CN115304472A - Synthetic method of intermediate 4-bromo-2-methylbenzoic acid of Freund Lei Lana - Google Patents
Synthetic method of intermediate 4-bromo-2-methylbenzoic acid of Freund Lei Lana Download PDFInfo
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- CN115304472A CN115304472A CN202210741275.5A CN202210741275A CN115304472A CN 115304472 A CN115304472 A CN 115304472A CN 202210741275 A CN202210741275 A CN 202210741275A CN 115304472 A CN115304472 A CN 115304472A
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- RVCJOGNLYVNRDN-UHFFFAOYSA-N 4-bromo-2-methylbenzoic acid Chemical compound CC1=CC(Br)=CC=C1C(O)=O RVCJOGNLYVNRDN-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 33
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 28
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 claims abstract description 26
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 20
- RGHJWZADAWEIFE-UHFFFAOYSA-N 4-amino-2-methylbenzonitrile Chemical compound CC1=CC(N)=CC=C1C#N RGHJWZADAWEIFE-UHFFFAOYSA-N 0.000 claims abstract description 16
- XRSQZFJLEPBPOZ-UHFFFAOYSA-N 4-amino-2-methylbenzoic acid Chemical compound CC1=CC(N)=CC=C1C(O)=O XRSQZFJLEPBPOZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000002923 oximes Chemical class 0.000 claims abstract description 12
- ZBHHWKBPSJWDBX-UHFFFAOYSA-N 4-amino-2-methylbenzaldehyde Chemical compound CC1=CC(N)=CC=C1C=O ZBHHWKBPSJWDBX-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000005893 bromination reaction Methods 0.000 claims abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 49
- 238000003756 stirring Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 22
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 22
- 238000001816 cooling Methods 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000012065 filter cake Substances 0.000 claims description 19
- 238000005406 washing Methods 0.000 claims description 19
- 239000007787 solid Substances 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 14
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 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 11
- 235000019253 formic acid Nutrition 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000004280 Sodium formate Substances 0.000 claims description 9
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 9
- 235000019254 sodium formate Nutrition 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 235000010288 sodium nitrite Nutrition 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 2
- 238000006170 formylation reaction Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 9
- 150000001875 compounds Chemical class 0.000 description 10
- 239000000463 material Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 239000008399 tap water Substances 0.000 description 6
- 235000020679 tap water Nutrition 0.000 description 6
- 231100000331 toxic Toxicity 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 3
- 238000007605 air drying Methods 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 2
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- 241000880922 Freyana Species 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- IFKWLKCPUIQXPU-UHFFFAOYSA-N (4-bromo-2-methylphenyl)methanol Chemical compound CC1=CC(Br)=CC=C1CO IFKWLKCPUIQXPU-UHFFFAOYSA-N 0.000 description 1
- QOGHRLGTXVMRLM-UHFFFAOYSA-N 4-bromo-1,2-dimethylbenzene Chemical group CC1=CC=C(Br)C=C1C QOGHRLGTXVMRLM-UHFFFAOYSA-N 0.000 description 1
- LPEBMDFRIKYFCF-UHFFFAOYSA-N 4-bromo-2-methylbenzonitrile Chemical compound CC1=CC(Br)=CC=C1C#N LPEBMDFRIKYFCF-UHFFFAOYSA-N 0.000 description 1
- 108010062745 Chloride Channels Proteins 0.000 description 1
- 102000011045 Chloride Channels Human genes 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 102000005915 GABA Receptors Human genes 0.000 description 1
