CN101412682B - Process for synthesizing aryl anthranilic acid and derivatives thereof - Google Patents
Process for synthesizing aryl anthranilic acid and derivatives thereof Download PDFInfo
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- CN101412682B CN101412682B CN2007100941522A CN200710094152A CN101412682B CN 101412682 B CN101412682 B CN 101412682B CN 2007100941522 A CN2007100941522 A CN 2007100941522A CN 200710094152 A CN200710094152 A CN 200710094152A CN 101412682 B CN101412682 B CN 101412682B
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- anthranilic acid
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- RWZYAGGXGHYGMB-UHFFFAOYSA-N o-aminobenzenecarboxylic acid Natural products NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 title claims abstract description 84
- -1 aryl anthranilic acid Chemical compound 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 20
- 230000002194 synthesizing effect Effects 0.000 title abstract description 21
- 239000004327 boric acid Substances 0.000 claims abstract description 21
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 239000011230 binding agent Substances 0.000 claims abstract description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 18
- 235000017550 sodium carbonate Nutrition 0.000 claims description 18
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 18
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- 238000005516 engineering process Methods 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 238000004064 recycling Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 6
- 238000000746 purification Methods 0.000 abstract description 3
- 150000001543 aryl boronic acids Chemical class 0.000 abstract 1
- 230000007547 defect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- 235000010338 boric acid Nutrition 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 230000008030 elimination Effects 0.000 description 16
- 238000003379 elimination reaction Methods 0.000 description 16
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 16
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 16
- 239000012046 mixed solvent Substances 0.000 description 16
- 238000001953 recrystallisation Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 238000000967 suction filtration Methods 0.000 description 16
- 238000004519 manufacturing process Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000003912 environmental pollution Methods 0.000 description 3
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 2
- XQNPSPIHRJPQKW-UHFFFAOYSA-N 1-iodoindole-2,3-dione Chemical compound C1=CC=C2N(I)C(=O)C(=O)C2=C1 XQNPSPIHRJPQKW-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- VUTJHOWRPUPHIG-UHFFFAOYSA-N (3-chloro-4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1Cl VUTJHOWRPUPHIG-UHFFFAOYSA-N 0.000 description 1
- CIYCFARZRPCICD-UHFFFAOYSA-N 2-amino-4-(3-chloro-4-fluorophenyl)benzoic acid Chemical compound C1=C(C(O)=O)C(N)=CC(C=2C=C(Cl)C(F)=CC=2)=C1 CIYCFARZRPCICD-UHFFFAOYSA-N 0.000 description 1
- KNGSOGQCWBIIQF-UHFFFAOYSA-N 2-amino-4-(3-hydroxyphenyl)benzoic acid Chemical compound C1=C(C(O)=O)C(N)=CC(C=2C=C(O)C=CC=2)=C1 KNGSOGQCWBIIQF-UHFFFAOYSA-N 0.000 description 1
- RTEZIPKAIWRJFQ-UHFFFAOYSA-N 2-amino-4-[3-(dimethylamino)phenyl]benzoic acid Chemical compound CN(C=1C=C(C=CC1)C=1C=C(C(C(=O)O)=CC1)N)C RTEZIPKAIWRJFQ-UHFFFAOYSA-N 0.000 description 1
- JYYLQSCZISREGY-UHFFFAOYSA-N 2-amino-4-chlorobenzoic acid Chemical compound NC1=CC(Cl)=CC=C1C(O)=O JYYLQSCZISREGY-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N Pseudoisatin Natural products C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- XLGLMVCAOMQNJT-UHFFFAOYSA-N boric acid;chlorobenzene Chemical compound OB(O)O.ClC1=CC=CC=C1 XLGLMVCAOMQNJT-UHFFFAOYSA-N 0.000 description 1
- OPPWASLOVKWHCT-UHFFFAOYSA-N boric acid;phenol Chemical compound OB(O)O.OC1=CC=CC=C1 OPPWASLOVKWHCT-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- KNPNGMXRGITFLE-UHFFFAOYSA-N methylperoxy(phenyl)borinic acid Chemical compound COOB(O)C1=CC=CC=C1 KNPNGMXRGITFLE-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
Abstract
The invention relates to a method for synthesizing novel aryl anthranilic acid and derivatives thereof. The method overcomes the defects of extremely-low yield, long route and difficult purification in post-treatment process in the prior method. The method adopts halogeno anthranilic acid and derivatives thereof as raw materials to react with arylboronic acid, heteratomic aromatic boric acid or boric acid ester directly in the presence of a Pd/C catalyst and an acid-binding agent to obtain corresponding aryl anthranilic acid and the derivatives thereof.
