CN113979887A - Synthetic method of aromatic amine carboxylic acid derivative - Google Patents
Synthetic method of aromatic amine carboxylic acid derivative Download PDFInfo
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- CN113979887A CN113979887A CN202111635561.5A CN202111635561A CN113979887A CN 113979887 A CN113979887 A CN 113979887A CN 202111635561 A CN202111635561 A CN 202111635561A CN 113979887 A CN113979887 A CN 113979887A
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- -1 aromatic amine carboxylic acid derivative Chemical class 0.000 title claims abstract description 76
- 238000010189 synthetic method Methods 0.000 title claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 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 7
- 238000006243 chemical reaction Methods 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000012452 mother liquor Substances 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 230000000171 quenching effect Effects 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- FKTXDTWDCPTPHK-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical group FC(F)(F)[C](F)C(F)(F)F FKTXDTWDCPTPHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims 1
- 241000607479 Yersinia pestis Species 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000012074 organic phase Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- TYKYOECSZNCUBC-UHFFFAOYSA-N 5-benzamido-2-fluorobenzoic acid Chemical compound C1=C(F)C(C(=O)O)=CC(NC(=O)C=2C=CC=CC=2)=C1 TYKYOECSZNCUBC-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- PIANCHDAVNRLDV-UHFFFAOYSA-N 2,5-dichloro-4-(1,1,2,3,3,3-hexafluoropropoxy)aniline Chemical compound NC1=CC(Cl)=C(OC(F)(F)C(F)C(F)(F)F)C=C1Cl PIANCHDAVNRLDV-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 150000008430 aromatic amides Chemical class 0.000 description 1
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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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 discloses a synthetic method of aromatic amine carboxylic acid derivatives, which comprises the following steps: s1: preparation of compound iii: the structural formula of the compound III is(ii) a S2: preparation of Compound IV: the structural formula of the compound IV is(ii) a S3: preparation of Compound V: the structural formula of the compound V is(ii) a S4: preparation of Compound VI: the structural formula of the compound VI is(ii) a S5: preparation of compound viii: the structural formula of the compound VIII is
Description
Technical Field
The invention belongs to the technical field of synthesis of aromatic amide derivatives, and particularly relates to a synthesis method of aromatic amine carboxylic acid derivatives.
Background
The prior art discloses methods for synthesizing various amide derivatives having agricultural pest control effects, respectively. Although the conventional synthesis methods and the types of amide derivatives have been disclosed in the prior patents, the disclosed types are not comprehensive enough, and the preparation methods, yields, routes and the like have many disadvantages.
Disclosure of Invention
The present invention has been made in an effort to solve the above-mentioned problems occurring in the background art by devising and disclosing a number of novel aromatic amine carboxylic acid derivatives having an effect of controlling pests and providing a method for synthesizing the aromatic amine carboxylic acid derivatives.
The invention provides a synthetic route of aromatic amine carboxylic acid derivatives, which comprises the following steps:
the first step is as follows:
the second step is that:
the third step:
the fourth step:
the fifth step:
in order to achieve the purpose, the invention provides the following technical scheme: a synthetic method of aromatic amine carboxylic acid derivatives is characterized in that: the method comprises the following steps in sequence:
s1: preparation of compound iii: dissolving a compound I in dichloromethane, adding a compound II to react in the presence of alkali, and then sequentially washing, extracting, washing and drying to obtain a compound III;
s2: preparation of Compound IV: dissolving the compound III obtained in the step in tetrahydrofuran, adding LiHMDS under the protection of nitrogen, and then adding R1Reacting, and then sequentially carrying out quenching reaction, extraction, water washing and drying to obtain a compound IV;
s3: preparation of Compound V: adding the compound IV and sodium hydroxide in the steps into water for reaction, adding 1N hydrochloric acid aqueous solution after the reaction is finished, adjusting the pH to be =2, and performing suction filtration to obtain a compound V;
s4: preparation of Compound VI: adding the compound V in the step into thionyl chloride for reaction, and evaporating unreacted thionyl chloride from mother liquor under negative pressure after the reaction is finished to obtain a compound VI;