- 108010005551 GABA Receptors Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 241001674048 Phthiraptera Species 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- -1 chlorine ions Chemical class 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- DFBKLUNHFCTMDC-PICURKEMSA-N dieldrin Chemical compound C([C@H]1[C@H]2[C@@]3(Cl)C(Cl)=C([C@]([C@H]22)(Cl)C3(Cl)Cl)Cl)[C@H]2[C@@H]2[C@H]1O2 DFBKLUNHFCTMDC-PICURKEMSA-N 0.000 description 1
- 229950006824 dieldrin Drugs 0.000 description 1
- NGPMUTDCEIKKFM-UHFFFAOYSA-N dieldrin Natural products CC1=C(Cl)C2(Cl)C3C4CC(C5OC45)C3C1(Cl)C2(Cl)Cl NGPMUTDCEIKKFM-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- MLBZKOGAMRTSKP-UHFFFAOYSA-N fluralaner Chemical compound C1=C(C(=O)NCC(=O)NCC(F)(F)F)C(C)=CC(C=2CC(ON=2)(C=2C=C(Cl)C=C(Cl)C=2)C(F)(F)F)=C1 MLBZKOGAMRTSKP-UHFFFAOYSA-N 0.000 description 1
- 229960004498 fluralaner Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 125000003971 isoxazolinyl group Chemical group 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005648 named reaction Methods 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/02—Formation of carboxyl groups in compounds containing amino groups, e.g. by oxidation of amino alcohols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
Abstract
The invention provides a synthetic method of an intermediate 4-bromo-2-methylbenzoic acid of Freund Lei Lana, which is characterized by comprising the following steps: the method comprises the steps of using 3-methylaniline as a raw material, firstly formylating the 3-methylaniline with phosphorus oxychloride to generate 2-methyl-4-aminobenzaldehyde, then reacting with hydroxylamine hydrochloride to generate oxime, dehydrating the oxime to obtain 2-methyl-4-aminobenzonitrile, then hydrolyzing the 2-methyl-4-aminobenzonitrile with sodium hydroxide to obtain 2-methyl-4-aminobenzoic acid, and finally carrying out Sandmeyer bromination reaction to obtain 4-bromo-2-methylbenzoic acid.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of a Freund Lei Lana intermediate 4-bromo-2-methylbenzoic acid.
Background
Freyn Lei Lana Fluralaner is an isoxazoline insecticide and acaricide, and chlorine ions cannot penetrate into a postsynaptic membrane by antagonizing a gamma-aminobutyric acid receptor and a glutamic acid receptor gated chloride ion channel, so that transmembrane signal transmission of a nervous system is interfered, and the insect nervous system is disturbed and then dies. The fluorine Lei Lana has no cross-resistance with dieldrin, and is the earliest and only one veterinary medical product capable of quickly and effectively killing lice and fleas.
4-bromo-2-methylbenzoic acid is used as an important intermediate of Freyana Lei Lana, and plays an important role in cost and quality control in the production process of Freyana medicaments. The synthesis methods of 4-bromo-2-methylbenzoic acid reported in the literature at present mainly comprise the following methods.
Patent WO2017034994 reports synthesis using (4-bromo-2-methylphenyl) methanol as a raw material, and the method is not easy to obtain the raw material, expensive and not beneficial to industrialization.
Patent CN112441907 reports that 4-bromo-1,2-xylene is used as a raw material, and a target product is synthesized by oxidation under the catalysis of noble metal. The process has the advantages of easily obtained raw materials, poor selectivity, low yield, main product yield of only 43 percent, generation of various byproducts in the oxidation process, difficult separation, difficult industrialization and high cost.
The preparation of the target product from a 4-bromo-2-methylbenzonitrile raw material was reported by Chiarelli et al in 2018. This protocol is simple to operate, however the cyanide used is toxic, expensive and not readily available.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a synthetic method of an intermediate 4-bromo-2-methylbenzoic acid of the Freund Lei Lana, which has the advantages of cheap and easily obtained raw materials, no use of a noble metal catalyst, avoidance of use of highly toxic cyanide, simple and convenient operation in the whole production process and contribution to industrialization.