Description
Technical field:
The present invention relates to the compound method of aryl anthranilic acid and verivate thereof.
Background technology:
With respect to the widespread use of anthranilic acid derivative at field of medicaments, aryl anthranilic acid has also caused the very big interest of Pharmaceutical Chemist as a kind of new medicine intermediate, but relevant its compound method is reported for work seldom.Bibliographical information two synthetic routes, the one, iodo isatin and aryl boric acid carry out Suzuki reaction and obtain the aryl isatin, oxydrolysis obtains aryl anthranilic acid (Tetrahedron 61,2005,6082-6087) then; The 2nd, directly carry out the Suzuki reaction, and then be reduced into anthranilic acid (Bioorg.Med.Chem.Lett. with the halides of anthranilic acid derivative; EN; 7; 13; 1997; 1595-1600.US2004/242572?A1(2004/12/02))。
Document synthetic route 1:
In document synthetic route 1, the long yield of route is low.When synthetic initial feed iodo isatin, it is not high to close the ring yield with the vitriol oil, and purification difficult also will be used valuable palladium catalyst and part, and the ydrogen peroxide 50 of final step reaction usefulness, very easily causes danger in the suitability for industrialized production.The vitriol oil of using in the building-up process, the concentrated sodium hydroxide aqueous solution, environmental pollution are very serious; For second method; Equally will be through two steps, and use valuable palladium catalyst and part in the Suzuki reaction equally and need oxygen free condition, reaction stability is poor; Products therefrom purification difficult and to use a large amount of toluene environmental pollutions also quite serious, suitability for industrialized production has certain difficulty.
In sum, do not have the applicable industries method at present and come substituted anthranilic acid of synthesizing aryl and verivate thereof.
Summary of the invention:
The object of the invention: develop a kind of simple, the practical aryl anthranilic acid and the compound method of verivate thereof.It is longer to solve in the present compound method route, severe reaction conditions, technical problem such as aftertreatment difficulty yield is lower.
Technical scheme of the present invention:
The synthetic route of aryl anthranilic acid of the present invention and verivate thereof is following:
The present invention be simple and easy to halo anthranilic acid or derivatives thereof be raw material, with aryl boric acid or aryl-boric acid ester (or heterocyclic aryl boric acid and heterocyclic aryl boric acid ester) be that reaction obtains corresponding aryl anthranilic acid or heterocyclic aryl anthranilic acid and verivate thereof under the catalyst action at palladium carbon.
In the above-mentioned technology, X is chlorine, bromine or iodine; Halogen and amino can be on phenyl ring any one position in ortho position, a position or the contraposition of carboxylic acid; Ar is for having substituent phenyl ring; Har is for having substituent aromatic heterocycle.The catalyzer that reaction is adopted is 5% or 10% palladium carbon, and water cut is 0%～100%, and consumption is 5%～20% (W/W).In addition, palladium carbon washs the back recycling through simple filtration after reaction is accomplished; Reaction solvent can be one or more the mixed mixed solvents that form in water and organic solvent methyl alcohol, ethanol, Virahol, the propyl carbinol; The ratio of organic solvent and water is (1: 1)～(10: 1); Acid binding agent is mineral alkalis such as yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, and consumption is 1～5 equivalent; Temperature of reaction is room temperature to a solvent refluxing temperature, and type of heating is oil bath or uses microwave heating that actual conditions is looked the substrate activity and decided.Some reaction will add some phase-transfer catalysts such as Tetrabutyl amonium bromide etc.This reaction need not protection of inert gas.
Beneficial effect of the present invention:
The present invention has overcome in the present compound method raw material and has been difficult for obtaining, and route is longer, and yield is low, severe reaction conditions, shortcoming such as environmental pollution is serious.The present invention be simple and easy to halo anthranilic acid and verivate thereof be raw material; Obtain corresponding aryl anthranilic acid with various aryl boric acids and the reaction of heterocyclic aryl boric acid ester, not only shortened the synthetic route in the document, improved product yield; Reduced production cost and environmentally friendly; The palladium carbon of using in the production can repeat to apply mechanically, and reaction conditions is gentle, can scale operation.
