CN117088785A - Preparation method of 4-amino-2-methylbenzoic acid - Google Patents
Preparation method of 4-amino-2-methylbenzoic acid Download PDFInfo
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- CN117088785A CN117088785A CN202311045487.0A CN202311045487A CN117088785A CN 117088785 A CN117088785 A CN 117088785A CN 202311045487 A CN202311045487 A CN 202311045487A CN 117088785 A CN117088785 A CN 117088785A
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- Prior art keywords
- methylbenzoic acid
- amino
- reaction
- solvent
- methylacetanilide
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- XRSQZFJLEPBPOZ-UHFFFAOYSA-N 4-amino-2-methylbenzoic acid Chemical compound CC1=CC(N)=CC=C1C(O)=O XRSQZFJLEPBPOZ-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 239000002994 raw material Substances 0.000 claims abstract description 33
- AQPDTYYKDYMCTH-UHFFFAOYSA-N 4-acetamido-2-methylbenzoic acid Chemical compound CC(=O)NC1=CC=C(C(O)=O)C(C)=C1 AQPDTYYKDYMCTH-UHFFFAOYSA-N 0.000 claims abstract description 31
- ALMHSXDYCFOZQD-UHFFFAOYSA-N n-(3-methylphenyl)acetamide Chemical compound CC(=O)NC1=CC=CC(C)=C1 ALMHSXDYCFOZQD-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
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 239000002841 Lewis acid Substances 0.000 claims abstract description 10
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims abstract description 4
- 230000003197 catalytic effect Effects 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- 239000000047 product Substances 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000012295 chemical reaction liquid Substances 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 17
- 230000008569 process Effects 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 15
- 239000005457 ice water Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 230000008034 disappearance Effects 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- 238000012544 monitoring process Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- 238000010025 steaming Methods 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 238000002386 leaching Methods 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 238000011010 flushing procedure Methods 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- GYHCTFXIZSNGJT-UHFFFAOYSA-N tolvaptan Chemical compound CC1=CC=CC=C1C(=O)NC(C=C1C)=CC=C1C(=O)N1C2=CC=C(Cl)C=C2C(O)CCC1 GYHCTFXIZSNGJT-UHFFFAOYSA-N 0.000 abstract description 4
- 229960001256 tolvaptan Drugs 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000000052 comparative effect Effects 0.000 description 9
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- XXXOBNJIIZQSPT-UHFFFAOYSA-N 2-methyl-4-nitrobenzoic acid Chemical compound CC1=CC([N+]([O-])=O)=CC=C1C(O)=O XXXOBNJIIZQSPT-UHFFFAOYSA-N 0.000 description 2
- RGHJWZADAWEIFE-UHFFFAOYSA-N 4-amino-2-methylbenzonitrile Chemical compound CC1=CC(N)=CC=C1C#N RGHJWZADAWEIFE-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229940071125 manganese acetate Drugs 0.000 description 2
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- GPZXFICWCMCQPF-UHFFFAOYSA-N 2-methylbenzoyl chloride Chemical compound CC1=CC=CC=C1C(Cl)=O GPZXFICWCMCQPF-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZBHHWKBPSJWDBX-UHFFFAOYSA-N 4-amino-2-methylbenzaldehyde Chemical compound CC1=CC(N)=CC=C1C=O ZBHHWKBPSJWDBX-UHFFFAOYSA-N 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- 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
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 4-amino-2-methylbenzoic acid, in particular to a preparation method of a tolvaptan intermediate raw material 4-amino-2-methylbenzoic acid, wherein 3-methylaniline is used as a raw material, 3-methylacetanilide is prepared by acylating agent, 4-acetamido-2-methylbenzoic acid is prepared by performing Friedel-crafts acylation on 3-methylacetanilide and oxalyl chloride under a Lewis acid catalytic system, and finally the 4-acetamido-2-methylbenzoic acid is deprotected under alkaline condition and then acidified to obtain a target compound 4-amino-2-methylbenzoic acid.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 4-amino-2-methylbenzoic acid, in particular to a preparation method of a raw material 4-amino-2-methylbenzoic acid of a tolvaptan intermediate.