In order to achieve the purpose, the invention is realized by the following technical scheme: a synthetic method of 4-bromo-2-methylbenzoic acid as an intermediate of Freund Lei Lana is characterized by comprising the following steps: the method comprises the following steps of taking 3-methylaniline as a raw material, firstly formylating the 3-methylaniline with phosphorus oxychloride to generate 2-methyl-4-aminobenzaldehyde, then reacting with hydroxylamine hydrochloride to generate oxime, dehydrating the oxime to obtain 2-methyl-4-aminobenzonitrile, hydrolyzing the 2-methyl-4-aminobenzonitrile to obtain 2-methyl-4-aminobenzoic acid, and finally carrying out Sandmeyer bromination reaction to obtain 4-bromo-2-methylbenzoic acid, wherein the reaction formula is as follows:
in the scheme, the operation steps of the formylation reaction of the 3-methylaniline and the phosphorus oxychloride comprise:
under the protection of nitrogen, adding a reaction solvent into a reaction container, controlling the temperature to be 0-5 ℃, dropwise adding phosphorus oxychloride into the system, after dropwise adding, continuously stirring and reacting for 1h at the temperature of 0-5 ℃, adding 3-methylaniline in batches at the temperature of 0-5 ℃, after adding, heating to 60-65 ℃ for reacting for 5-6h, detecting until the raw materials disappear, cooling to room temperature, adding ice water at the temperature of 0-5 ℃, adjusting the pH to be 8-9, filtering, washing a filter cake with water, and drying to obtain a yellow solid.
The reaction solvent is DMF or ethanol, and the molar ratio of the 3-methylaniline to the phosphorus oxychloride is 1:1-1.5.
The temperature is controlled to react at 0-5 ℃, phosphorus oxychloride is selectively dropped into the system, the generation of side reactions is reduced, the selective reaction is carried out at the para position of amino, DMF or ethanol is selected as a solvent, on one hand, the temperature requirement of the reaction can be met, on the other hand, DMF and ethanol can be mutually dissolved with water, the product is insoluble in water, and the product can be washed out by directly adding water during subsequent treatment, so that the crystallization and filtration of the product can be realized, the operation is simple, and the method is suitable for industrial production. The yield of the step can reach more than 87%, and the purity of the product is 99.5%.
In the scheme, the reaction steps of the 2-methyl-4-aminobenzaldehyde and the hydroxylamine hydrochloride are as follows: sequentially adding 2-methyl-4-aminobenzaldehyde, a solvent and hydroxylamine hydrochloride into a reaction vessel, heating and refluxing for 3-4h after the addition is finished, completely reacting, cooling to 0-5 ℃, continuously stirring until the crystallization is complete, filtering, washing a filter cake with the solvent, and drying to obtain the product. The molar ratio of the 2-methyl-4-aminobenzaldehyde to the hydroxylamine hydrochloride is 1:1-1.2, and the solvent is ethanol or DMF. The reaction at 0-5 ℃ is selected to reduce side reaction, and similarly, ethanol and DMF are selected as solvents, so that the subsequent operation is simpler, the product is crystallized without distilling to remove the solvent, the yield is high and can reach more than 95%, and the purity is 99.8%.
In the scheme, the step of obtaining the 2-methyl-4-aminobenzonitrile by oxime dehydration comprises the following steps: adding oxime, formic acid and sodium formate into a reaction vessel, heating to 100 ℃ for reaction for 3-4h, cooling to room temperature after the reaction is finished, removing the formic acid by decompression and concentration, adding water into the system, continuing stirring for crystallization, filtering, washing a filter cake with water, and drying to obtain the 2-methyl-4-aminobenzonitrile. The molar ratio of the oxime to sodium formate is 1.5-2. The reaction yield can reach more than 93 percent and the product purity can reach 99.8 percent through the setting of conditions in the step.
In the scheme, the step of hydrolyzing the 2-methyl-4-aminobenzonitrile to obtain the 2-methyl-4-aminobenzoic acid comprises the following steps: adding 2-methyl-4-aminobenzonitrile, water and sodium hydroxide into a reaction vessel, heating to reflux reaction for 6-8h, cooling to room temperature after the reaction is finished, adjusting the pH value to 3-4 by hydrochloric acid, continuously stirring at 0-5 ℃ for crystallization, filtering, washing a filter cake with water, and drying to obtain the 2-methyl-4-aminobenzoic acid.
