007818 Grignard reagent Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical group [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- 125000003158 alcohol group Chemical group 0.000 claims description 4
- 230000031709 bromination Effects 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 150000004795 grignard reagents Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 235000010288 sodium nitrite Nutrition 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 125000002346 iodo group Chemical group I* 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 230000026045 iodination Effects 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 231100000956 nontoxicity Toxicity 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000700721 Hepatitis B virus Species 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- ZNSMNVMLTJELDZ-UHFFFAOYSA-N Bis(2-chloroethyl)ether Chemical compound ClCCOCCCl ZNSMNVMLTJELDZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 150000002212 flavone derivatives Chemical class 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention providesA method for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde, belonging to the field of synthesis technology. The method comprises the following steps: and (3) carrying out a formaldehyde reaction on the compound VI to obtain 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde. The method for preparing the 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde has the advantages of easily available raw materials, mild reaction conditions, simple steps, low cost, safety, no toxicity, easiness in large-scale production, capability of obviously improving the total yield and purity of the target product 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde and wide application prospect.
Description
Technical Field
The invention belongs to the field of synthesis processes, and particularly relates to a method for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde.
Background
Hepatitis B Virus (HBV) infection is one of the most common viral infections and is the leading cause of chronic hepatitis. It is estimated that around 20 million people worldwide have evidence of past or present infection with HBV. Currently, more than 2.5 million individuals are chronically infected with HBV and, therefore, are at high risk of developing liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). International patent application publication No. WO2020070088a1 discloses a flavone derivative for the treatment and prevention of hepatitis b virus diseases, 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde being a key pharmaceutical intermediate for the preparation of the flavone derivative.
The current method for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde (i.e. compound TM in the scheme) is mainly:
however, this method has the following problems: (1) the raw material compound 10 adopted in the step I is expensive, so that the production cost is increased; (2) the method adopts dichloroethyl ether with strong irritation to skin and eyes, and has certain toxicity to human body; (3) the yield of the first step is only 73 percent, the yield of the second step is only 24 percent, the yield of the second step is only 17.5 percent, and the yield is too low, so the method is not suitable for industrial production.
Therefore, the development of a method for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde with lower cost and higher yield is of great significance.
Disclosure of Invention
The invention aims to provide a method for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde with low cost, high yield and high purity.
The present invention provides a method for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde, comprising the steps of: performing a formalization reaction on the compound VI to obtain 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde;
further, the formaldehyde reaction is carried out by taking a compound VI and N, N-dimethylformamide as raw materials, wherein the mass ratio of the compound VI to the N, N-dimethylformamide is 300 (200-300); the temperature of the hydroformylation reaction is less than or equal to-10 ℃, the time is 1-3 hours, and the solvent is an organic solvent.
Further, the mass ratio of the compound VI to the N, N-dimethylformamide is 300: 230; the temperature of the hydroformylation reaction is-5 ℃, the time is 2 hours, and the solvent is tetrahydrofuran; the formaldehyde reaction is carried out under the action of a Grignard reagent; preferably, the Grignard reagent is isopropyl magnesium chloride, and the mass ratio of the compound VI to the isopropyl magnesium chloride is 300 (85-95).
Further, the preparation method of the compound VI comprises the following steps:
carrying out bromination reaction on the compound IV to obtain a compound V;
performing iodination reaction on the compound V to obtain a compound VI;
further, the bromination reaction is carried out by taking a compound IV and a bromination reagent as raw materials, wherein the mass ratio of the compound IV to the bromination reagent is 270: (200-300); the temperature of the bromination reaction is 10-20 ℃, the time is 2-6 hours, and the solvent is an organic solvent;
the iodination reaction is carried out by taking a compound V and an iodinating reagent as raw materials, wherein the mass ratio of the compound V to the iodinating reagent is 280: (300-400); the temperature of the iodination reaction is 0-10 ℃, the time is 1-3 hours, and the solvent is a mixed solution of an organic solvent and water.
Further, the mass ratio of the compound IV to the brominating reagent is 270: 235; the temperature of the bromination reaction is 15 ℃, the time is 4 hours, and the solvent is N, N-dimethylformamide; the brominating reagent is N-bromosuccinimide;
the mass ratio of the compound V to the iodo reagent is 280: 344; the temperature of the iodination reaction is 5 ℃, the time is 2 hours, and the solvent is a mixed solution of acetonitrile and water; the iodination reaction is carried out under the action of sulfuric acid and sodium nitrite, and the mass ratio of the compound V to the sulfuric acid to the nitrous acid is 280 (100-200) to 100-200.
Further, the iodinating reagent is sodium iodide, and the mass ratio of the compound V to the sulfuric acid to the nitrous acid is 280:152: 130.
