CN110204450B - Synthesis method of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate - Google Patents
Synthesis method of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate Download PDFInfo
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- FUYMYLYDBVWEHG-UHFFFAOYSA-N 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone;hydrate;hydrochloride Chemical compound O.Cl.NC1=CC=C(Cl)C=C1C(=O)C(F)(F)F FUYMYLYDBVWEHG-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 238000001308 synthesis method Methods 0.000 title claims abstract description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 26
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 23
- 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 abstract description 22
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 20
- 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 abstract description 20
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 20
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 239000011777 magnesium Substances 0.000 claims abstract description 16
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 7
- 238000005917 acylation reaction Methods 0.000 claims abstract description 5
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 5
- 239000011261 inert gas Substances 0.000 claims abstract description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 230000002194 synthesizing effect Effects 0.000 claims description 17
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- WXBWKMLIVXELSF-UHFFFAOYSA-N 2,2,2-trifluoro-n,n-dimethylacetamide Chemical compound CN(C)C(=O)C(F)(F)F WXBWKMLIVXELSF-UHFFFAOYSA-N 0.000 claims description 6
- 150000001448 anilines Chemical class 0.000 claims description 6
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 5
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims description 5
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 5
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 4
- VMVNZNXAVJHNDJ-UHFFFAOYSA-N methyl 2,2,2-trifluoroacetate Chemical compound COC(=O)C(F)(F)F VMVNZNXAVJHNDJ-UHFFFAOYSA-N 0.000 claims description 4
- 229950009390 symclosene Drugs 0.000 claims description 4
- AOPBDRUWRLBSDB-UHFFFAOYSA-N 2-bromoaniline Chemical compound NC1=CC=CC=C1Br AOPBDRUWRLBSDB-UHFFFAOYSA-N 0.000 claims description 3
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 claims description 3
- ZKQDCIXGCQPQNV-UHFFFAOYSA-N Calcium hypochlorite Chemical compound [Ca+2].Cl[O-].Cl[O-] ZKQDCIXGCQPQNV-UHFFFAOYSA-N 0.000 claims description 3
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 3
- CODXZFSZJFCVBE-UHFFFAOYSA-N n,n-diethyl-2,2,2-trifluoroacetamide Chemical compound CCN(CC)C(=O)C(F)(F)F CODXZFSZJFCVBE-UHFFFAOYSA-N 0.000 claims description 3
- SATVIFGJTRRDQU-UHFFFAOYSA-N potassium hypochlorite Chemical compound [K+].Cl[O-] SATVIFGJTRRDQU-UHFFFAOYSA-N 0.000 claims description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 64
- 239000002994 raw material Substances 0.000 abstract description 11
- 238000009776 industrial production Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- 238000004809 thin layer chromatography Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- KNVQTRVKSOEHPU-UHFFFAOYSA-N o-Chloroacetanilide Chemical compound CC(=O)NC1=CC=CC=C1Cl KNVQTRVKSOEHPU-UHFFFAOYSA-N 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- XJDANTDMTCZGNQ-UHFFFAOYSA-N n-(2-chlorophenyl)-2,2-dimethylpropanamide Chemical compound CC(C)(C)C(=O)NC1=CC=CC=C1Cl XJDANTDMTCZGNQ-UHFFFAOYSA-N 0.000 description 6
- CLZQAQVPPKCQIV-UHFFFAOYSA-N n-chloro-n-(2-chlorophenyl)acetamide Chemical compound CC(=O)N(Cl)C1=CC=CC=C1Cl CLZQAQVPPKCQIV-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 229960003804 efavirenz Drugs 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 230000006957 competitive inhibition Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 2
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 239000002912 waste gas Substances 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 229910020323 ClF3 Inorganic materials 0.000 description 1
- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical group C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- XGLLQDIWQRQROJ-UHFFFAOYSA-N methyl 3,3,3-trifluoro-2-oxopropanoate Chemical compound COC(=O)C(=O)C(F)(F)F XGLLQDIWQRQROJ-UHFFFAOYSA-N 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- -1 nucleoside triphosphates Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000006490 viral transcription Effects 0.000 description 1
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- 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
-
- 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
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/02—Compounds containing nitrogen-to-halogen bonds
- C07C239/06—N-halogenated carboxamides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
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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 synthesis method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the invention comprises the following steps: dissolving o-haloaniline in an organic solvent, adding alkali, then adding an acylating agent, and carrying out an acylation reaction on the o-haloaniline and the acylating agent under an alkaline condition to obtain a compound I; performing chlorination reaction on a compound I and a chlorinating agent under a weak alkaline condition to obtain a compound II; in an inert gas environment, reacting a compound II with magnesium to obtain a Grignard reagent intermediate, and reacting the Grignard reagent intermediate with a trifluoroacetic acid derivative to obtain a compound III; reacting the compound III with concentrated hydrochloric acid to obtain 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate. The method has mild reaction conditions, easily obtained raw materials and low cost, and the prepared target product has the total yield of 80.35 percent and the purity of 99.8 percent and is suitable for industrial production.