The molar ratio of the 2-methyl-4-aminobenzonitrile to the sodium hydroxide is 1.5-2. By strictly controlling conditions, side reactions are few, the yield of the step can reach 96%, and the purity of the step can reach 99.3%.
In the scheme, the sandmeyer bromination reaction is as follows: adding 2-methyl-4-aminobenzoic acid, hydrobromic acid and water into a reaction vessel, stirring for dissolving, cooling to 0-5 ℃, dropwise adding a sodium nitrite aqueous solution, continuously stirring for about 1h after dropwise adding, controlling the temperature to be 0-5 ℃, adding a copper bromide aqueous solution, heating to room temperature after adding, stirring until the reaction is complete, filtering, washing a filter cake with water, and drying to obtain the product.
The molar ratio of the 2-methyl-4-aminobenzoic acid to the sodium nitrite is 1.2-1.5, and the molar ratio of the 2-methyl-4-aminobenzoic acid to the copper bromide is 1.1-1.4. The method is a classical name reaction, the yield is up to 88 percent and the purity of the final product is more than 99.5 percent by controlling conditions
Has the beneficial effects that:
1) The raw material used in the invention is 3-methylaniline which is easy to obtain, the price is about 10 yuan per kilogram, and the cost is low. Phosphorus oxychloride, hydroxylamine hydrochloride, sodium formate, sodium hydroxide, sodium nitrite, copper bromide and the like used in the reaction process are conventional reagents, and have the advantages of low cost, easiness in obtaining and small toxic and side effects.
2) In the whole process steps of the invention, the used solvents are ethanol, DMF, formic acid and a large amount of water, which are conventional solvents, and the invention has the advantages of low cost, small toxic and side effects and convenient treatment.
3) The invention adopts elaborate design of process route, not only the selected raw materials are cheap and easy to obtain, the toxic and side effects are small, but also the whole reaction operation is easy, the used equipment only needs a conventional reaction kettle, no special equipment or special reagent is needed, and the industrial production is easy to realize.
4) The method has the advantages of high yield, high purity, high total yield, good product quality, low cost, no waste gas and solid waste discharge and contribution to environmental protection through the careful design of the conditions of each step of the reaction route.
Detailed Description
The present invention will be further described with reference to the following examples.
The reaction formula of the invention is:
example 1
Synthesis of Compound 2
Operation of the reaction
Under the protection of nitrogen, 600mL of DMF was added to a 2L three-necked flask. And controlling the temperature at 0-5 ℃, and dropwise adding 343g of phosphorus oxychloride into the system. Stirring is continued for 1 hour at 0-5 ℃ after the dropwise addition. The temperature was controlled at 0-5 ℃ and compound 1 200g was added in portions. After the addition, the cold pump was removed. The temperature is raised to 60-65 ℃ and the reaction is kept for 5-6 hours, and TLC (PE: EA = 3:1) detection is carried out until the raw materials disappear. Cooling to room temperature. The temperature was controlled at 0-5 ℃ and the above system was poured into 2L of ice water with stirring. Adjusting pH to 8-9 with 10% sodium hydroxide. Filtering, and washing a filter cake to obtain a yellow solid. Vacuum drying at 40 deg.C for 8 hr gave 220g of yellow solid in 87% yield and 99.5% purity.