Further, the preparation method of the compound IV comprises the following steps:
carrying out nitration reaction on the compound I to obtain a compound II;
carrying out methoxylation reaction on the compound II to obtain a compound III;
carrying out nitro reduction reaction on the compound III to obtain a compound IV;
further, the nitration reaction is carried out by taking a compound I and nitric acid as raw materials, wherein the mass-volume ratio of the compound I to the nitric acid is 350: (100-200) g/mL; the temperature of the nitration reaction is 20-60 ℃, the time is 3-7 hours, and the solvent is acid;
the methoxylation reaction is carried out by taking a compound II and sodium methoxide as raw materials, wherein the mass ratio of the compound II to the sodium methoxide is 400: (90-100); the temperature of the methoxylation reaction is 40-60 ℃, the time is 2-6 hours, and the solvent is an alcohol solvent;
the nitro reduction reaction is carried out in a hydrogen atmosphere; the temperature of the nitro reduction reaction is 40-60 ℃, the time is 10-14 hours, the solvent is an alcohol solvent, and the pressure is 1.0-2.0 Mpa.
Further, the mass-to-volume ratio of the compound I to the nitric acid is 350: 175 g/mL; the temperature of the nitration reaction is room temperature, the time is 5 hours, and the solvent is sulfuric acid;
the mass ratio of the compound II to sodium methoxide is 400: 96; the temperature of the methoxylation reaction is 50 ℃, the time is 4 hours, and the solvent is methanol;
the temperature of the nitro reduction reaction is 50 ℃, the time is 12 hours, the solvent is methanol, and the pressure is 1.0-1.5 Mpa; the nitro reduction reaction is carried out under the action of a hydrogenation catalyst, and the hydrogenation catalyst is preferably Raney nickel.
In the present invention, room temperature means 25. + -. 2 ℃.
Compared with the prior art, the method for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde has the following advantages:
1. the starting material compound I adopted by the invention is cheap and easy to obtain, the cost is low, the reaction condition is mild, and the steps are simple;
2. the invention avoids using the toxic raw material dichloroethylether which has strong irritation to skin and eyes, and the reagent adopted by the invention has no toxicity to human body and is environment-friendly;
3. the purity of the final product 4-bromo-2-methoxy-5-trifluoromethyl benzaldehyde prepared by the method is up to 98.32%, the yield of the step of performing hydroformylation reaction on the compound VI to obtain 4-bromo-2-methoxy-5-trifluoromethyl benzaldehyde is up to 73.1%, and the total yield of the six steps is up to 39.72%.
In a word, the method for preparing the 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde has the advantages of easily available raw materials, mild reaction conditions, simple steps, low cost, safety, no toxicity, easiness for large-scale production, capability of obviously improving the yield and purity of the target product 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde and wide application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
Example 1 Process for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde
The synthetic route comprises the following six steps:
the first step is as follows: synthesis of Compound II
1.0L of sulfuric acid was added to a 3L three-necked flask at room temperature, and 350g of p-chlorotrifluoromethylene (i.e., compound I) was poured in with stirring. And (3) dropwise adding 175mL of nitric acid, reacting violently to release heat, and cooling in a water bath to control the internal temperature of the three-necked flask to be 50-60 ℃. After the addition, naturally cooling to room temperature, and reacting for 5 h. A sample was taken and tested by HPLC to show completion of the reaction.
The reaction system was diluted with 3.0L of ice water, extracted three times with 2.0L of dichloromethane, the organic phases were combined, washed twice with 1.0L of saturated aqueous sodium carbonate solution and once with 1.0L of saturated aqueous sodium chloride solution in this order, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain Compound II (410g, purity: 99%, yield: 94%). 1H-NMR δ ppm (DMS0-d6,400mhz),8.39(s, 1H),7.85(d, J ═ 8.0Hz,1H),7.65(d, J ═ 8.0Hz,1H).
The second step is that: synthesis of Compound III
400g of the compound II is dissolved in 300mL of methanol solution, 321g of sodium methoxide solution (the mass concentration of sodium methoxide in the sodium methoxide solution is 30%) is added, the temperature is raised to 50 ℃, and the reaction is carried out for 4 hours. Detecting the reaction by thin layer chromatography, and completely reacting the compound II.
Cooling the reaction system to 20-30 ℃, and dropwise adding 350mL of 1M hydrochloric acid aqueous solution to adjust the pH value to 5-6. Then, the mixture was concentrated to remove most of methanol, diluted with water to 1.0L, extracted three times with 500mL of dichloromethane, and the organic phases were combined, washed twice with 500mL of saturated brine, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound III (365g, purity 99%, yield: 96%). 1H NMR (cdcl3,200mhz): δ 4.08(s,3H),7.28(d, J ═ 8.8Hz,1H),7.84(m, J ═ 0.6,2.3,8.8Hz,1H),8.15(d, J ═ 1.9, Hz,1H) ppm.
