CN116143635B - A preparation method of 9-dichloromethylene-5-amino-benzonorbornene - Google Patents
A preparation method of 9-dichloromethylene-5-amino-benzonorbornene Download PDFInfo
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- CN116143635B CN116143635B CN202211531933.4A CN202211531933A CN116143635B CN 116143635 B CN116143635 B CN 116143635B CN 202211531933 A CN202211531933 A CN 202211531933A CN 116143635 B CN116143635 B CN 116143635B
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- dichloromethylene
- anisole
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims abstract description 50
- GGKYLHNARFFORH-UHFFFAOYSA-N 2-amino-6-nitrobenzoic acid Chemical compound NC1=CC=CC([N+]([O-])=O)=C1C(O)=O GGKYLHNARFFORH-UHFFFAOYSA-N 0.000 claims abstract description 27
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims abstract description 25
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims abstract description 21
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000006722 reduction reaction Methods 0.000 claims abstract description 16
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 15
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 13
- 238000005893 bromination reaction Methods 0.000 claims abstract description 12
- 230000035484 reaction time Effects 0.000 claims abstract description 12
- 238000007162 Favorskii rearrangement reaction Methods 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 66
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 26
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 238000004440 column chromatography Methods 0.000 claims description 12
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- 239000007868 Raney catalyst Substances 0.000 claims description 10
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 10
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 8
- 238000001514 detection method Methods 0.000 description 16
- 239000012295 chemical reaction liquid Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 238000005698 Diels-Alder reaction Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000006385 ozonation reaction Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 239000005737 Benzovindiflupyr Substances 0.000 description 3
- CCCGEKHKTPTUHJ-UHFFFAOYSA-N N-[9-(dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl]-3-(difluoromethyl)-1-methylpyrazole-4-carboxamide Chemical compound FC(F)C1=NN(C)C=C1C(=O)NC1=CC=CC2=C1C1CCC2C1=C(Cl)Cl CCCGEKHKTPTUHJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 244000068988 Glycine max Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 241000209140 Triticum Species 0.000 description 2
- 235000021307 Triticum Nutrition 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- JORVCRLRRRRLFI-UHFFFAOYSA-N 1,3-dichloro-2-fluorobenzene Chemical compound FC1=C(Cl)C=CC=C1Cl JORVCRLRRRRLFI-UHFFFAOYSA-N 0.000 description 1
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 241000221785 Erysiphales Species 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000006713 insertion reaction Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000007342 radical addition reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
- C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
- C07C209/365—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst by reduction with preservation of halogen-atoms in compounds containing nitro groups and halogen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/60—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members
- C07C2603/66—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members containing five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/72—Ethanonaphthalenes; Hydrogenated ethanonaphthalenes
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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 relates to a preparation method of 9-dichloromethylene-5-amino-benzonorbornene. The reaction product of the isoamyl nitrite, the 6-nitroanthranilic acid and the anisole is subjected to bromination reaction and Favorskii rearrangement reaction to obtain 5-nitro-8-carboxyl-benzonorbornene, the reaction of the 5-nitro-8-carboxyl-benzonorbornene and phosphorus pentachloride to obtain 9-dichloromethylene-5-nitro-benzonorbornene, and the hydrogenation reduction reaction of the 9-dichloromethylene-5-nitro-benzonorbornene to obtain the 9-dichloromethylene-5-amino-benzonorbornene. The 9-dichloromethylene-5-amino-benzonorbornene prepared by the method has a shorter reaction route and shorter reaction time, so that the overall yield of the reaction is greatly increased. And the cost is reduced, the three wastes are reduced, the practical value is high, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 9-dichloromethylene-5-amino-benzonorbornene.
Background
The benzovindiflupyr (benzovindiflupyr) is an SDHI high-efficiency bactericide developed by Qianzhengda corporation, has good control effects on Asian soybean rust, wheat fusarium wilt and peanut black-white complications, has special effects on wheat powdery mildew, soybean rust corn small spot and gray mold, can be matched with various bactericides, and has no interactive resistance. Benzovindiflupyr is usually formed by splicing two modules, wherein one module is 9-dichloromethylene-5-amino-benzonorbornene.
The chemical structural formula is as follows:
currently, there are 3 main methods for synthesizing 9-dichloromethylene-5-amino-benzonorbornene.
The first is to take cyclopentadiene and 2-amino-6-nitrobenzoic acid as starting materials, and finally generate 9-dichloromethylene-5-amino-benzonorbornene through condensation addition, diels-Alder reaction, hydrogenation reduction, ozonization, chlorination and other reactions, as reported in the published report of Zhen-CN 101296913A and Zhen-CN 101677558. The preparation method has the following defects:
(1) The reaction requires 2 times of selective reduction hydrogenation, which results in low yield and obviously increased catalyst consumption.