Background
2-methyl-4-N- (2-methylbenzoyl) benzoic acid is an important intermediate for the synthesis of tolvaptan. In the prior art, the 2-methyl-4-aminobenzoic acid and the o-methylbenzoyl chloride are usually acylated under the condition of an acid binding agent to prepare the 2-methyl-4-aminobenzoic acid, and the preparation method of the 2-methyl-4-N- (2-methylbenzoyl) benzoic acid is reported in the related art, but has a plurality of defects and is difficult to produce in a large scale.
As reported in CN109928890, 3-methylaniline is used as a raw material, firstly formylated with phosphorus oxychloride to produce 2-methyl-4-aminobenzaldehyde, then dehydrated with hydroxylamine hydrochloride in the presence of formic acid and sodium methoxide to obtain 2-methyl-4-aminobenzonitrile, and then hydrolyzed with sodium hydroxide to obtain 2-methyl-4-aminobenzonitrile. The reaction formula is as follows:
the total yield of the three-step reaction in the patent is only 71.93%, the purity of the product is 99.4%, and meanwhile, as hazardous materials such as phosphorus oxychloride, hydroxylamine hydrochloride, sodium methoxide and the like are used, the products of each step can enter the next step of working procedure only by separating and drying, and a large amount of ammonia nitrogen is brought to the hydrolysis of reaction solvents such as DMF, hydroxylamine hydrochloride and cyano, so that the three-waste treatment cost is greatly increased.
In addition, as CN104418803, 2-methyl-4-nitrobenzoic acid is used as raw material and reduced by reductant (tin dichloride, iron powder and zinc powder) to obtain 2-methyl-4-aminobenzoic acid with a reduction yield of 63.4-75.3%. The reaction formula is as follows:
the reaction steps in the patent are simple and well controlled, but the raw material of 2-methyl-4-nitrobenzoic acid is not easy to obtain and has high price.
As another example, CN113678831 reports the use of ortho-xylene as a starting material in sulfuric acid/NO 2 Intermediate 1 is prepared under the condition, intermediate 1, N-hydroxyphthalimide, nitric acid, cobalt chloride and manganese acetate are refluxed to prepare intermediate 2, and finally intermediate 2 is prepared under the condition of Raney nickel and 25% hydrazine hydrate to prepare intermediate 3, namely a target product. The reaction formula is as follows:
the patent relates to a nitration reaction liquid using reddish brown NO 2 As a nitro source, the production environment is poor, the requirements on equipment and facilities are high, and the use of heavy metal reagents such as manganese acetate, cobalt chloride and the like is involved; the intermediate 2 is reduced under the condition of Raney nickel/hydrazine hydrate to prepare a target product, and Raney nickel is easy to burn when being exposed in the air, has high price and is not beneficial to industrial production.
In view of the above, it is necessary to develop a process for preparing 4-amino-2-methylbenzoic acid which is simple in process conditions, safe and environment-friendly, has high recovery rate and is low in cost.
Disclosure of Invention
Aiming at the defects or improvement demands of the prior art, the invention provides a preparation method of a raw material 4-amino-2-methylbenzoic acid of a tolvaptan intermediate, which has the advantages of low-cost and easily obtained raw materials, low requirements on production equipment, simple process conditions, obvious cost advantage and easy implementation of industrial production.
In order to achieve the above object, the present invention provides a method for preparing 4-amino-2-methylbenzoic acid, comprising: 3-methylaniline is used as a raw material, the raw material is prepared into a formula II with an acylating agent, friedel-crafts acylation is carried out on the formula II and oxalyl chloride under a Lewis acid catalytic system to prepare a formula III, and finally the formula III is deprotected under alkaline conditions, and then acidized to obtain a target compound formula I, wherein the reaction formula is as follows:
wherein the compound of formula I is 4-amino-2-methylbenzoic acid, the compound of formula II is 3-methylacetanilide, and the compound of formula III is 4-acetamido-2-methylbenzoic acid.