Description
Technical Field
The invention relates to a synthesis method of an efavirenz intermediate, in particular to a synthesis method of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate.
Background
Efavirenz was developed and produced by Mossando, under the chemical name 4(S) -6-Chloro-4- (cyclopropylacetylene) -4- (trifluoromethyl) -benzo-1, 4-dihydrooxazol-2-one, under the chemical name (4S) -6-Chloro-4- (cyclopropyrethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one, and under the molecular formula C14H9ClF3NO2Molecular weight is 315.68, CAS registry number 154598-52-4. Efavirenz is the first-line anti-HIV drug of choice, belonging to the selective non-nucleoside reverse transcriptase inhibitor (NNRTIS) of human immunodeficiency virus-1 type (HIV-1), acting on templates, primers or nucleoside triphosphates by non-competitive binding and inhibition of HIV-1 Reverse Transcriptase (RT) activity, with a small portion of competitive inhibition, thereby preventing viral transcription and replication. EfavirenzIs used for treating adults, adolescents and children infected by HIV-1 by combining with other antiviral drugs, and has become one of the main medicines of the cocktail therapy at present due to good curative effect, low toxicity and low side effect.
The 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate is a key intermediate of the anti-AIDS drug efavirenz, and a plurality of synthetic methods are reported in documents. For example, the literature Tetrahedron (1991, 3207), j. org. chem.63(23) (1998, 8536-8543), US5932726 and US05925789 report the synthesis of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate starting from p-chloroaniline; chinese patent CN106496051 reports the synthesis of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate using aniline as a starting material, all of which use n-butyllithium which is expensive and highly dangerous, and chinese patent CN102675125B reports that although n-butyllithium is not used in the preparation method, methyl trifluoropyruvate or ethyl ester is used in the reaction, which is more expensive than n-butyllithium.
In addition, the method reported in the Chinese patent CN106518636A has the disadvantages of easily available raw materials and low price, but relates to three dangerous processes of format, nitration and hydrogenation, and has huge risk on production.
Disclosure of Invention
The invention aims to solve the problems of expensive raw materials and high production risk, and aims to provide a synthesis method of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate, which has cheap and easily obtained raw materials and mild reaction conditions.
The invention provides a method for synthesizing 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate, which is characterized by comprising the following steps:
dissolving o-haloaniline in an organic solvent, adding alkali, then adding an acylating agent, and carrying out acylation reaction on the o-haloaniline and the acylating agent under an alkaline condition to obtain a compound I, wherein the structural formula of the compound I is shown in the specification
Step two, adopting a compound I and a chlorinating agentPerforming chlorination reaction under alkalescent condition to obtain a compound II, wherein the structural formula of the compound II is shown in the specification
Step three, in an inert gas environment, reacting a compound II with magnesium to obtain a Grignard reagent intermediate, and reacting the Grignard reagent intermediate with a trifluoroacetic acid derivative to obtain a compound III, wherein the structural formula of the Grignard reagent intermediate is shown in the specification
The structural formula of the compound III is
Step four, reacting the compound III with concentrated hydrochloric acid to obtain 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate, wherein the structural formula of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate is shown in the specification
In the synthesis method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the invention, the method can also have the following characteristics: wherein, in the step one, the o-halogenated aniline is any one of o-chloroaniline, o-bromoaniline and o-iodoaniline.