Example 2
Synthesis of Compound 2
Under the protection of nitrogen, 600mL of ethanol is added into a 2L three-neck flask. And (3) dropwise adding 315g of phosphorus oxychloride into the system at the temperature of between 0 and 5 ℃. Stirring is continued for 1 hour at 0-5 ℃ after the dropwise addition is finished. The temperature was controlled at 0-5 ℃ and compound 1 200g was added in portions. After the addition, the cold pump was removed. The temperature is raised to 60-65 ℃ and the reaction is kept for 5-6 hours, and TLC (PE: EA = 3:1) detection is carried out until the raw materials disappear. Cooling to room temperature. The temperature was controlled at 0-5 ℃ and the above system was poured into 2L of ice water with stirring. Adjusting pH to 8-9 with 10% sodium hydroxide. Filtering, and washing a filter cake to obtain a yellow solid. Vacuum drying at 40 deg.C for 8 hr gave 216g of yellow solid in 85.4% yield and 99.5% purity.
Example 3
Synthesis of Compound 2
Under the protection of nitrogen, 600mL of DMF was added to a 2L three-necked flask. And (3) controlling the temperature to be 0-5 ℃, and dropwise adding 430g of phosphorus oxychloride into the system. Stirring is continued for 1 hour at 0-5 ℃ after the dropwise addition is finished. The temperature was controlled at 0-5 ℃ and compound 1 200g was added in portions. After the addition, the cold pump was removed. The temperature is raised to 60-65 ℃ and the reaction is kept for 5-6 hours, and TLC (PE: EA = 3:1) detection is carried out until the raw materials disappear. Cooling to room temperature. The temperature was controlled at 0-5 ℃ and the above system was poured into 2L of ice water with stirring. Adjusting pH to 8-9 with 10% sodium hydroxide. Filtering, and washing a filter cake to obtain a yellow solid. Vacuum drying at 40 deg.C for 8 hr gave 218g of yellow solid in 86.2% yield and 99.5% purity.
Example 4
Synthesis of Compound 3
Operation of the reaction
In a 2L three-neck flask, compound 2 200g, ethanol 800ml and hydroxylamine hydrochloride 103g are added in sequence, after the addition, the temperature is raised and the reflux is carried out for 3-4 hours, and TLC (PE: EA = 2:1) detection is carried out until the raw materials disappear. Cooling to 0-5 deg.C, and stirring for half an hour. And (5) filtering. Forced air drying at 60 ℃ for 4 hours gave 211g of a yellow solid in 95% yield and 99.8% purity.
Example 5
Synthesis of Compound 3
Operation of the reaction
In a 2L three-neck flask, compound 2 200g, DMF800ml and hydroxylamine hydrochloride 123.6g are added in sequence, after the addition, the temperature is raised and the reflux is carried out for 3-4 hours, and TLC (PE: EA = 2:1) detection is carried out until the raw materials disappear. Cooling to 0-5 deg.C, and stirring for half an hour. And (4) filtering. Air-blast drying at 60 ℃ for 4 hours gave 208g of yellow solid in 93.6% yield and 99.8% purity.
Example 6
Synthesis of Compound 4
Material proportioning
| Name of material | Molecular weight | Molar weight of | Molecular ratio of | Feed amount | Univalent (kilogram) |
| Compound 3 | 150.08 | 1.33mol | 1 | 200g | |
| Sodium formate | 68.01 | 2mol | 1.5 | 136g | |
| Formic acid | 800ml |
Operation of the reaction
In a 2L three-necked flask, 3 200g of compound, 800ml of formic acid and 136g of sodium formate were sequentially added. The temperature is raised to 100 ℃ for reaction for 3-4 hours, and TLC (PE: EA = 3:1) detection is carried out until the raw material disappears. Cooling to room temperature. The formic acid is removed by concentration under reduced pressure. 2L of tap water was added to the system and stirring was continued for 1 hour. Filtering and washing a filter cake with water. Forced air drying at 60 ℃ for 4 hours gave 163g of yellow solid in 93% yield, purity, 99.8%, H NMR (300MHz, DMSO-d 6): 2.28 (3H, s), 6.04 (2H, bs), 6.44 (1H, m), 6.48 (1H, m), 7.31 (1H, m).