The invention takes 3-methylaniline as raw material, the target product can be obtained in three steps, the used raw materials are safer and more accessible, the requirements on production equipment are not high, the preparation can be completed in a conventional reactor, the cost advantage is obvious, meanwhile, the invention creatively takes 4-acetamido-2-methylbenzoic acid as an important intermediate product, the reaction yield and the purity are both high, the target product can be obtained only by deprotection under alkaline condition and acidification, the process condition is simple, and the industrial production is easy.
Further, the preparation method specifically comprises the following steps:
(1) Preparation of 3-methylacetanilide: adding an acylating agent and a solvent A into a three-port reaction bottle, controlling the temperature to be 15-50 ℃ under the stirring state, starting to dropwise add 3-methylaniline, reacting for 15-20min at room temperature after the dropwise adding process has obvious heat release, flushing the reaction liquid into pre-cooled ice water after TLC monitoring the disappearance of the raw materials, stirring for 25-35min, adding a solvent B for extraction, adding the solvent B into the water phase for extraction again, merging the organic phase, decompressing and spin-drying, and steaming for 2-3 times by using a fresh solvent B to obtain 3-methylacetanilide;
(2) Preparation of 4-acetamido-2-methylbenzoic acid: sequentially adding 3-methylacetanilide, lewis acid and solvent C obtained in the step (1) into a three-port reaction bottle, stirring and cooling to 0-5 ℃, dropwise adding oxalyl chloride from a constant pressure dropping funnel, controlling the temperature to 0-5 ℃ after the dropwise adding is finished, reacting for 7-8 hours after TLC detects disappearance of raw materials, slowly pouring the reaction liquid into precooled ice water, heating the mixed liquid to 60-70 ℃, distilling at normal pressure to remove the solvent C, cooling to room temperature after the temperature reaches 70 ℃ and no liquid flows out, filtering to obtain a wet 4-acetamido-2-methylbenzoic acid product, and drying to obtain a dry 4-acetamido-2-methylbenzoic acid product;
(3) Preparation of 4-amino-2-methylbenzoic acid: adding the dry 4-acetamido-2-methylbenzoic acid and water obtained in the step (2) into a reaction bottle, then adding 30% sodium hydroxide solution to adjust the pH of the system to be alkaline, heating and refluxing, reacting for 22-26h, monitoring the TLC until the raw materials disappear, namely, cooling to room temperature, adjusting the pH of the system to be acidic by using concentrated hydrochloric acid, filtering, leaching a filter cake by using a proper amount of water to obtain a wet 4-amino-2-methylbenzoic acid product, and drying to obtain a finished 4-amino-2-methylbenzoic acid product. The invention has the advantages of fully reacting by strictly controlling the proportion of each raw material and the reaction condition, and effectively improving the production efficiency and the yield.
Further, in the step (1) of the above technical scheme, the acylating agent is acetic anhydride or acetyl chloride, and the molar ratio of the acylating agent to the 3-methylaniline is 0.9-1.1:1, preferably 1.01-1.1:1; more preferably 1.05:1; the solvent A is any one of glacial acetic acid, ethyl acetate, dichloromethane and dichloroethane, and further, the solvent A can also be other halogenated hydrocarbons, and the volume mass ratio of the solvent A to the acylating agent is 2-2.6:1.
Further, in the step (1) of the above technical scheme, the temperature of the acylation reaction is 20-30 ℃; the volume of the ice water is 6-7 times of that of the reaction liquid; the solvent B is any one of toluene, ethyl acetate and methylene dichloride.