Embodiment:
Embodiment 1
Synthesizing of 4-(3-chloro-4 p-methoxy-phenyls) anthranilic acid
Palladium carbon (moisture 50%) and the mixed solvent of 1000mL (Virahol: water 2: 1) join reflux 36h in the 3000mL round-bottomed flask, put the board raw material primitive reaction and finish with 100g 4-bromine anthranilic acid (1 equivalent), 87g 3-chloro-4-methoxyphenylboronic acid (1 equivalent), 162g technical grade yellow soda ash (3.3 equivalent), 1g10%.Elimination palladium carbon, concentrating under reduced pressure reaction solution add 500mL water to 300mL, and the Hydrogen chloride with 10% transfers to PH2～3, stir 3h, suction filtration, and the gained solid gets pure article 96g, yield 75% with 70% ethanol water recrystallization.H
1-NMR(300MHz，DMSO-d6)δ7.72(d，J＝8.4，2H)，7.64(s，1H)，7.55(d，J＝8.4，1H)，7.20(d，J＝8.7，1H)，6.99(s，1H)，6.77(d，J＝8.7，1H)，3.87(s，3H)。MS(ESI)m/z?278(M+1)，260(M-H
2O+H
+)。
Embodiment 2
Synthesizing of 4-(3-hydroxy phenyl) anthranilic acid
Palladium carbon (moisture 50%) and the mixed solvent of 700mL (Virahol: water 2: 1) join reflux 36h in the 2000mL round-bottomed flask, put the board raw material primitive reaction and finish with 100g 4-bromine anthranilic acid (1 equivalent), 64g 3-hydroxybenzene boric acid (1 equivalent), 162g technical grade yellow soda ash (3.3 equivalent), 1g10%.Elimination palladium carbon, concentrating under reduced pressure reaction solution add 500mL water to 300mL, and the Hydrogen chloride with 10% transfers to PH2～3, stir 3h, suction filtration, and the gained solid gets pure article 70g, yield 65% with 65% ethanol water recrystallization.H
1-NMR(300MHz，DMSO-d6)δ9.6(sbr，1H)，7.72(d，J＝8.1，1H)，7.23(t，J＝7.5，1H)，7.01～6.94(m，3H)，6.74(d，J＝8.0，1H)，4.25(sbr，2H)。MS(ESI)m/z?230.2(M+1)，212(M-H
2O+H
+)。
Embodiment 3
Synthesizing of 4-(3-chloro-phenyl-) anthranilic acid
Palladium carbon (moisture 50%) and the mixed solvent of 800mL (Virahol: water 2: 1) join reflux 36h in the 2000mL round-bottomed flask, put the board raw material primitive reaction and finish with 100g 4-bromine anthranilic acid (1 equivalent), 72.4g 3-chlorobenzene boric acid (1 equivalent), 162g technical grade yellow soda ash (3.3 equivalent), 1g10%.Elimination palladium carbon, concentrating under reduced pressure reaction solution add 500mL water to 300mL, and the Hydrogen chloride with 10% transfers to PH2～3, stir 3h, suction filtration, and the gained solid gets pure article 57g, yield 50% with 75% ethanol water recrystallization.H
1-NMR(300MHz，DMSO-d6)δ7.75(d，J＝8.4，1H)，7.62(s，1H)，7.56(d，J＝7.2，1H)，7.51～7.43(m，2H)，7.03(s，1H)，6.80(d，J＝8.3，1H)，4.45(sbr，2H)。MS(ESI)m/z?248(M+1)，230(M-H
2O+H
+)。
Embodiment 4
Synthesizing of 4-(3-dimethylamino phenyl) anthranilic acid
Palladium carbon (moisture 50%) and the mixed solvent (Virahol: water 2: 1) join reflux 36h in the 2000mL round-bottomed flask of 800mL with 100g 4-bromine anthranilic acid (1 equivalent), 77g 3-dimethylamino phenylo boric acid (1 equivalent), 162g technical grade yellow soda ash (1 equivalent), 1g 10%.Be chilled to room temperature, elimination palladium carbon, concentration of reaction solution add 500mL water to 300mL, and the Hydrogen chloride with 10% transfers to PH6～7, stirs 3h, suction filtration, and the gained solid gets pure article 59 g, yield 50% with 85% ethanol water recrystallization.H