In the synthesis method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the invention, the method can also have the following characteristics: wherein, the alkali in the first step is sodium hydroxide or potassium hydroxide.
In the synthesis method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the invention, the method can also have the following characteristics: wherein, the acylating agent in the step one is any one of straight chain acylating agents or branched chain acylating agents with the carbon number not more than 5, including acetic anhydride, acetyl chloride, propionyl chloride, valeryl chloride and pivaloyl chloride.
In the synthesis method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the invention, the method can also have the following characteristics: wherein, in the step one, the mol ratio of the o-halogenated aniline to the acylating agent is 1: 1-1: 1.3.
in the synthesis method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the invention, the method can also have the following characteristics: wherein, the organic solvent in the first step is any one of benzene, toluene and methyl tert-butyl ether.
In the synthesis method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the invention, the method can also have the following characteristics: wherein, the chlorinating agent in the second step is any one of trichloroisocyanuric acid, hypochlorous acid, sodium hypochlorite, potassium hypochlorite and calcium hypochlorite.
In the synthesis method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the invention, the method can also have the following characteristics: wherein, the molar ratio of the compound II, the magnesium and the trifluoroacetic acid derivative in the third step is 1:1: 1-1: 1.3: 1.3.
In the synthesis method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the invention, the method can also have the following characteristics: wherein, the trifluoroacetyl derivative in the third step is any one of ethyl trifluoroacetate, methyl trifluoroacetate, trifluoroacetyldimethylamine and trifluoroacetyldiethylamine.
In the synthesis method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the invention, the method can also have the following characteristics: wherein, the concentration of the concentrated hydrochloric acid in the step four is 30 to 35 percent.
Action and Effect of the invention
According to the preparation method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate, o-haloaniline reacts with an acylating agent to obtain a compound I through amino protection, the compound I is chlorinated to obtain a compound II, the compound II reacts with metal magnesium to obtain a Grignard reagent intermediate, the Grignard reagent intermediate reacts with a trifluoroacetic acid derivative to obtain a compound III, the compound III and concentrated hydrochloric acid are subjected to reflux reaction to obtain a target product, namely the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate, the total yield of the target product is higher than 80.35% in terms of o-haloaniline, and the purity can reach more than 99.8% through High Performance Liquid Chromatography (HPLC) detection.
In addition, compared with the expensive n-butyl lithium, methyl trifluoroacetate or ethyl ester, the adopted raw materials such as o-haloaniline, acylating agent and chlorinating agent are easy to obtain and have low price.
In addition, the preparation method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the invention is adopted, so that the yield of each step is over 90 percent, no waste gas is generated, and the solvent in the organic phase can be recycled, so that the pollution is small, a special waste liquid treatment procedure is not required, and the cost is reduced.
Therefore, the preparation method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the invention does not involve nitration reaction and hydrogenation reaction, has mild reaction conditions, is simple to operate, easily obtains used raw materials, has low cost, can obtain the target product with the total yield of 80.35 percent and the purity of more than 99.8 percent, has good product quality, and is suitable for industrial production.
Drawings
FIG. 1 is a diagram showing the results of HPLC analysis of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate in the first example of the present invention; and
FIG. 2 is a diagram showing the results of high performance liquid chromatography detection of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate in example II of the present invention.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the following examples and the accompanying drawings specifically describe the synthesis method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate.
The raw materials and reagents used in the following examples were purchased from conventional biochemical reagent stores, unless otherwise specified.
The reaction route of the invention is as follows:
the invention provides a synthesis method of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate, which specifically comprises the following steps:
adding o-haloaniline, alkali and an acylating agent into an organic solvent, and carrying out an acylation reaction on the o-haloaniline and the acylating agent under an alkaline condition to obtain a compound I;
secondly, performing chlorination reaction on the compound I and a chlorinating agent under a weak alkaline condition to obtain a compound II;
reacting the compound II with magnesium in an inert gas environment to obtain a Grignard reagent intermediate, and reacting the Grignard reagent intermediate with a trifluoroacetic acid derivative to obtain a compound III;
and step four, reacting the compound III with concentrated hydrochloric acid to obtain 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate.