Further, in the step (2) of the above technical scheme, the lewis acid is any one of anhydrous aluminum chloride, zinc chloride, ferric chloride and lithium chloride, preferably anhydrous aluminum chloride; the molar ratio of the Lewis acid to the 3-methylacetanilide is 1-5:1, preferably 2-4:1.
Further, in the step (2) of the above technical scheme, the solvent C is dichloromethane, and the volume ratio of dichloromethane to 3-methylacetanilide is 4-8:1.
Further, in the step (2) of the above technical scheme, the molar ratio of the oxalyl chloride to the 3-methylacetanilide is 1.10-2.00:1, preferably 1.10-1.5:1; the volume of the ice water is 4-6 times of that of the reaction liquid.
Further, in the step (3) of the technical scheme, the mass-volume ratio g/mL of the dry 4-acetamido-2-methylbenzoic acid and water is 1:1.
Further, in the step (3) of the technical scheme, the temperature is increased to 85-95 ℃ for reflux; the pH of the alkaline condition is more than or equal to 10, preferably the pH is 10-11; the pH of the acidic condition is 3-4. In the technical scheme, the reflux temperature and the reaction pH are strictly controlled, so that the reaction is smooth and full, and the yield and the purity are effectively improved.
Further, in the step (2) of the technical scheme, the drying temperature is 40-45 ℃; in the step (3), the drying temperature is 55-60 ℃.
Compared with the prior art, the invention has the beneficial effects that:
1. according to the invention, 3-methylaniline is used as a raw material, 3-methylacetanilide is prepared by using an acylating agent, 3-methylacetanilide and oxalyl chloride are subjected to Friedel-crafts acylation under a Lewis acid catalytic system to prepare 4-acetamido-2-methylbenzoic acid, and finally the 4-acetamido-2-methylbenzoic acid is deprotected under an alkaline condition, and then acidified to obtain a target compound 4-amino-2-methylbenzoic acid, wherein the raw material used in the preparation method is low in cost and easy to obtain, the requirements on production equipment are low, the process condition is simple, the safety coefficient is high, no three wastes such as ammonia nitrogen and the like are generated, the cost is low, and industrial production is easy to implement;
2. the invention creatively prepares the 4-acetamido-2-methylbenzoic acid firstly, and then only needs deprotection and acidification to obtain the target product, so that the process is simpler, no ammonia nitrogen waste liquid is generated, and the method is more environment-friendly;
3. by reasonably controlling the reaction conditions, the method has the advantages that the reaction of each step is complete, the purity is up to more than 99.8 percent, the yield is up to more than 90 percent, and the method has obvious cost advantage.
Detailed Description
The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials used in the following examples are all commercially available and commercially available unless otherwise specified.
The above technical features of the present invention and the technical features specifically described in the following (embodiment) may be combined with each other to form a new or preferred technical solution.
Example 1: preparation of 3-methylacetanilide (formula II)
Acetic anhydride (99 g,0.971 mol) and glacial acetic acid (200 mL) are added into a 500mL three-port reaction bottle, 3-methylaniline (100 g,0.933 mol) starts to be added dropwise under stirring at the temperature of 25 ℃, the dropwise adding process has obvious heat release, the dropwise adding process is completed, the reaction is carried out for 20min at the temperature of 25 ℃, after TLC monitors the disappearance of the raw materials, the reaction liquid is flushed into 2.5L of precooled ice water, toluene (100 mL) is added after stirring for 30min for extraction, toluene (100 mL) is added again for extraction of the water phase, the organic phases are combined and dried under reduced pressure, fresh toluene (50 mL/time) is used for steaming for 2 times, and 139.2g of dried materials (the yield is 100%) of 3-methylacetanilide is obtained, and can be directly used for the next reaction.