1-NMR(300MHz，DMSO-d6)δ7.75(d，J＝8.3，1H)，7.23(t，J＝8.3，1H)，7.01(s，1H)，6.86～6.80(m，2H)，6.78(d，J＝8.3，1H)，6.72(d，J＝7.9，1H)，2.90(s，6H)。MS(ESI)m/z?257(M+1)。
Embodiment 5
Synthesizing of 4-(3-chloro-4-fluorophenyl) anthranilic acid
Palladium carbon (moisture 50%) and the mixed solvent (Virahol: water 2: 1) join reflux 36h in the 2000mL round-bottomed flask of 1000mL with 100g 4-bromine anthranilic acid (1 equivalent), 81g 3-chloro-4-fluorophenyl phenylo boric acid (1 equivalent), 162g technical grade yellow soda ash (3.3 equivalent), 1g 10%.Be chilled to room temperature, elimination palladium carbon, concentration of reaction solution add 500mL water to 300mL, and the Hydrogen chloride with 10% transfers to PH6～7, stirs 3h, suction filtration, and the gained solid gets pure article 83.6g, yield 68% with 80% ethanol water recrystallization.H
1-NMR(300MHz，DMSO-d6)δ7.79～7.73(m，2H)，7.76～7.56(m，1H)，7.48(t，J＝8.7，1H)，7.0(s，1H)，6.80(d，J＝8.7，1H)，4.50(sbr，2H)。MS(ESI)m/z266(M+1)，248(M-H
2O+H
+)。
Embodiment 6
Synthesizing of 4-(4-p-methoxy-phenyl) anthranilic acid
100g 4-bromine anthranilic acid (1 equivalent), 70g are mixed solvent (Virahol: water 2: 1) join reflux 36h in the 2000mL round-bottomed flask to palladium carbon (moisture 50%) and the 1000mL of methoxyphenylboronic acid (1 equivalent), 162g technical grade yellow soda ash (3.3 equivalent), 1g 10%.Be chilled to room temperature, elimination palladium carbon, concentration of reaction solution add 500mL water to 300mL, and the Hydrogen chloride with 10% transfers to PH6～7, stirs 3h, suction filtration, and the gained solid gets pure article 45g, yield 40% with 85% ethanol water recrystallization.H
1-NMR(300MHz，DMSO-d6)δ7.71(d，J＝8.29，1H)，7.43(d，J＝8.67，2H)，7.00(d，J＝8.67，2H)，6.95(s，1H)，6.76(d，J＝8.29，1H)，4.50(br，1H)，6.86～6.80(m，2H)，3.78(s，3H)。MS(ESI)m/z?244(M+1)，226(M-H
2O+H
+)。
Embodiment 7
Synthesizing of 4-[N-methyl-5-indoles] anthranilic acid
Palladium carbon (moisture 50%) and the mixed solvent (Virahol: water 2: 1) join reflux 18h in the 2000mL round-bottomed flask of 1500mL with 100g 4-bromine anthranilic acid (1 equivalent), 81g N-methyl-5-indoles boric acid (1 equivalent), 162g technical grade yellow soda ash (3.3 equivalent), 1g10%.Be chilled to room temperature, elimination palladium carbon, concentration of reaction solution add 500mL water to 300mL, and the Hydrogen chloride with 10% transfers to PH3～4, stirs 3h, suction filtration, and the gained solid gets pure article 98.5g, yield 80% with 85% ethanol water recrystallization.H
1-NMR(400MHz，DMSO-d6)δ7.78(s，1H)，7.72(d，J＝8.8，1H)，7.48(d，J＝8.8，2H)，7.39(dd，J＝8.8，2H)，7.33(d，J＝3.20，1H)，7.035(s，1H)，6.82(dd，J＝8.4，1H)，6.46(d，J＝3.2，1H)。MS(ESI)m/z?267(M+1)，259(M-H
2O+H
+)。
Embodiment 8
Synthesizing of 4-[N-methyl-5-indoles] anthranilic acid
Palladium carbon and the mixed solvent (propyl carbinol: water 2: 1) join reflux 24h in the 2000m round-bottomed flask of 1500mL with 100g 4-bromine anthranilic acid (1 equivalent), 81g N-methyl-5-indoles boric acid (1 equivalent), 162g technical grade yellow soda ash (3.3 equivalent), 2.5g 5%.Be chilled to room temperature, elimination palladium carbon, concentration of reaction solution add 500mL water to 200mL, and the Hydrogen chloride with 10% transfers to PH3～4, stirs 3h, suction filtration, and the gained solid gets pure article 74.0g, yield 60% with 85% ethanol water recrystallization.