Dissolving o-haloaniline and alkali in an organic solvent in the first step, and adding an acylating agent at 0-20 ℃, wherein the o-haloaniline is any one of o-chloroaniline, o-bromoaniline and o-iodoaniline; the alkali is sodium hydroxide or potassium hydroxide; the acylating agent is any one of acetic anhydride, acetyl chloride, propionyl chloride, valeryl chloride and pivaloyl chloride; the organic solvent is any one of benzene, toluene and methyl tert-butyl ether, preferably methyl tert-butyl ether; the mol ratio of the o-halogenated aniline to the acylating agent is 1: 1-1: 1.3, preferably 1: 1.08; the molar ratio of the o-halogenated aniline to the sodium hydroxide or the potassium hydroxide is 1: 1-1: 2.
in addition, the weak base in the second step is sodium bicarbonate; the chlorinating agent is any one of trichloroisocyanuric acid, hypochlorous acid, sodium hypochlorite, potassium hypochlorite and calcium hypochlorite.
In addition, in the third step, the compound II and magnesium chips are dissolved in an organic solvent, and react at the reaction temperature of 0-100 ℃, preferably 10-30 ℃ to obtain the Grignard reagent intermediate, and the reaction temperature of the Grignard reagent intermediate and the trifluoroacetic acid derivative is-10 ℃, preferably 0-5 ℃. The trifluoroacetyl derivative is any one of ethyl trifluoroacetate, methyl trifluoroacetate, trifluoroacetyldimethylamine and trifluoroacetyldiethylamine; the molar ratio of the compound II to the magnesium to the trifluoroacetic acid derivative is 1:1: 1-1: 1.3:1.3, and the preferable ratio is 1:1.1: 1.1. The organic solvent in the third step is one or more of tetrahydrofuran, methyl tert-butyl ether, benzene, toluene, hexane and heptane.
In addition, in the fourth step, the compound III and concentrated hydrochloric acid are subjected to reflux reaction at the temperature of 60-65 ℃, and the concentration of the concentrated hydrochloric acid is 30-35%.
In the examples of the present invention, the conditions used for High Performance Liquid Chromatography (HPLC) testing were the same.
< example one >
Step one, synthesis of a compound I, namely N- (2-chlorophenyl) acetamide, according to the following reaction equation:
in this embodiment, the specific operations are as follows:
adding 51.2g of o-chloroaniline and 150ml of methyl tert-butyl ether into a reaction bottle, stirring, dissolving, cooling to 0-5 ℃, adding 84g of 30% potassium hydroxide aqueous solution, stirring vigorously, dropwise adding 45g of acetic anhydride at 0-20 ℃, stirring for 3 hours after dropwise adding, reacting for 3 hours at 0-20 ℃, and sampling and detecting from the reaction solution. Detection by Thin Layer Chromatography (TLC), developing solvent is ethyl acetate: and (3) developing the color under 245nm ultraviolet with petroleum ether being 1:1, comparing with the o-chloroaniline serving as the raw material, and judging that the reaction is complete when the color development of the o-chloroaniline in the reaction liquid disappears.
Standing and layering after the reaction is finished, washing an organic layer twice, discarding a water phase, cooling the organic phase to 0-5 ℃, then preserving heat for 2 hours, performing suction filtration, washing a filter cake with a proper amount of water, performing vacuum drying on the filter cake after the suction filtration, and weighing to obtain 67g of N- (2-chlorophenyl) acetamide with the yield of 98.6% (calculated by taking o-chloroaniline as a standard).
In this example, the molar ratio of o-chloroaniline, acetic anhydride, and potassium hydroxide was 1:1.1: 1.11.
Step two, synthesizing a compound II, namely N-chloro-N- (2-chlorphenyl) acetamide, wherein the reaction equation is as follows:
in this embodiment, the specific operation of step two is as follows:
adding 34g of N- (2-chlorphenyl) acetamide and 1000ml of methyl tert-butyl ether into a reaction bottle, stirring for dissolving, adding a sodium bicarbonate aqueous solution prepared from 50.4g of sodium bicarbonate and 400ml of water, cooling to 0 ℃, adding 73.2g of trichloroisocyanuric acid for three times, reacting for 3 hours at 0-5 ℃, and sampling and detecting from the reaction solution. Detection by Thin Layer Chromatography (TLC), developing solvent is ethyl acetate: petroleum ether showed color development under 245nm UV light at 1:3, in contrast to N- (2-chlorophenyl) acetamide, and the reaction was considered complete when the color development of N- (2-chlorophenyl) acetamide in the reaction mixture disappeared.