The third step: synthesis of Compound IV
And (3) adding 350g of compound III, 2.6L of methanol and 70g of Raney nickel into a 5L autoclave, sequentially replacing the reaction device with nitrogen for 3 times and hydrogen for 2 times, and controlling the pressure to be 1.0-1.5 MPa by using a hydrogen filling gas. Heating to 50 ℃, reacting for 12h, detecting the reaction by thin-layer chromatography, and completely reacting.
The reaction solution pad was filtered through celite to remove raney nickel and the filter cake was washed twice with 400mL methanol. The filtrate was collected, concentrated under reduced pressure, and dried to obtain Compound IV as a pale yellow solid (300g, purity: 99%, yield: 94.8%). 1H NMR (cdcl3,200mhz): δ 3.87(s,3H),3.94(br s,2H),6.74(d, J ═ 8.3Hz,1H),6.95(m, J ═ 0.8,2.1,8.3Hz,1H) ppm,7.94(d, J ═ 2.0, Hz,1H).
The fourth step: synthesis of Compound V
270g of compound IV are dissolved in 1.5L of DMF and the temperature is reduced to 15 ℃ in an ice-water bath. Adding 235g N-bromosuccinimide (NBS for short) in batches with stirring, and reacting for 4h at 15 ℃. Detecting the reaction by thin layer chromatography, and completing the reaction.
While stirring, 300g of potassium carbonate was added to the reaction solution to quench the reaction, and the mixture was stirred for 30 min. The reaction solution was poured into 10L of water and stirred for 10min, 5L of methyl tert-butyl ether was added and extracted three times, the organic phases were combined and washed twice with 5L of water and once with 5L of saturated sodium chloride solution. The washed organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to give 400g of crude product, which was added with 1.6L of petroleum ether and slurried, filtered, and the filtered solid was dried to give Compound V (300g, purity: 97.4%, yield: 80.6%).1H-NMRδppm(DMS0-d6,400MHz):3.86(s,J＝8.0Hz,3H),5.31(s,J＝8.0Hz,2H),7.11(d,J＝8.0Hz,2H).
The fifth step: synthesis of Compound VI
280g of Compound V are dissolved in 1.8L of acetonitrile, 152g of sulfuric acid are dissolved in 1.5L of water and added dropwise to the reaction mixture. The temperature is reduced to 5 ℃, 130g of sodium nitrite is dissolved in 1.5L of water and then is dripped into the reaction solution. The reaction is carried out for 10min, the thin-layer chromatography detects the reaction, and the raw materials are completely converted. Dropwise adding the reaction solution into 1.5L of a stirred aqueous solution containing 344g of potassium iodide, reacting at 5 ℃ for 2h, and detecting the reaction by thin layer chromatography to complete the reaction.
The reaction solution was extracted three times with 2.0L of methyl tert-butyl ether (MTBE), the organic phases were combined, washed once with 1L of a saturated aqueous sodium sulfite solution and 1L of a saturated aqueous potassium carbonate solution, twice with 2.0L of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried to give a off-white solid compound VI (380g, purity: 98%, yield: 78.8%).1H-NMRδppm(DMS0-d6,400MHz)：3.88(s,J＝8.0Hz,3H),7.05(s,J＝8.0Hz,1H),7.88(s,J＝8.0Hz,1H).
And a sixth step: synthesis of 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde (i.e., Compound TM)
300g of compound VI was added to 3.0L of THF, the reaction apparatus was replaced three times with nitrogen and the temperature was lowered to-5 ℃. 433mL of 2M isopropyl magnesium chloride in tetrahydrofuran was added dropwise, and the reaction was carried out at this temperature for 20 min. 230g of DMF was added dropwise and the reaction was carried out at-5 ℃ for 2 hours. HPLC detection showed the reaction was complete.
The reaction solution was slowly poured into 4.0L of saturated aqueous ammonium chloride solution to quench the reaction, and the mixture was allowed to stand for liquid separation, and the aqueous phase was extracted twice with 3L of methyl t-butyl ether. Combining the organic phases, washing with 4.0L of 1M dilute hydrochloric acid, separating the liquid, and retaining the organic phase; back extraction was performed once by adding 2.0L of methyl t-butyl ether to the separated aqueous phase, and the organic phase was retained. The organic phases which remained twice were combined and washed once by adding 4.0L of a saturated aqueous sodium chloride solution. Then, the organic phase washed with a saturated aqueous solution of sodium chloride was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 164g of a crude product.
The crude product was added to 500mL of a mixed solution of PET and EA (where the volume ratio of PET: EA was 10:1) and slurried to give an off-white compound TM, i.e., 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde, purity 98.32%, yield 73.1%.1H-NMRδppm(DMS0-d6,400MHz)：10.27(s,1H),7.84(s,1H),7.47(s,1H),3.95(s,3H).