Embodiment 9
Synthesizing of 4-[N-methyl-5-indoles] anthranilic acid
Palladium carbon and the mixed solvent (ethanol: water 5: 1) join reflux 24h in the 2000m round-bottomed flask of 1500mL with 100g 4-bromine anthranilic acid (1 equivalent), 81g N-methyl-5-indoles boric acid (1 equivalent), 162g technical grade yellow soda ash (3.3 equivalent), 1.2g 10%.Be chilled to room temperature, elimination palladium carbon, concentration of reaction solution add 500mL water to 100mL, and the Hydrogen chloride with 10% transfers to PH3～4, stirs 3h, suction filtration, and the gained solid gets pure article 49.5g, yield 40% with 85% ethanol water recrystallization.MS(ESI)m/z?267(M+1)，259(M-H
2O+H
+)。
Embodiment 10
Synthesizing of 4-[N-methyl-5-indoles] anthranilic acid
Palladium carbon and the 1200mL Virahol of 100g 4-bromine anthranilic acid (1 equivalent), 81g N-methyl-5-indoles boric acid (1 equivalent), 245g technical grade yellow soda ash (5.0 equivalent), 0.8g 10% are joined reflux 36h in the 2000m round-bottomed flask.Be chilled to room temperature, elimination palladium carbon, concentration of reaction solution add 500mL water to 100mL, and the Hydrogen chloride with 10% transfers to PH3～4, stirs 3h, suction filtration, and the gained solid gets pure article 36.7g, yield 30% with 85% ethanol water recrystallization.MS(ESI)m/z?267(M+1)，259(M-H
2O+H
+)。
Embodiment 11
Synthesizing of 4-[N-methyl-5-indoles] anthranilic acid
Palladium carbon and 1200mL (Virahol: water=1: 1) join reflux 20h in the 2000m round-bottomed flask with 100g 4-bromine anthranilic acid (1 equivalent), 81g N-methyl-5-indoles boric acid (1 equivalent), 288g technical grade salt of wormwood (4.5 equivalent), 3g 5%.Be chilled to room temperature, elimination palladium carbon, concentration of reaction solution add 500mL water to 100mL, and the Hydrogen chloride with 10% transfers to PH3～4, stirs 3h, suction filtration, and the gained solid gets pure article 86.6g, yield 65% with 85% ethanol water recrystallization.MS(ESI)m/z?267(M+1)，259(M-H
2O+H
+)。
Embodiment 12
Synthesizing of 4-[N-methyl-5-indoles] anthranilic acid
Palladium carbon and 1200mL (Virahol: water=1: 1) join reflux 20h in the 2000m round-bottomed flask with 100g 4-bromine anthranilic acid (1 equivalent), 81g N-methyl-5-indoles boric acid (1 equivalent), 131g sodium hydrogencarbonate (3.3 equivalent), 2g 10%.Be chilled to room temperature, elimination palladium carbon, concentration of reaction solution add 500mL water to 100mL, and the Hydrogen chloride with 10% transfers to PH3～4, stirs 3h, suction filtration, and the gained solid gets pure article 60.0g, yield 45% with 85% ethanol water recrystallization.MS(ESI)m/z?267(M+1)，259(M-H
2O+H