After the reaction, filtering, standing and layering the filtrate to obtain an organic layer and a water layer. The organic layer was retained, the aqueous layer was extracted once with 200ml of methyl t-butyl ether, and the extracted methyl t-butyl ether was combined in the organic layer. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was distilled under reduced pressure in a water bath at 30 ℃ to remove methyl t-butyl ether, to give the product N-chloro-N- (2-chlorophenyl) acetamide, which was weighed at 38.1g and was obtained in 93.4% yield (based on N- (2-chlorophenyl) acetamide).
Step three, synthesizing a compound III, namely N-chloro-N- (2-trifluoroacetylphenyl) acetamide, wherein the reaction equation is as follows:
in this embodiment, the specific operations are as follows:
under the protection of nitrogen, 4g of magnesium chips and 15g of tetrahydrofuran were added into a reaction flask, and a mixed solution of 30.6g of N-chloro-N- (2-chlorophenyl) acetamide and 375mL of methyl tert-butyl ether was added dropwise. After about 10ml of the solution is dripped, bubbles are produced on the magnesium chips to indicate that the reaction starts, then the temperature is controlled to be 10-30 ℃, the remaining mixed solution is dripped for reaction, and after the dripping is finished, the temperature is kept at 10-30 ℃ for 3h for continuous reaction to obtain the Grignard reagent intermediate. After the heat preservation is finished, cooling to 0-5 ℃, slowly dropwise adding 23.4g of ethyl trifluoroacetate, and stirring for 30min after the dropwise adding is finished. Samples were taken every 10min and monitored by Thin Layer Chromatography (TLC) using ethyl acetate as developing solvent: petroleum ether showed a color development under 245nm uv, and the reaction was confirmed to be complete when the color development of N-chloro-N- (2-chlorophenyl) acetamide in the reaction mixture was almost disappeared in comparison with N-chloro-N- (2-chlorophenyl) acetamide.
After the reaction is completed, the temperature is controlled to be lower than-10 ℃, 75mL of water is dripped into the reaction liquid, then 1mol/L hydrochloric acid is used for regulating the pH value to be 2.5-3.5, the mixture is fully stirred and then separated into an aqueous layer and an organic layer, the organic layer is washed twice by water, and the solvent is distilled off from the washed organic layer under reduced pressure to obtain 38.1g of oily matter, namely a compound III, in the embodiment, N-chloro-N- (2-trifluoroacetylphenyl) acetamide, wherein the yield is 95.5 percent (calculated by taking N-chloro-N- (2-chlorophenyl) acetamide as a standard).
In this example, the molar ratio of N-chloro-N- (2-chlorophenyl) acetamide, magnesium turnings and ethyl trifluoroacetate was 1:1.11: 1.1.
Step four, synthesizing 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate, wherein the reaction equation is as follows:
in this embodiment, the specific operations are as follows:
26.6g of N-chloro-N- (2-trifluoroacetylphenyl) acetamide is added into a reaction bottle, then 52g of 35 percent hydrochloric acid is added, and the mixture is heated to 60 to 65 ℃ under vigorous stirring for reflux reaction for 5 hours. Samples were then taken and the developing solvent was monitored by Thin Layer Chromatography (TLC) as ethyl acetate: petroleum ether (1: 3) developed color under 245nm ultraviolet, and the reaction was confirmed to be completed when the color development of N-chloro-N- (2-trifluoroacetylphenyl) acetamide in the reaction mixture was almost disappeared in comparison with N-chloro-N- (2-trifluoroacetylphenyl) acetamide.
After the reaction is finished, 210g of acetic acid is added into the reaction solution, the temperature is continuously raised to 100-105 ℃ for reaction for 4h, then the temperature is lowered to 0 ℃ and the mixture is stirred for 2h, the filter cake is filtered, the ethyl acetate is used for washing for 2 times, the obtained solid is dried in vacuum at 50 ℃ to obtain 26.2g of the target product 4-chloro-2-trifluoroacetylanilide hydrochloride hydrate, and the yield is 94.2% (calculated by taking N-chloro-N- (2-trifluoroacetylphenyl) acetamide as a standard).