s5: preparation of compound viii: dissolving the compound VI and the compound VII obtained in the step in acetonitrile, reacting in the presence of alkali, and then sequentially extracting, washing with water, drying and purifying to obtain a compound VIII;
wherein the structural formula of the compound I isThe structural formula of the compound II isThe structural formula of the compound III isThe structural formula of the compound IV is(ii) a The structural formula of the compound V isThe structural formula of the compound VI isThe structural formula of the compound VII isThe structural formula of the compound VIII isAnd R is1Comprises one of H, Me, Et, n-Pr, n-Bu, acetyl and propionyl; r2Including phenyl, 4-fluorophenyl, 6- (trifluoromethyl) -3-pyridyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl, 2, 6-difluorophenyl, 3, 5-difluorophenyl, 2, 3-difluorophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-chloro-2-pyridyl, 6-chloro-3-pyridyl, 5-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, Me, CF3, Et, N-Pr, i-Pr, N-ethyl-N-methylaminocarbonyl, N-ethyl-aminocarbonyl, 2,2, 2-trifluoroethylaminocarbonyl, N-methyl-2-pyridyl, N-methyl-3-pyridyl, N-ethyl-aminocarbonyl, N-methyl-2-pyridyl, N-methyl-pyridyl, N-ethyl-2-pyridyl, 3-pyridyl, 2-cyano-pyridyl, N-methyl-2-pyridyl, N-methyl-pyridyl, N-ethyl-2-pyridyl, N-methyl-ethyl-2-pyridyl, N-ethyl-2-pyridyl, One of N- (2,2, 2-trifluoroethyl) -N-methylaminocarbonyl, 4-nitrophenyl and methoxymethyl; x1Including F, Cl, Br, I; x2Comprises one of H, Cl, Me and CF 3; x3Comprises one of H, Cl, Br and 3-chloro-5- (trifluoromethyl) pyridine-2-oxyl; x4Comprises one of 1,1,2, 2-tetrafluoroethoxy, 1,2,3,3, 3-hexafluoropropoxy, 1, 2-trifluoro-2-trifluoromethoxy-ethoxy, 2-chloro-4- (trifluoromethyl) phenoxy, 3-chloro-5- (trifluoromethyl) pyridine-2-oxy, Cl, F and heptafluoroisopropyl; x5One of H, Cl; x6Comprises one of H, Cl, F and Br.
Preferably, in step S1, the reaction conditions are 0 ℃, the reaction is carried out for 12h, the washing is performed with 1N hydrochloric acid aqueous solution, the extraction is performed with ethyl acetate, and the drying is performed with anhydrous sodium sulfate.
In any of the above schemes, preferably, in step S2, the reaction time is 1h, the quenching reaction is completed by adding acetic acid at 0 ℃, the extraction is performed by using ethyl acetate, and the drying is performed by using anhydrous sodium sulfate.
In any of the above schemes, preferably, in step S3, the reaction is performed under stirring at 60 ℃ for 2 h.
In any of the above schemes, preferably, in step S4, the reaction conditions are 75 ℃ stirring reaction for 2 h.
In any of the above schemes, preferably, in step S5, the reaction conditions are 110 ℃ for 3 h.
In any of the above schemes, preferably, in step S5, the extracting is performed with ethyl acetate, the drying is performed with anhydrous sodium sulfate, and the purifying is performed as a crude product by a silica gel column chromatography.
In any of the above schemes, preferably, in step S1, the base is one of pyridine, triethylamine, sodium hydroxide, and potassium hydroxide, but is not limited to the above three.
The invention has the technical effects and advantages that: the invention designs and synthesizes brand-new aromatic amine carboxylic acid derivatives, which provides resources for finding better pest control drugs with higher cost performance, and has the advantages of easily obtained raw materials, reasonable route design and easy industrialization; the invention discloses a plurality of brand-new compounds and preparation processes thereof, the compounds also have excellent pest control effect, and the preparation method is simple, high in yield and low in cost.
Detailed Description
The following will clearly and completely describe the technical solutions in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
This example is given by X1=F,R2= phenyl group as an example, but the present invention is not limited to this example.
Synthesis of 5-benzamido-2-fluoro-ethyl benzoate:
dissolving 5-amino-2-fluoro-ethyl benzoate (400 mg, 2.184 mmol, 1 equiv) in dichloromethane, sequentially adding benzoyl chloride (306.95 mg, 2.184 mmol, 1 equiv), pyridine (345.5 mg, 4.368 mmol, 2 equiv) at 0 ℃, stirring at room temperature for 12h after the addition is finished, detecting by TLC (PE/EA =3:1, Rf = 0.5), adding 20ml of 1N hydrochloric acid aqueous solution to wash an organic phase, extracting with ethyl acetate, combining the organic phases, washing with water once, drying the organic phase with anhydrous sodium sulfate, evaporating the solvent under negative pressure, and purifying a crude product by a silica gel column (PE/EA =3: 1) to obtain 5-benzamido-2-fluoro-ethyl benzoate (600 mg, 96%) as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 10.48 (s, 1H), 8.35 (m, 1H), 8.06 (m, 1H), 8.01-7.95 (m, 2H), 7.65-7.51 (m, 3H), 7.35 (m, 1H), 4.34 (m, 2H), 1.32 (m, 3H)。
LCMS: (ESI, m/z): [M+1]+= 288.1。
Example 2
This example is given by X1=F,R2= phenyl, R1By way of example, Me is described, but the present invention is not limited to this example.