+)。
Embodiment 13
Synthesizing of 4-(3 indyl) anthranilic acid
Palladium carbon (moisture 50%) and the mixed solvent (Virahol: water 2: 1) join reflux 20h in the 2000mL round-bottomed flask of 1500mL with 100g 4-bromine anthranilic acid (1 equivalent), 125g 3-(N-tertbutyloxycarbonyl) indoles boric acid (1 equivalent), 162g technical grade yellow soda ash (3.3 equivalent), 1g 10%.Be chilled to room temperature, elimination palladium carbon, concentration of reaction solution add 500mL water to 300mL, and the Hydrogen chloride with 10% transfers to PH3～4, stirs 3h, suction filtration, and the gained solid gets pure article 52.5g, yield 45% with 80% ethanol water recrystallization.H
1-NMR(400MHz，DMSO-d6)δ10.7(s，1H)，7.51(d，J＝8.03，1H)，7.26～7.24(m，2H)，6.96(t，J＝7.80，1H)，6.88～74(m，2H)，6.55(d，J＝7.0，1H)，6.31(t，J＝7.30?1H)。MS(ESI)m/z?253(M+1)，235(M-H
2O+H
+)。
Embodiment 14
Synthesizing of 4-(4-isopropyl phenyl)-3-benzaminic acid
Palladium carbon (moisture 50%) and the mixed solvent (Virahol: water 2: 1) join reflux 15h in the 2000mL round-bottomed flask of 1000mL with 100g 4-bromo-3-benzaminic acid (1 equivalent), 78g 4-isopropyl acid (1 equivalent), 162g technical grade yellow soda ash (3.3 equivalent), 1g 10%.Be chilled to room temperature, elimination palladium carbon, concentration of reaction solution add 500mL water to 300mL, and the Hydrogen chloride with 10% transfers to PH1-2, stirs 3h, suction filtration, and the gained solid gets pure article 90g, yield 75% with 80% ethanol water recrystallization.H
1-NMR(400MHz，DMSO-d6)δ12.7(br，1H)，7.41～7.39(m，2H)，7.36(d，J＝2.0，1H)，7.33(d，J＝8.0，2H)，7.05(d，J＝8.08，1H)，6.97(dd，J＝8.08，1H)，5.50(br，2H)。MS(ESI)m/z?256(M+1)，238(M-H
2O+H
+)。
Embodiment 15
Synthesizing of 4-(4-p-methoxy-phenyl) anthranilic acid
With the mixed solvent of palladium carbon (moisture 50%), 0.05g Tetrabutyl amonium bromide and the 20mL of 1.0g 4-chloroanthranilic acid (1 equivalent), 0.93g 4-methoxyphenylboronic acid (1 equivalent), 0.2g technical grade yellow soda ash (3.3 equivalent), 0.1g 10% (Virahol: water 2: 1) join in the 40mL microwave tube, under the 100W microwave radiation, reacted ten minutes in 120 ℃.Aftertreatment gets product 0.43g, yield 30% with embodiment 6.
Embodiment 16
Synthesizing of 4-(4-p-methoxy-phenyl) anthranilic acid
(Virahol: water 2: 1) join in the 50mL round-bottomed flask, vigorous stirring is 24 hours under the room temperature condition with the palladium carbon (moisture 50%) of 1.0g 4-iodine anthranilic acid (1 equivalent), 0.6g 4-methoxyphenylboronic acid (1 equivalent), 1.33g technical grade yellow soda ash (3.3 equivalent), 0.1g 10% and the mixed solvent of 20mL.Aftertreatment gets product 0.79g, yield 86% with embodiment 6.