The obtained 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate was detected by High Performance Liquid Chromatography (HPLC), and the detection results are shown in FIG. 1.
FIG. 1 is a diagram showing the results of HPLC analysis of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate in the first example of the present invention.
As shown in fig. 1, there are a plurality of peak positions on the graph, and as compared with the retention time of the standard substance tested under the same conditions, the peak with the retention time of 7.364min is the peak of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate prepared in this example, and the purity of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate is 99.8655% by using the area normalization method.
< example two >
Step one, synthesizing a compound I, namely N- (2-chlorphenyl) pivaloamide, and obtaining a reaction formula as follows:
in this embodiment, the specific operations are as follows:
adding 51.2g of o-chloroaniline and 150ml of methyl tert-butyl ether into a reaction bottle, stirring, dissolving, cooling to 0-5 ℃, adding 60g of 30% sodium hydroxide aqueous solution, stirring vigorously, dropwise adding 53.5g of pivaloyl chloride at the temperature of 0-20 ℃, stirring for reacting for 3 hours at the temperature of 0-20 ℃ after dropwise adding is finished for about 3 hours, and sampling and detecting from the reaction solution. Detected by Thin Layer Chromatography (TLC), the developing solvent is ethyl acetate: petroleum ether showed color development under 245nm UV, and the reaction was considered complete when the color development of N- (2-chlorophenyl) acetamide in the reaction mixture disappeared as compared with the starting material N- (2-chlorophenyl) acetamide.
Standing and layering after the reaction is finished, washing an organic layer twice, discarding a water phase, cooling the organic phase to 0-5 ℃, then preserving heat for 2 hours, performing suction filtration, washing a filter cake with a proper amount of water, performing vacuum drying on the filter cake after the suction filtration, and weighing to obtain 83.2g of N- (2-chlorphenyl) pivaloyl amide with the yield of 98.2% (calculated by taking o-chloroaniline as a standard).
In this example, the molar ratio of o-chloroaniline, sodium hydroxide, and pivaloyl chloride was 1:1.12: 1.1.
Step two, synthesizing a compound II, namely N-chloro-N- (2-chlorphenyl) pivaloyl amide, wherein the reaction equation is as follows:
in this embodiment, the specific operation of step two is as follows:
adding 42.4g of N- (2-chlorphenyl) pivalic amide and 1000mL of methyl tert-butyl ether into a reaction bottle, stirring to dissolve, adding a sodium bicarbonate aqueous solution prepared from 50.4g of sodium bicarbonate and 400mL of water, cooling to 0 ℃, slowly adding a sodium hypochlorite aqueous solution prepared from 70g of sodium hypochlorite and 800mL of water, reacting at 0 ℃ for 3 hours, and sampling from a reaction solution for detection. Detected by Thin Layer Chromatography (TLC), the developing solvent is ethyl acetate: petroleum ether showed color development under 245nm UV, and the reaction was considered complete when the color development of N- (2-chlorophenyl) pivaloyl amide in the reaction mixture disappeared, as compared with N- (2-chlorophenyl) pivaloyl amide.
After the reaction, the mixture is kept still for layering to obtain an organic layer and a water layer. The organic layer was retained, the aqueous layer was extracted once with 200ml of methyl t-butyl ether, and the extracted methyl t-butyl ether was combined in the organic layer. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was subjected to distillation under reduced pressure in a water bath at 30 ℃ to remove methyl t-butyl ether, whereby N-chloro-N- (2-chlorophenyl) pivaloamide was obtained, and 45g was weighed, and the yield was 91.5% (based on N- (2-chlorophenyl) pivaloamide).