Synthesis of ethyl 2-fluoro-5- (N-methylbenzamido) benzoate:
dissolving 5-benzamido-2-fluoro-ethyl benzoate (1 g, 3.481 mmol, 1 equiv) in tetrahydrofuran (10ml), cooling to-78 ℃ with liquid nitrogen under the protection of nitrogen, starting to dropwise add LiHMDS (0.87 g, 5.221 mmol, 1.5 equiv), after dropwise addition, dropwise adding methyl iodide (0.74 g, 5.221 mmol, 1.5 equiv), after 10 min, stirring at room temperature for reaction for 1h, detecting by TLC (PE/EA =4:1, Rf = 0.5), after reaction, adding 2ml acetic acid at 0 ℃ for quenching reaction, extracting ethyl acetate, combining organic phases, washing once with water, drying the organic phases with anhydrous sodium sulfate, evaporating the solvent under negative pressure, purifying the crude product by a silica gel column (PE/EA =4: 1) to obtain 2-fluoro-5- (N-methylbenzamido) ethyl benzoate (750 mg, 72%) yellow oily liquid.
1H NMR (400 MHz, Chloroform-d) δ 7.69 (m, 1H), 7.32-7.26 (m, 3H), 7.21 (m, 2H), 7.12 (m, 1H), 6.96 (m, 1H), 4.36 (m, 2H), 3.49 (s, 3H), 1.37 (m, 3H)。
LCMS: (ESI, m/z): [M+1]+= 302.0。
Example 3
This example is given by X1=F,R2= phenyl, R1By way of example, Me is described, but the present invention is not limited to this example.
Synthesis of 2-fluoro-5- (N-methylbenzamido) benzoic acid
Adding ethyl 2-fluoro-5- (N-methylbenzamido) benzoate (750 mg, 2.489 mmol, 1 equiv) and sodium hydroxide (199.11 mg, 4.978 mmol, 2 equiv) into water (10ml), stirring for reaction for 2h at 60 ℃, cooling to room temperature after TLC (PE/EA =1:1, Rf = 0.4) detection reaction is finished, adding 1N hydrochloric acid aqueous solution to adjust pH =2, extracting with ethyl acetate, washing an organic phase with water, drying with anhydrous sodium sulfate, and evaporating the solvent under negative pressure to obtain 2-fluoro-5- (N-methylbenzamido) benzoic acid (620 mg, 91%) yellow oily liquid.
1H NMR (400 MHz, Chloroform-d) δ 7.79 (m, 1H), 7.34-7.27 (m, 3H), 7.25-7.16 (m, 3H), 7.01 (m, 1H), 3.51 (s, 3H)。
LCMS: (ESI, m/z): [M+1]+= 274.0。
Example 4
This example is given by X1=F,X2=H,X3=Cl,X4=1,1,2,3,3, 3-hexafluoropropoxy, X5=H,X6=Cl,R2= phenyl, R1By way of example, Me is described, but the present invention is not limited to this example.
Synthesis of N- [2, 5-dichloro-4- (1,1,2,3,3, 3-hexafluoropropoxy) phenyl ] -2-fluoro-5- (N-methylbenzamido) benzamide
Adding 2-fluoro-5- (N-methylbenzamido) benzoic acid (50 mg, 0.183 mmol, 1 equiv) into thionyl chloride (1 ml), stirring and reacting at 75 ℃ for 2h, evaporating redundant thionyl chloride from the obtained mother liquor under negative pressure, and directly using the mother liquor for the next reaction without purification. 2, 5-dichloro-4- (1,1,2,3,3, 3-hexafluoropropoxy) aniline (42.02 mg, 0.128 mmol, 0.7 equiv) was dissolved in acetonitrile (1 ml), and KI (6.07 mg, 0.037 mmol, 0.2 equiv) and triethylamine (37.03 mg, 0.366 mmol, 2.0 equiv) were added in that order. At room temperature, the acyl chloride acetonitrile solution obtained in the previous step is added dropwise, and the reaction is carried out for 3 hours at the temperature of 110 ℃. After the reaction is finished, cooling to room temperature, adding water, extracting by ethyl acetate, washing an organic phase by water, drying by anhydrous sodium sulfate, evaporating the solvent under negative pressure, and purifying a crude product by a chromatographic silica gel column (PE/EA =9: 1) to obtain N- [2, 5-dichloro-4- (1,1,2,3,3, 3-hexafluoropropoxy) phenyl ] -2-fluoro-5- (N-methylbenzamide) benzamide (50.66 mg, 68%) as a white solid.