Example 7
Synthesis of Compound 4
Material proportioning
| Name of material | Molecular weight | Molar weight of | Molecular ratio | Feed amount | Univalent (kilogram) |
| Compound 3 | 150.08 | 1.33mol | 1 | 200g | |
| Sodium formate | 68.01 | 2.66mol | 2 | 180.8g | |
| Formic acid | 800ml |
Operation of the reaction
In a 2L three-neck flask, 3 200g of compound, 800ml of formic acid and 3242 g of sodium formate 180.8g are added in sequence. The temperature is raised to 100 ℃ for reaction for 3-4 hours, and TLC (PE: EA = 3:1) detection is carried out until the raw material disappears. Cooling to room temperature. The formic acid is removed by concentration under reduced pressure. 2L of tap water was added to the system and stirring was continued for 1 hour. Filtering and washing a filter cake with water. Forced air drying at 60 ℃ for 4 hours gave 158g of a yellow solid in 90.7% yield, purity, 99.8%, H NMR (300MHz, DMSO-d 6): 2.28 (3H, s), 6.04 (2H, bs), 6.44 (1H, m), 6.48 (1H, m), 7.31 (1H, m).
Example 8
Synthesis of Compound 5
Material proportioning
Operation of the reaction
In a 1L three-necked flask, 132g of the compound 4, 600g of tap water and 60g of sodium hydroxide were sequentially charged. The reaction was warmed to reflux for 6-8 hours and monitored by TLC (PE: EA = 1:1) until the starting material disappeared. Cooling to room temperature. And adding 10% hydrochloric acid dropwise while stirring to adjust the pH value to 3-4. Stirring was continued for 1 hour at 0-5 ℃. Filtering and washing a filter cake with water. Air-blast drying at 60 ℃ for 4 hours gave 145g of a yellow solid in 96% yield and 99.3% purity. HNMR (300MHz, CD3OD) 7.80 (d, J =8.4Hz,1H, H6), 7.48 (s, 1H, H3), 7.42 (d, J =8.4Hz,1H, H5), 2.56 (s, 3H, CH3)
Example 9
Synthesis of Compound 5
Material proportioning
Operation of the reaction
In a 1L three-necked flask, 132g of the compound 4, 600g of tap water and 80g of sodium hydroxide were sequentially charged. The reaction was warmed to reflux for 6-8 hours and monitored by TLC (PE: EA = 1:1) until the starting material disappeared. And cooling to room temperature. And adding 10% hydrochloric acid dropwise while stirring to adjust the pH value to 3-4. Stirring was continued for 1 hour at 0-5 ℃. Filtering and washing a filter cake with water. Air-blast drying at 60 ℃ for 4 hours gave 146g of yellow solid in 96.6% yield and 99.3% purity. HNMR (300MHz, CD3OD) 7.80 (d, J =8.4Hz,1H, H6), 7.48 (s, 1H, H3), 7.42 (d, J =8.4Hz,1H, H5), 2.56 (s, 3H, CH3)
Example 10
Synthesis of Compound 6
Material proportioning
Operation of the reaction
In a 2L three-necked flask, 5 100g of the compound, 300ml of hydrobromic acid and 500ml of tap water were sequentially added, and the mixture was stirred to dissolve. Cooling to 0-5 deg.C. 120mL of an aqueous solution of 54.8g of sodium nitrite was slowly added dropwise at 0 to 5 ℃ while controlling the temperature (the addition time was about 1 hour). After the dropwise addition, stirring was continued at 0-5 ℃ for 1 hour. 400ml of an aqueous solution of 162g of copper bromide was added to the above system while controlling the temperature at 0 to 5 ℃. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight. Filtering and washing a filter cake with water. Air-blast drying at 60 ℃ for 4 hours gave 124g of a yellow solid in 88% yield and 99.5% purity. H-NMR (300MHz, DMSO-d6,) 11.79 (1H, brs, COOH), 7.63 (1H, dd, J =9.2,2.8Hz, C6-H), 6.38 (2H, m, C3, 5-H), 2.41 (3H, s, CH1).