Example 2: preparation of 3-methylacetanilide (formula II)
Acetyl chloride (100 g, 0.980mol) and ethyl acetate (200 mL) are added into a 500mL three-port reaction bottle, 3-methylaniline (100 g,0.933 mol) starts to be added dropwise under stirring at the temperature of 30 ℃, the dropwise adding process has obvious heat release, the dropwise adding process is completed, the reaction is carried out for 15min at the temperature of 30 ℃, after TLC monitors the disappearance of the raw materials, the reaction liquid is flushed into 2.5L of precooled ice water, ethyl acetate (100 mL) is added after stirring for 30min for extraction and layering, ethyl acetate (100 mL) is added into the water phase for extraction again, the organic phases are combined for drying under reduced pressure, and fresh ethyl acetate (50 mL/time) is used for steaming for 2 times, so that 139.2g of dry material (the yield is 100%) is obtained, namely 3-methylacetanilide, and the reaction liquid can be directly used for the next reaction.
Example 3: preparation of 4-acetamido-2-methylbenzoic acid (formula III)
3-methylacetanilide (130 g,0.871 mol), anhydrous aluminum chloride (348 g,2.610 mol) and methylene dichloride (750 mL) obtained in example 1 are sequentially added into a 2L three-port reaction bottle, stirred and cooled to 0-5 ℃, oxalyl chloride (144 g,1.134 mol) is added dropwise from a constant pressure dropping funnel, the reaction is carried out for 8h at the temperature of 0 ℃ after the dropping, TLC detection of the disappearance of the raw materials is finished, the reaction liquid is slowly poured into 5L precooled ice water (slowly poured while stirring) after the reaction is finished, the mixed liquid is heated to 60-70 ℃ and distilled under normal pressure to remove methylene dichloride, after the temperature reaches 70 ℃ and no liquid flows out, the temperature is cooled to room temperature, a 4-acetamido-2-methylbenzoic acid wet product is obtained after filtration, 160g (the yield is 95.0% and the purity is 99.0%) is obtained after drying at 45 ℃.
Example 4: preparation of 4-acetamido-2-methylbenzoic acid (formula III)
3-methylacetanilide oil (130 g,0.871 mol) obtained in example 2, anhydrous zinc chloride (355 g,2.610 mol) and dichloromethane (750 ml) are sequentially put into a 2L three-port reaction bottle, stirred and cooled to 0-5 ℃, oxalyl chloride (144 g,1.134 mol) is added dropwise from a constant pressure dropping funnel, the reaction is carried out for 7h at a temperature of 5 ℃ after the completion of the dripping, TLC detects the disappearance of the raw materials, the reaction liquid is slowly poured into 5L precooled ice water (slowly poured while stirring) after the completion of the reaction, the mixed liquid is heated to 60-70 ℃, the dichloromethane is distilled and removed under normal pressure, after the temperature reaches 70 ℃ and no liquid flows out, the temperature is cooled to room temperature, a 4-acetamido-2-methylbenzoic acid wet product is obtained after filtration, 153.3g (yield is 91% and purity is 99.0%) is obtained after drying at 40 ℃.
Example 5: preparation of 4-amino-2-methylbenzoic acid (formula I)
A100 mL reaction flask was charged with the dry 4-acetamido-2-methylbenzoic acid product (20 g,0.104 mol) obtained in example 3 and water (20 mL), then a 30% sodium hydroxide solution was added to adjust the pH of the system to 10, the temperature was raised to 85℃for reflux, the reaction was carried out for 24 hours, TLC was monitored until the starting material disappeared, the reaction was completed, the temperature was reduced to room temperature, the pH of the system was adjusted to 3 with concentrated hydrochloric acid, filtration was carried out, the cake was rinsed with an appropriate amount of water to obtain a wet 4-amino-2-methylbenzoic acid product, and the wet 4-amino-2-methylbenzoic acid product was dried at 60℃to obtain 14.8g of a final product (pale yellow powdery solid, melting point 160-165 ℃, yield 95.0%, purity 99.8%). Wherein, the combined molar yield of the first two steps and the three steps is 90.25 percent.