1H NMR (400 MHz, Chloroform-d) δ 9.11 (m, 1H), 8.82 (s, 1H), 7.99 (m, 1H), 7.44 (m, 1H), 7.35-7.27 (m, 3H), 7.26-7.15 (m, 3H), 7.06 (m, 1H), 5.08 (m, 1H), 3.52 (s, 3H)。
LCMS: (ESI, m/z): [M+1]+= 583.0。
Example 5:
this example is given by X1=F,R2= phenyl, R1Description will be made with = H as an example, but the present invention is not limited to this example.
Synthesis of 5-benzamido-2-fluoro-benzoic acid
Adding 5-benzamido-2-fluoro-benzoic acid ethyl ester (300 mg, 1.044 mmol, 1 equiv) and sodium hydroxide (62.65 mg, 1.566 mmol, 1.5 equiv) into water (3 ml), stirring for reaction for 2h at 60 ℃, cooling to room temperature after TLC (PE/EA =1:1, Rf = 0.3) detection reaction is finished, adding 1N hydrochloric acid aqueous solution to adjust pH =2, and performing suction filtration to obtain 5-benzamido-2-fluoro-benzoic acid (235.5 mg, 87%) as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 10.45 (s, 1H), 8.34 (m, 1H), 8.07-7.91 (m, 3H), 7.56 (m, 3H), 7.31 (m, 1H)。
LCMS: (ESI, m/z): [M+1]+= 260.1。
Example 6
This example is given by X1=F,X2=H,X3=Cl,X4=1,1,2,3,3, 3-hexafluoropropoxy, X5=H,X6=Cl,R2= phenyl, R1Description will be made with = H as an example, but the present invention is not limited to this example.
Synthesis of 5-benzamido-N- [2, 5-dichloro-4- (1,1,2,3,3, 3-hexafluoropropoxy) phenyl ] -2-fluorobenzamide
5-benzamido-2-fluoro-benzoic acid (50 mg, 0.193 mmol, 1 equiv) is added into thionyl chloride (1 ml), the mixture is stirred and reacted for 2h at 75 ℃, and the obtained mother liquor is directly used for the next reaction without purification after excessive thionyl chloride is evaporated under negative pressure. 2, 5-dichloro-4- (1,1,2,3,3, 3-hexafluoropropoxy) aniline (44.29 mg, 0.135 mmol, 0.7 equiv) was dissolved in acetonitrile (1 ml), and KI (6.40 mg, 0.039 mmol, 0.2 equiv) and triethylamine (39.04 mg, 0.386 mmol, 2.0 equiv) were added in that order. At room temperature, the acyl chloride acetonitrile solution obtained in the previous step is added dropwise, and the reaction is carried out for 3 hours at the temperature of 110 ℃. After the reaction is finished, cooling to room temperature, adding water, extracting by ethyl acetate, washing an organic phase by water, drying by anhydrous sodium sulfate, evaporating the solvent under negative pressure, and purifying a crude product by a chromatographic silica gel column (PE/EA =9: 1) to obtain 5-benzamido-N- [2, 5-dichloro-4- (1,1,2,3,3, 3-hexafluoropropoxy) phenyl ] -2-fluorobenzamide (47.5 mg, 62%) as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 10.51 (s, 1H), 10.19 (s, 1H), 8.25 (m, 1H), 8.19 (s, 1H), 8.09-7.95 (m, 3H), 7.79 (m, 1H), 7.67-7.51 (m, 3H), 7.41 (m, 1H), 6.60 (m, 0H), 6.49 (m, 0H).
LCMS: (ESI, m/z): [M-1]-= 566.9.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments or portions thereof without departing from the spirit and scope of the invention.