Example 11
Synthesis of Compound 6
Material proportioning
Operation of the reaction
In a 2L three-necked flask, 5 100g of the compound, 300ml of hydrobromic acid and 500ml of tap water were sequentially added, and the mixture was stirred to dissolve. Cooling to 0-5 deg.C. 120mL of an aqueous solution of 68.3g of sodium nitrite was slowly added dropwise at 0 to 5 ℃ while controlling the temperature (the addition time was about 1 hour). After the dropwise addition, stirring was continued at 0-5 ℃ for 1 hour. 400ml of an aqueous solution of 206g of copper bromide was added to the above system while controlling the temperature at 0-5 ℃. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight. Filtering and washing a filter cake with water. Air-blast drying at 60 ℃ for 4 hours gave 126g of a yellow solid in 89.4% yield and 99.5% purity. H-NMR (300MHz, DMSO-d6,) 11.79 (1H, brs, COOH), 7.63 (1H, dd, J =9.2,2.8Hz, C6-H), 6.38 (2H, m, C3, 5-H), 2.41 (3H, s, CH1).
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (11)
1. A synthetic method of 4-bromo-2-methylbenzoic acid as an intermediate of Freund Lei Lana is characterized by comprising the following steps: the method comprises the following steps of taking 3-methylaniline as a raw material, firstly formylating the 3-methylaniline with phosphorus oxychloride to generate 2-methyl-4-aminobenzaldehyde, then reacting with hydroxylamine hydrochloride to generate oxime, dehydrating the oxime to obtain 2-methyl-4-aminobenzonitrile, hydrolyzing the 2-methyl-4-aminobenzonitrile to obtain 2-methyl-4-aminobenzoic acid, and finally carrying out Sandmeyer bromination reaction to obtain 4-bromo-2-methylbenzoic acid, wherein the reaction formula is as follows:
2. the method for synthesizing 4-bromo-2-methylbenzoic acid as an intermediate of Fr Lei Lana as claimed in claim 1, wherein the operating steps of the formylation reaction of 3-methylaniline and phosphorus oxychloride are as follows:
under the protection of nitrogen, adding a reaction solvent into a reaction container, controlling the temperature to be 0-5 ℃, dropwise adding phosphorus oxychloride into the system, after dropwise adding, continuously stirring and reacting for 1h at the temperature of 0-5 ℃, adding 3-methylaniline in batches at the temperature of 0-5 ℃, after adding, heating to 60-65 ℃ for reacting for 5-6h, detecting until the raw materials disappear, cooling to room temperature, adding ice water at the temperature of 0-5 ℃, adjusting the pH to be 8-9, filtering, washing a filter cake with water, and drying to obtain a yellow solid.
3. The method of synthesizing 4-bromo-2-methylbenzoic acid as an intermediate of Fr Lei Lana as claimed in claim 2, wherein: the reaction solvent is DMF or ethanol, and the molar ratio of the 3-methylaniline to the phosphorus oxychloride is 1:1-1.5.
4. A process for the synthesis of 4-bromo-2-methylbenzoic acid as an intermediate in accordance with any one of claims 1 to 3 of french Lei Lana, wherein the reaction of 2-methyl-4-aminobenzaldehyde with hydroxylamine hydrochloride comprises the steps of: sequentially adding 2-methyl-4-aminobenzaldehyde, a solvent and hydroxylamine hydrochloride into a reaction vessel, heating and refluxing for 3-4h after the addition is finished, completely reacting, cooling to 0-5 ℃, continuously stirring until the crystallization is complete, filtering, washing a filter cake with the solvent, and drying to obtain the product.
5. The method for synthesizing the intermediate 4-bromo-2-methylbenzoic acid of claim 4 in the form of a Fr Lei Lana, which comprises the following steps: the molar ratio of the 2-methyl-4-aminobenzaldehyde to the hydroxylamine hydrochloride is 1:1-1.2, and the solvent is ethanol or DMF.