Example 6: preparation of 4-amino-2-methylbenzoic acid (formula I)
The dry 4-acetamido-2-methylbenzoic acid (20 g,0.104 mol) obtained in example 4 and water (20 mL) were added to a 100mL reaction flask, then a 30% sodium hydroxide solution was added to adjust the pH of the system to 11, the temperature was raised to 95℃for reflux, the reaction was performed for 22 hours, TLC was monitored until the starting material disappeared, the reaction was completed, the temperature was reduced to room temperature, the pH of the system was adjusted to 4 with concentrated hydrochloric acid, filtration was performed, the filter cake was rinsed with an appropriate amount of water to obtain a wet 4-amino-2-methylbenzoic acid product, and the wet 4-amino-2-methylbenzoic acid product was dried at 55℃to obtain 14.8g of a final product (pale yellow powder solid, melting point 160-165 ℃, yield 95.0%, purity 99.8%). Wherein, the combined molar yield of the first two steps and the three steps is 86.45 percent.
Comparative example 1: preparation of 3-methylacetanilide (formula II)
Acetic anhydride (99 g,0.971 mol) and glacial acetic acid (200 mL) are added into a 500mL three-port reaction bottle, 3-methylaniline (100 g,0.933 mol) starts to be added dropwise under stirring at the temperature of 60 ℃, the dropwise adding process has obvious heat release, the dropwise adding process is completed, the reaction is carried out for 20min at the temperature of 60 ℃, after TLC monitors the disappearance of the raw materials, the reaction liquid is flushed into 2.5L of precooled ice water, toluene (100 mL) is added after stirring for 30min for extraction, toluene (100 mL) is added again for extraction of the water phase, the organic phases are combined, the organic phases are dried under reduced pressure in a spinning mode, and fresh toluene (50 mL/time) is used for steaming for 2 times, so that 114.1g (yield 80.0%) of oily substance, namely 3-methylacetanilide oil is obtained.
Comparative example 2: preparation of 4-acetamido-2-methylbenzoic acid (formula III)
3-methylacetanilide oil (130 g,0.871 mol), anhydrous aluminum chloride (348 g,2.610 mol) and dichloromethane (750 mL) obtained in example 1 are sequentially added into a 2L three-port reaction bottle, stirred and cooled to 0-5 ℃, oxalyl chloride (144 g,1.134 mol) is added dropwise from a constant pressure dropping funnel, the reaction is carried out for 8 hours at a temperature of 10 ℃ after the dropping, TLC detects the disappearance of the raw materials, the reaction liquid is slowly poured into 5L precooled ice water (slowly poured while stirring) after the reaction is finished, the mixed liquid is heated to 60-70 ℃, the dichloromethane is distilled off under normal pressure, after the temperature reaches 70 ℃ and no liquid flows out, the temperature is cooled to room temperature, a wet 4-acetamido-2-methylbenzoic acid product is obtained after filtration, 144.8g (the yield is 86.0% and the purity is 97.0%) is obtained after drying at 45 ℃.
Comparative example 3: preparation of 4-amino-2-methylbenzoic acid (formula I)
The dry 4-acetamido-2-methylbenzoic acid (20 g,0.104 mol) obtained in example 3 and water (20 mL) are added into a 100mL reaction bottle, then 30% sodium hydroxide solution is added to adjust the pH of the system to 9, the temperature is raised to 85 ℃ for reflux, the reaction lasts 24 hours, a large amount of obvious raw materials still fail to react completely after TLC monitoring, the temperature is reduced to room temperature, the pH of filtrate is adjusted to 3 by concentrated hydrochloric acid after filtration, filtration and a filter cake is leached by a proper amount of water to obtain a wet 4-amino-2-methylbenzoic acid product, 8.57g of finished product (pale yellow powder solid, melting point 160-165 ℃, yield 55% and purity 98.3%) is obtained after drying at 60 ℃. Wherein, the combined molar yield of the first two steps and the three steps is 52.25 percent.