Embodiment 17
Synthesizing of 3-(4-fluorophenyl)-4-benzaminic acid
(Virahol: water 2: 1) join in the 2L round-bottomed flask, reflux is 14 hours under the intense agitation with the palladium carbon (moisture 50%) of 50g 3-bromo-4-benzaminic acid (1 equivalent), 35g 4-fluorobenzoic boric acid (1 equivalent), 81g technical grade yellow soda ash (3.3 equivalent), 5g 10% and the mixed solvent of 1000mL.Be chilled to room temperature, elimination palladium carbon, concentration of reaction solution add 500mL water to 100mL, and the Hydrogen chloride with 10% transfers to PH2～3, stirs 3h, suction filtration, and the gained solid gets pure article 45.5g, yield 85% with 80% ethanol water recrystallization.H
1-NMR(400MHz，DMSO-d6)δ7.63(dd，J
1＝8.53，J
2＝2.0，1H)，7.53(d，J＝2.0，1H)，7.45～7.41(m，2H)，7.27(t，J＝8.8，2H)，6.78(d，J＝8.53，1H)5.0(br，2H)。MS(ESI)m/z?232(M+1)
Embodiment 18
Synthesizing of 2-(4-fluorophenyl)-5-benzaminic acid
(Virahol: water 2: 1) join in the 1L round-bottomed flask, reflux is 14 hours under the intense agitation with the palladium carbon (moisture 50%) of 20g 2-bromo-5-benzaminic acid (1 equivalent), 13g 4-fluorobenzoic boric acid (1 equivalent), 33g technical grade yellow soda ash (3.3 equivalent), 2g 10% and the mixed solvent of 500mL.Be chilled to room temperature, elimination palladium carbon, concentration of reaction solution add 350mL water to 70mL, and the Hydrogen chloride with 10% transfers to PH2～3, stirs 3h, suction filtration, and the gained solid gets pure article 8.6g, yield 40% with 80% ethanol water recrystallization.H
1-NMR(400MHz，DMSO-d6)δ7.23～7.17(m，2H)，7.12(t，J＝9.0，2H)，6.99(d，J＝8.28，1H)，6.92(d，J＝t，J＝2.5，1H)，6.70(dd，J1＝8.28，J2＝2.5，1H)。MS(ESI)m/z?232(M+1)
Claims (5)
1. the compound method of aryl anthranilic acid and verivate thereof; It is characterized in that: with halo anthranilic acid or derivatives thereof is raw material; Directly under the catalysis of palladium carbon, obtain corresponding aryl anthranilic acid and verivate thereof with aryl or heteroaromatic boric acid or boric acid ester reaction, its reaction formula is following:
In the above-mentioned technology; X is a kind of in chlorine, the bromine or iodine; Halogen and amino can be on phenyl ring any one position in ortho position, a position or the contraposition of carboxylic acid, Ar is for having substituent phenyl ring, Har is for having substituent aromatic heterocycle; Reaction solvent is one or more mixed the forming in water and organic solvent methyl alcohol, ethanol, Virahol, the propyl carbinol, and the ratio of organic solvent and water is 1: 1～10: 1; Acid binding agent is a mineral alkali yellow soda ash, salt of wormwood, and sodium hydrogencarbonate, a kind of in the saleratus, consumption is 1～5 equivalent.
2. the compound method of aryl anthranilic acid according to claim 1 and verivate thereof is characterized in that: described palladium-carbon catalyst is 5% or 10% palladium carbon, and water cut is 0%～100%, and palladium carbon consumption weight ratio is 5%～20%.
3. the compound method of aryl anthranilic acid according to claim 1 and 2 and verivate thereof is characterized in that: palladium carbon can be through simple filtration washing back recycling after reaction is accomplished.
4. the compound method of aryl anthranilic acid according to claim 1 and verivate thereof is characterized in that: the reaction needs heating is carried out, and temperature of reaction is room temperature to a solvent refluxing temperature.
5. the compound method of aryl anthranilic acid according to claim 4 and verivate thereof is characterized in that: type of heating is oil bath or microwave heating.
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Citations (2)
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|---|---|---|---|---|
| CN1678591A (en) * | 2002-08-24 | 2005-10-05 | 贝林格尔英格海姆法玛两合公司 | New carboxamide compounds having melanin concentrating hormone antagonistic activity, pharmaceutical preparations comprising these compounds and process for their manufacture |
| CN101094829A (en) * | 2004-12-07 | 2007-12-26 | 富山化学工业株式会社 | Novel anthranilic acid derivative or salt thereof |
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2007
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1678591A (en) * | 2002-08-24 | 2005-10-05 | 贝林格尔英格海姆法玛两合公司 | New carboxamide compounds having melanin concentrating hormone antagonistic activity, pharmaceutical preparations comprising these compounds and process for their manufacture |
| CN101094829A (en) * | 2004-12-07 | 2007-12-26 | 富山化学工业株式会社 | Novel anthranilic acid derivative or salt thereof |
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|---|
| Anne-Laure Gérard等.Direct synthesis of new arylanthranilic acids via a Suzuki cross-coupling reaction from iodoisatins.《Tetrahedron》.2005,第61卷(第25期),6082-6087. * |
| M.L. Quan等.Biaryl substituted alkylboronate esters as thrombin inhibitors.《Bioorganic & Medicinal Chemistry Letters》.1997,第7卷(第13期),第1595-1600页. |
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| Medicinal Chemistry Letters》.1997,第7卷(第13期),第1595-1600页. * |
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