Claims (8)
1. A synthetic method of aromatic amine carboxylic acid derivatives is characterized in that: the method comprises the following steps in sequence:
s1: preparation of compound iii: dissolving a compound I in dichloromethane, adding a compound II to react in the presence of alkali, and then sequentially washing, extracting, washing and drying to obtain a compound III;
s2: preparation of Compound IV: dissolving the compound III obtained in the step in tetrahydrofuran, adding LiHMDS under the protection of nitrogen, and then adding R1Reacting, and then sequentially carrying out quenching reaction, extraction, water washing and drying to obtain a compound IV;
s3: preparation of Compound V: adding the compound IV and sodium hydroxide in the steps into water for reaction, adding 1N hydrochloric acid aqueous solution after the reaction is finished, adjusting the pH to be =2, and performing suction filtration to obtain a compound V;
s4: preparation of Compound VI: adding the compound V in the step into thionyl chloride for reaction, and evaporating unreacted thionyl chloride from mother liquor under negative pressure after the reaction is finished to obtain a compound VI;
s5: preparation of compound viii: dissolving the compound VI and the compound VII obtained in the step in acetonitrile, reacting in the presence of alkali, and then sequentially extracting, washing with water, drying and purifying to obtain a compound VIII;
wherein the structural formula of the compound I isThe structural formula of the compound II isThe structural formula of the compound III isThe structural formula of the compound IV is(ii) a The structural formula of the compound V isThe structural formula of the compound VI isThe structural formula of the compound VII isThe structural formula of the compound VIII isAnd R is1Comprises one of H, Me, Et, n-Pr, n-Bu, acetyl and propionyl; r2Including phenyl, 4-fluorophenyl, 6- (trifluoromethyl) -3-pyridyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl, 2, 6-difluorophenyl, 3, 5-difluorophenyl, 2, 3-difluorophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-chloro-2-pyridyl, 6-chloro-3-pyridyl, 5-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, Me, CF3, Et, N-Pr, i-Pr, N-ethyl-N-methylaminocarbonyl, N-ethyl-aminocarbonyl, 2,2, 2-trifluoroethylaminocarbonyl, N-methyl-2-pyridyl, N-methyl-3-pyridyl, N-ethyl-aminocarbonyl, N-methyl-2-pyridyl, N-methyl-pyridyl, N-ethyl-2-pyridyl, 3-pyridyl, 2-cyano-pyridyl, N-methyl-2-pyridyl, N-methyl-pyridyl, N-ethyl-2-pyridyl, N-methyl-ethyl-2-pyridyl, N-ethyl-2-pyridyl, One of N- (2,2, 2-trifluoroethyl) -N-methylaminocarbonyl, 4-nitrophenyl and methoxymethyl; x1Including F, Cl, Br, I; x2Comprises one of H, Cl, Me and CF 3; x3Comprises one of H, Cl, Br and 3-chloro-5- (trifluoromethyl) pyridine-2-oxyl; x4Comprises one of 1,1,2, 2-tetrafluoroethoxy, 1,2,3,3, 3-hexafluoropropoxy, 1, 2-trifluoro-2-trifluoromethoxy-ethoxy, 2-chloro-4- (trifluoromethyl) phenoxy, 3-chloro-5- (trifluoromethyl) pyridine-2-oxy, Cl, F and heptafluoroisopropyl; x5One of H, Cl; x6Comprises one of H, Cl, F and Br.
2. The method for synthesizing an aromatic amine carboxylic acid derivative according to claim 1, wherein: in step S1, the reaction conditions were 0 ℃, the reaction time was 12 hours, the washing was performed with 1N hydrochloric acid aqueous solution, the extraction was performed with ethyl acetate, and the drying was performed with anhydrous sodium sulfate.
3. The method for synthesizing an aromatic amine carboxylic acid derivative according to claim 1, wherein: in step S2, the reaction time is 1h, the quenching reaction is completed by adding acetic acid at 0 ℃, the extraction is performed with ethyl acetate, and the drying is performed with anhydrous sodium sulfate.
4. The method for synthesizing an aromatic amine carboxylic acid derivative according to claim 1, wherein: in step S3, the reaction is carried out under the condition of 60 ℃ and stirring for 2 h.
5. The method for synthesizing an aromatic amine carboxylic acid derivative according to claim 1, wherein: in step S4, the reaction conditions were 75 ℃ stirring reaction for 2 h.
6. The method for synthesizing an aromatic amine carboxylic acid derivative according to claim 1, wherein: in step S5, the reaction condition is 110 ℃ for 3 h.
7. The method for synthesizing an aromatic amine carboxylic acid derivative according to claim 1, wherein: in step S5, ethyl acetate is used for extraction, anhydrous sodium sulfate is used for drying, and the crude product is purified by chromatography on silica gel column.
8. The method for synthesizing an aromatic amine carboxylic acid derivative according to claim 1, wherein: in step S1, the base is one of pyridine, triethylamine, sodium hydroxide, and potassium hydroxide.
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