Comparative example 4: preparation of 4-amino-2-methylbenzoic acid (formula I)
The dry 4-acetamido-2-methylbenzoic acid (20 g,0.104 mol) obtained in example 3 and water (20 mL) are added into a 100mL reaction bottle, then 30% sodium hydroxide solution is added to adjust the pH of the system to 10, the temperature is raised to 80 ℃ for reflux, the reaction lasts 24 hours, the obvious raw materials still exist after TLC monitoring, the temperature is reduced to room temperature, the pH of the filtrate is adjusted to 3 by concentrated hydrochloric acid after filtration, filtration and filter cake leaching by proper amount of water are carried out, thus obtaining wet 4-amino-2-methylbenzoic acid, and 12.8g (pale yellow powder solid, melting point 160-165 ℃, yield 82.2% and purity 99.5%) of finished product is obtained after drying at 60 ℃. Wherein, the combined molar yield of the first two steps and the three steps is 78.1 percent.
Comprehensive conclusion:
as can be seen from the results of examples 1-2 and comparative example 1, the yield of 3-methylacetanilide obtained by the preparation method of the present invention can reach 100%, while when the reaction temperature is further increased, the yield is lowered, and the product is an oil, which also shows that the reaction temperature is too high and by-products are formed, which is not suitable for the reaction, from the viewpoint of monitoring the reaction liquid TLC.
As can be seen from the results of examples 3 to 4 and comparative example 2, the yield of 4-acetamido-2-methylbenzoic acid obtained by the preparation method of the present invention can reach 95% or more, and when the reaction temperature is further increased, the yield is greatly reduced, which mainly produces para-position products but does not produce 4-acetamido-2-methylbenzoic acid, indicating that the reaction temperature is critical for the production of 4-acetamido-2-methylbenzoic acid.
As can be seen from the results of examples 5 to 6 and comparative examples 3 to 4, the yield of 4-amino-2-methylbenzoic acid prepared by the preparation method of the present invention can reach 95% or more, the purity is 99.8% or more, and in comparative example 3, when the reaction pH is lowered to 9, the reaction is difficult to be completely carried out, the yield is very low, which indicates that the pH is very important for the reaction; when the reaction temperature was lowered in comparative example 4, the raw materials remained in the reaction system, and the yield was lowered, indicating that the reaction was insufficient at too low a temperature.
Finally, it should be emphasized that the foregoing description is merely illustrative of the preferred embodiments of the invention, and that various changes and modifications can be made by those skilled in the art without departing from the spirit and principles of the invention, and any such modifications, equivalents, improvements, etc. are intended to be included within the scope of the invention.
Claims (10)
1. A method for preparing 4-amino-2-methylbenzoic acid, which is characterized by comprising the following steps: 3-methylaniline is used as a raw material, the raw material is prepared into a formula II with an acylating agent, friedel-crafts acylation is carried out on the formula II and oxalyl chloride under a Lewis acid catalytic system to prepare a formula III, and finally the formula III is deprotected under alkaline conditions, and then acidized to obtain a target compound formula I, wherein the reaction formula is as follows:
wherein the compound of formula I is 4-amino-2-methylbenzoic acid, the compound of formula II is 3-methylacetanilide, and the compound of formula III is 4-acetamido-2-methylbenzoic acid.