In the preparation method of this example, the total yield of six steps was 39.72%, and the product purity was 98.32%.
In summary, the present invention provides a process for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde. The method has the advantages of easily available raw materials, mild reaction conditions, simple steps, low cost, safety, no toxicity and easiness in large-scale production, can obviously improve the total yield and purity of the target product 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde, and has wide application prospect.
Claims (10)
1. A method for producing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde, characterized by: the method comprises the following steps: performing a formalization reaction on the compound VI to obtain 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde;
2. the method of claim 1, wherein: the formaldehyde reaction is carried out by taking a compound VI and N, N-dimethylformamide as raw materials, wherein the mass ratio of the compound VI to the N, N-dimethylformamide is 300 (200-300); the temperature of the hydroformylation reaction is less than or equal to-10 ℃, the time is 1-3 hours, and the solvent is an organic solvent.
3. The method of claim 2, wherein: the mass ratio of the compound VI to the N, N-dimethylformamide is 300: 230; the temperature of the hydroformylation reaction is-5 ℃, the time is 2 hours, and the solvent is tetrahydrofuran; the formaldehyde reaction is carried out under the action of a Grignard reagent; preferably, the Grignard reagent is isopropyl magnesium chloride, and the mass ratio of the compound VI to the isopropyl magnesium chloride is 300 (85-95).
4. The production method according to any one of claims 1 to 3, characterized in that: the preparation method of the compound VI comprises the following steps:
carrying out bromination reaction on the compound IV to obtain a compound V;
performing iodination reaction on the compound V to obtain a compound VI;
5. the method of claim 4, wherein: the bromination reaction is carried out by taking a compound IV and a bromination reagent as raw materials, wherein the mass ratio of the compound IV to the bromination reagent is 270: (200-300); the temperature of the bromination reaction is 10-20 ℃, the time is 2-6 hours, and the solvent is an organic solvent;
the iodination reaction is carried out by taking a compound V and an iodinating reagent as raw materials, wherein the mass ratio of the compound V to the iodinating reagent is 280: (300-400); the temperature of the iodination reaction is 0-10 ℃, the time is 1-3 hours, and the solvent is a mixed solution of an organic solvent and water.
6. The method of claim 5, wherein: the mass ratio of the compound IV to the brominating reagent is 270: 235; the temperature of the bromination reaction is 15 ℃, the time is 4 hours, and the solvent is N, N-dimethylformamide; the brominating reagent is N-bromosuccinimide;
the mass ratio of the compound V to the iodo reagent is 280: 344; the temperature of the iodination reaction is 5 ℃, the time is 2 hours, and the solvent is a mixed solution of acetonitrile and water; the iodination reaction is carried out under the action of sulfuric acid and sodium nitrite, and the mass ratio of the compound V to the sulfuric acid to the nitrous acid is 280 (100-200) to 100-200.
7. The method of claim 6, wherein: the iodination reagent is sodium iodide, and the mass ratio of the compound V to the sulfuric acid to the nitrous acid is 280:152: 130.
8. The method of claim 4, wherein: the preparation method of the compound IV comprises the following steps:
carrying out nitration reaction on the compound I to obtain a compound II;
carrying out methoxylation reaction on the compound II to obtain a compound III;
carrying out nitro reduction reaction on the compound III to obtain a compound IV;
9. the method of claim 8, wherein: the nitration reaction is carried out by taking a compound I and nitric acid as raw materials, wherein the mass-volume ratio of the compound I to the nitric acid is 350: (100-200) g/mL; the temperature of the nitration reaction is 20-60 ℃, the time is 3-7 hours, and the solvent is acid;
the methoxylation reaction is carried out by taking a compound II and sodium methoxide as raw materials, wherein the mass ratio of the compound II to the sodium methoxide is 400: (90-100); the temperature of the methoxylation reaction is 40-60 ℃, the time is 2-6 hours, and the solvent is an alcohol solvent;
the nitro reduction reaction is carried out in a hydrogen atmosphere; the temperature of the nitro reduction reaction is 40-60 ℃, the time is 10-14 hours, the solvent is an alcohol solvent, and the pressure is 1.0-2.0 Mpa.
10. The method of claim 9, wherein: the mass-to-volume ratio of the compound I to the nitric acid is 350: 175 g/mL; the temperature of the nitration reaction is room temperature, the time is 5 hours, and the solvent is sulfuric acid;
the mass ratio of the compound II to sodium methoxide is 400: 96; the temperature of the methoxylation reaction is 50 ℃, the time is 4 hours, and the solvent is methanol;
the temperature of the nitro reduction reaction is 50 ℃, the time is 12 hours, the solvent is methanol, and the pressure is 1.0-1.5 Mpa; the nitro reduction reaction is carried out under the action of a hydrogenation catalyst, and the hydrogenation catalyst is preferably Raney nickel.
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