Step three, synthesizing a compound III, namely N-chloro-N- (2-trifluoroacetylphenyl) pivaloyl amide, wherein the reaction equation is as follows:
in this embodiment, the specific operations are as follows:
under the protection of nitrogen, 2.7g of magnesium chips and 10g of tetrahydrofuran are added into a reaction bottle, and a mixed solution prepared from 24.6g N-chloro-N- (2-chlorophenyl) pivaloyl amide and 250mL of methyl tert-butyl ether is added dropwise. After about 10ml of the solution is dripped, bubbles are produced on the magnesium chips to indicate that the reaction starts, then the temperature is controlled to be 10-30 ℃, the remaining mixed solution is dripped for reaction, and after the dripping is finished, the temperature is kept at 10-30 ℃ for 3h for continuous reaction to obtain the Grignard reagent intermediate. After the heat preservation is finished, cooling to 0-5 ℃, slowly dripping 15.6g of trifluoroacetyldimethylamine, and stirring for 30min after dripping. Samples were taken every 10min and monitored by Thin Layer Chromatography (TLC) using ethyl acetate as developing solvent: petroleum ether 1:3 developed color under 245nm uv, and when the color development of N-chloro-N- (2-chlorophenyl) pivaloyl amide in the reaction mixture was almost disappeared, it was found that the reaction was completed.
After the reaction, the temperature was controlled to be lower than-10 ℃, 50mL of water was dropped into the reaction solution, then the pH was adjusted to 2.5 to 3.5 with 1mol/L hydrochloric acid, the mixture was fully stirred and then separated into an aqueous layer and an organic layer, the organic layer was washed twice with water, and the solvent was distilled off under reduced pressure from the washed organic layer to obtain 29.1g of an oily substance, i.e., compound iii, which is N-chloro-N- (2-trifluoroacetylphenyl) pivalamide in the present example, with the yield of 95.34% (calculated using N-chloro-N- (2-chlorophenyl) pivalamide as a standard).
In this example, the molar ratio of N-chloro-N- (2-chlorophenyl) pivaloyl amide, magnesium turnings and trifluoroacetyldimethylamine was 1:1.11: 1.24.
Step four, synthesizing 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate, wherein the reaction equation is as follows:
in this embodiment, the specific operations are as follows:
30.8g of N-chloro-N- (2-trifluoroacetylphenyl) pivaloamide is added into a reaction bottle, then 52g of 35% hydrochloric acid is added, and the mixture is heated to 60-65 ℃ under vigorous stirring for reflux reaction for 5 hours. Samples were then taken and monitored by Thin Layer Chromatography (TLC) using ethyl acetate as the developing solvent: petroleum ether 1:3 developed color under 245nm ultraviolet, and when the color development of N-chloro-N- (2-trifluoroacetylphenyl) pivaloyl amide in the reaction mixture was substantially disappeared, the reaction was confirmed to be completed, as compared with N-chloro-N- (2-trifluoroacetylphenyl) pivaloyl amide.
After the reaction is finished, 210g of acetic acid is added into the reaction solution, the temperature is continuously raised to 100-105 ℃ for reaction for 4h, after the reaction is finished, the temperature is reduced to 0 ℃ and the stirring is carried out for 2h, the filtration is carried out, the filter cake is washed by ethyl acetate for 2 times, the obtained solid is dried in vacuum at 50 ℃ to obtain 26.2g of the target product 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate, and the yield is 94.2% (calculated by taking N-chloro-N- (2-trifluoroacetylphenyl) pivalamide as a standard).
The obtained 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate was detected by High Performance Liquid Chromatography (HPLC), and the detection results are shown in FIG. 2.
FIG. 2 is a diagram showing the results of HPLC analysis of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate in example II of the present invention.
As shown in fig. 2, there are a plurality of peak positions on the graph, and as compared with the retention time of the standard substance tested under the same conditions, the peak with the retention time of 7.366min is the peak of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate prepared in this example, and the purity of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate is 99.8372% by using the area normalization method.
Effects and effects of the embodiments
According to the preparation method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the embodiment of the invention, o-chloroaniline reacts with an acylating agent to obtain a compound I, the compound I is chlorinated to obtain a compound II, the compound II reacts with metal magnesium to obtain a Grignard reagent intermediate, the Grignard reagent intermediate reacts with a trifluoroacetic acid derivative to obtain a compound III, the compound III then reacts with concentrated hydrochloric acid in a reflux manner to obtain a target product, namely the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate, wherein the total yield of the target product is more than 80.35% in terms of o-chloroaniline, and the purity can reach more than 99.8% through HPLC detection.