2. The method for preparing 4-amino-2-methylbenzoic acid according to claim 1, which is characterized by comprising the following steps:
(1) Preparation of 3-methylacetanilide: adding an acylating agent and a solvent A into a three-port reaction bottle, controlling the temperature to be 15-50 ℃ under the stirring state, starting to dropwise add 3-methylaniline, reacting for 15-20min at room temperature after the dropwise adding process has obvious heat release, flushing the reaction liquid into pre-cooled ice water after TLC monitoring the disappearance of the raw materials, stirring for 25-35min, adding a solvent B for extraction, adding the solvent B into the water phase for extraction again, merging the organic phase, decompressing and spin-drying, and steaming for 2-3 times by using a fresh solvent B to obtain 3-methylacetanilide;
(2) Preparation of 4-acetamido-2-methylbenzoic acid: sequentially adding 3-methylacetanilide, lewis acid and solvent C obtained in the step (1) into a three-port reaction bottle, stirring and cooling to 0-5 ℃, dropwise adding oxalyl chloride from a constant pressure dropping funnel, controlling the temperature to 0-5 ℃ after the dropwise adding is finished, reacting for 7-8 hours after TLC detects disappearance of raw materials, slowly pouring the reaction liquid into precooled ice water, heating the mixed liquid to 60-70 ℃, distilling at normal pressure to remove the solvent C, cooling to room temperature after the temperature reaches 70 ℃ and no liquid flows out, filtering to obtain a wet 4-acetamido-2-methylbenzoic acid product, and drying to obtain a dry 4-acetamido-2-methylbenzoic acid product;
(3) Preparation of 4-amino-2-methylbenzoic acid: adding the dry 4-acetamido-2-methylbenzoic acid and water obtained in the step (2) into a reaction bottle, then adding 30% sodium hydroxide solution to adjust the pH of the system to be alkaline, heating and refluxing, reacting for 22-26h, monitoring the TLC until the raw materials disappear, namely, cooling to room temperature, adjusting the pH of the system to be acidic by using concentrated hydrochloric acid, filtering, leaching a filter cake by using a proper amount of water to obtain a wet 4-amino-2-methylbenzoic acid product, and drying to obtain a finished 4-amino-2-methylbenzoic acid product.
3. The process for the preparation of 4-amino-2-methylbenzoic acid according to claim 2, wherein in step (1), the acylating agent is acetic anhydride or acetyl chloride, the molar ratio of the acylating agent to the 3-methylaniline being 0.9-1.1:1, preferably 1.01-1.1:1; the solvent A is any one of glacial acetic acid, ethyl acetate, dichloromethane and dichloroethane, and the volume mass ratio of the solvent A to the acylating agent is 2-2.6:1.
4. The method for producing 4-amino-2-methylbenzoic acid according to claim 2, wherein in the step (1), the temperature of the acylation reaction is 20 to 30 ℃; the volume of the ice water is 6-7 times of that of the reaction liquid; the solvent B is any one of toluene, ethyl acetate and methylene dichloride.
5. The method for preparing 4-amino-2-methylbenzoic acid according to claim 2, wherein in the step (2), the lewis acid is any one of anhydrous aluminum chloride, zinc chloride, ferric chloride and lithium chloride, preferably anhydrous aluminum chloride; the molar ratio of the Lewis acid to the 3-methylacetanilide is 1-5:1, preferably 2-4:1.
6. The method for producing 4-amino-2-methylbenzoic acid according to claim 2, wherein in the step (2), the solvent C is methylene chloride, and the volume ratio of the methylene chloride to the 3-methylacetanilide is 4-8:1.
7. The process for the preparation of 4-amino-2-methylbenzoic acid according to claim 2, characterized in that in step (2), the molar ratio of oxalyl chloride to 3-methylacetanilide is 1.10-2.00:1, preferably 1.10-1.5:1; the volume of the ice water is 4-6 times of that of the reaction liquid.
8. The method for producing 4-amino-2-methylbenzoic acid according to claim 2, wherein in the step (3), the mass/volume ratio g/mL of the dry 4-acetamido-2-methylbenzoic acid to water is 1:1.
9. The process for producing 4-amino-2-methylbenzoic acid according to claim 2, wherein in the step (3), the reflux is carried out by raising the temperature to 85 to 95 ℃; the pH of the alkaline condition is more than or equal to 10, preferably the pH is 10-11; the pH of the acidic condition is 3-4.
10. The method for producing 4-amino-2-methylbenzoic acid according to claim 2, wherein in the step (2), the drying temperature is 40 to 45 ℃; in the step (3), the drying temperature is 55-60 ℃.
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