6. The method for synthesizing 4-bromo-2-methylbenzoic acid as an intermediate of Fr Lei Lana of claim 5, wherein the step of dehydrating an oxime to obtain 2-methyl-4-aminobenzonitrile comprises: adding oxime, formic acid and sodium formate into a reaction vessel, heating to 100 ℃ for reaction for 3-4h, cooling to room temperature after the reaction is finished, removing the formic acid by decompression and concentration, adding water into the system, continuously stirring for crystallization, filtering, washing a filter cake with water, and drying to obtain the 2-methyl-4-aminobenzonitrile.
7. The process of synthesizing 4-bromo-2-methylbenzoic acid as an intermediate in accordance with claim 6 of fr Lei Lana, wherein the molar ratio of oxime to sodium formate is 1.5 to 2.
8. The method for synthesizing 4-bromo-2-methylbenzoic acid as an intermediate of Fr Lei Lana as claimed in claim 6, wherein the step of hydrolyzing 2-methyl-4-aminobenzonitrile to obtain 2-methyl-4-aminobenzoic acid comprises: adding 2-methyl-4-aminobenzonitrile, water and sodium hydroxide into a reaction vessel, heating to reflux reaction for 6-8h, cooling to room temperature after the reaction is finished, adjusting the pH value to 3-4 by hydrochloric acid, continuously stirring at 0-5 ℃ for crystallization, filtering, washing a filter cake with water, and drying to obtain the 2-methyl-4-aminobenzoic acid.
9. The method for synthesizing the intermediate 4-bromo-2-methylbenzoic acid of claim 8, which is an intermediate of f Lei Lana, wherein the method comprises the following steps: the molar ratio of the 2-methyl-4-aminobenzonitrile to the sodium hydroxide is 1.5-2.
10. The method of synthesizing 4-bromo-2-methylbenzoic acid as an intermediate of f Lei Lana as claim 8, wherein said sandmeyer bromination reaction is: adding 2-methyl-4-aminobenzoic acid, hydrobromic acid and water into a reaction vessel, stirring for dissolving, cooling to 0-5 ℃, dropwise adding a sodium nitrite aqueous solution, continuously stirring for about 1h after dropwise adding, controlling the temperature to be 0-5 ℃, adding a copper bromide aqueous solution, heating to room temperature after adding, stirring until the reaction is complete, filtering, washing a filter cake with water, and drying to obtain the product.
11. The method of synthesizing 4-bromo-2-methylbenzoic acid as an intermediate in accordance with claim 1 of fr Lei Lana, wherein: the molar ratio of the 2-methyl-4-aminobenzoic acid to the sodium nitrite is 1.2-1.5, and the molar ratio of the 2-methyl-4-aminobenzoic acid to the copper bromide is 1.1-1.4.
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| CN101437804A (en) * | 2006-03-10 | 2009-05-20 | 辉瑞产品公司 | Dibenzyl amine compounds and derivatives |
| CN101500995A (en) * | 2006-03-17 | 2009-08-05 | 美国政府卫生与公共服务部 | 1-oxo-isoindoline compounds for the treatment of spinal muscular atrophy and other uses |
| CN109928890A (en) * | 2017-12-15 | 2019-06-25 | 重庆常捷医药有限公司 | A kind of preparation method of tolvaptan intermediate 2- methyl -4-N- (2- toluyl) benzoic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101437804A (en) * | 2006-03-10 | 2009-05-20 | 辉瑞产品公司 | Dibenzyl amine compounds and derivatives |
| CN101500995A (en) * | 2006-03-17 | 2009-08-05 | 美国政府卫生与公共服务部 | 1-oxo-isoindoline compounds for the treatment of spinal muscular atrophy and other uses |
| CN109928890A (en) * | 2017-12-15 | 2019-06-25 | 重庆常捷医药有限公司 | A kind of preparation method of tolvaptan intermediate 2- methyl -4-N- (2- toluyl) benzoic acid |
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