In addition, the temperature of acylation reaction of o-chloroaniline and an acylating agent is 0-20 ℃, the reaction temperature of a compound I for chlorination to obtain a compound II is 0-5 ℃, the compound II and metal magnesium react at 10-30 ℃ to obtain a Grignard reagent intermediate, the Grignard reagent intermediate reacts with a trifluoroacetic acid derivative at 0-5 ℃ to obtain a compound III, the compound III and concentrated hydrochloric acid undergo reflux reaction at 60-65 ℃ to obtain a target product, and the required minimum temperature in the whole reaction treatment process is-10 ℃ and the maximum temperature is 105 ℃. According to the process conditions, the reaction conditions are mild, and the energy consumption is greatly reduced.
In addition, all the raw materials and reagents used, such as o-chloroaniline, trifluoroacetyldimethylamine, magnesium chips, methyl tert-butyl ether, tetrahydrofuran and the like, are common chemical raw materials, are easy to obtain, and have low cost.
In addition, due to the synthetic route of the invention, the yield of each step is more than 90%, no waste gas is generated, the solvent in the organic phase can be recycled, the pollution is low, and meanwhile, no special waste liquid treatment procedure is needed, and the cost is reduced.
Therefore, the preparation method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate provided by the embodiment of the invention has the advantages of mild reaction conditions, greatly reduced energy consumption, simple operation, less pollution, easily obtained raw materials, low cost, total yield of the prepared target product of 80.35 percent, purity of more than 99.8 percent, good product quality and suitability for industrial production.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (10)
1. The synthesis method of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate is characterized by comprising the following steps of:
dissolving o-haloaniline in an organic solvent, adding alkali, then adding an acylating agent, and carrying out acylation reaction on the o-haloaniline and the acylating agent under an alkaline condition to obtain a compound I, wherein the structural formula of the compound I is shown in the specification
Secondly, performing chlorination reaction on the compound I and a chlorinating agent under a weak alkaline condition to obtain a compound II, wherein the structural formula of the compound II is shown in the specification
Thirdly, reacting the compound II with magnesium in an inert gas environment to obtain a Grignard reagent intermediate, and reacting the Grignard reagent intermediate with a trifluoroacetic acid derivative to obtain a compound III, wherein the structural formula of the Grignard reagent intermediate is shown in the specification
The structural formula of the compound III is
Step four, reacting the compound III with concentrated hydrochloric acid to obtain 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate, wherein the structural formula of the 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate is shown in the specification
2. The method for synthesizing 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate according to claim 1, characterized in that:
wherein, in the step one, the o-halogenated aniline is any one of o-chloroaniline, o-bromoaniline and o-iodoaniline.
3. The method for synthesizing 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate according to claim 1, characterized in that:
wherein, the alkali in the first step is sodium hydroxide or potassium hydroxide.
4. The method for synthesizing 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate according to claim 1, characterized in that:
wherein, the acylating agent in the step one is any one of a straight chain acylating agent or a branched chain acylating agent with the carbon number not more than 5.
5. The method for synthesizing 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate according to claim 1, characterized in that:
wherein the mol ratio of the o-halogenated aniline to the acylating agent in the step one is 1: 1-1: 1.3.
6. the method for synthesizing 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate according to claim 1, characterized in that:
wherein, in the step one, the organic solvent is any one of benzene, toluene and methyl tert-butyl ether.
7. The method for synthesizing 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate according to claim 1, characterized in that:
and in the second step, the chlorinating agent is any one of trichloroisocyanuric acid, hypochlorous acid, sodium hypochlorite, potassium hypochlorite and calcium hypochlorite.
8. The method for synthesizing 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate according to claim 1, characterized in that:
wherein, the molar ratio of the compound II, the magnesium and the trifluoroacetic acid derivative in the third step is 1:1: 1-1: 1.3: 1.3.
9. The method for synthesizing 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate according to claim 1, characterized in that:
wherein, in the third step, the trifluoroacetyl derivative is any one of ethyl trifluoroacetate, methyl trifluoroacetate, trifluoroacetyldimethylamine and trifluoroacetyldiethylamine.
10. The method for synthesizing 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate according to claim 1, characterized in that:
wherein, the concentration of the concentrated hydrochloric acid in the step four is 30 to 35 percent.
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