(2) The route involves high-risk processes of ozonization fracture, increasing the difficulty of scale-up and practical operation.
The next day takes cyclopentadiene and 2-amino-6-nitrobenzoic acid as initial raw materials, cyclopentadiene and carbon tetrachloride are subjected to free radical addition, then hydrogen chloride is removed under the condition of sodium hydroxide, and 9-dichloromethylene-5-amino-benzonorbornene is finally generated through Diels-Alder reaction and hydrogenation reduction. Such as Zhengda-CN 102197016, zhengda-CN 103068780. The preparation method has the following defects:
when cyclopentadiene and carbon tetrachloride are added into free radicals, the yield is low, so that the manpower and material resources are increased to remove accumulated materials, and excessive three wastes are caused, so that the method has no obvious significance for industrial production and is not suitable for industrial production
And thirdly, taking 6, 6-dimethyl-5-methylene-1, 3-cyclopentadiene as a starting material, firstly carrying out Diels-Alder reaction with 2, 6-dichloro fluorobenzene, then carrying out selective reduction, ozonization cleavage and chlorination reaction, and finally carrying out palladium catalysis amino insertion to obtain 9-dichloro methylene-5-amino-benzonorbornene, as disclosed in the published report of Zhen-CN 102858749A. The preparation method has the following defects:
(1) The format reagent used in the reaction needs to be subjected to Diels-Alder reaction at extremely low temperature, which is not beneficial to industrial production.
(2) The route involves high-risk process of ozonization fracture, and increases the difficulty of amplification and practical operation.
(3) The method involves palladium catalysis amino insertion reaction, the reaction yield is low, the palladium catalysis reagent is expensive, and the method has no obvious significance for industrial production and is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of 9-dichloromethylene-5-amino-benzonorbornene suitable for industrial production.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the preparation method of 9-dichloromethylene-5-amino-benzonorbornene comprises the steps of carrying out bromination reaction and Favorskii rearrangement reaction on reaction products of isoamyl nitrite, 6-nitroanthranilic acid and anisole to obtain 5-nitro-8-carboxyl-benzonorbornene, carrying out reaction on the 5-nitro-8-carboxyl-benzonorbornene and phosphorus pentachloride to obtain 9-dichloromethylene-5-nitro-benzonorbornene, and carrying out hydrogenation reduction reaction on the 9-dichloromethylene-5-nitro-benzonorbornene to obtain the 9-dichloromethylene-5-amino-benzonorbornene.
Preferably, the isoamyl nitrite, 6-nitroanthranilic acid and anisole are reacted in the presence of a catalyst, the catalyst being trifluoroacetic acid.
Preferably, the isoamyl nitrite, 6-nitroanthranilic acid and anisole are reacted in 2-methyltetrahydrofuran.
Preferably, the reaction temperature of the isoamyl nitrite, the 6-nitroanthranilic acid and the anisole is 75 ℃ to 85 ℃ and the reaction time is 2h to 3h.
Preferably, the feeding mass ratio of the isoamyl nitrite, the 6-nitroanthranilic acid and the anisole is (0.5-1.5): 1 (0.5-1.5).
Further preferably, the feeding mass ratio of the isoamyl nitrite, the 6-nitroanthranilic acid and the anisole is (0.8-1.2): 1 (0.8-1.2).
Preferably, the 6-nitroanthranilic acid and the anisole are mixed with part of the reaction solvent and then are added in a dropwise manner, the dropwise addition temperature is controlled between 40 ℃ and 55 ℃, and the dropwise addition is controlled between 30 min and 60 min.
Preferably, the reaction solvent for the bromination reaction is 2-methyltetrahydrofuran.
Preferably, the bromination reaction is carried out at a reaction temperature of 5-35 ℃ and a reaction time of 2-3 h.
Preferably, the mass ratio of the reaction product of the isoamyl nitrite, the 6-nitroanthranilic acid and the anisole to the liquid bromine is (0.5-1.5): 1.
Further preferably, the ratio of the reaction product of isoamyl nitrite, 6-nitroanthranilic acid and anisole to the liquid bromine is 1 to 1.2 by mass.
And/or mixing liquid bromine and part of the reaction solvent, and then feeding in a dropwise adding mode, wherein the dropwise adding temperature is controlled to be 15-25 ℃, and the dropwise adding time is controlled to be 30-60 min.
Preferably, the Favorskii rearrangement reaction is carried out in the presence of an alkaline substance, the alkaline substance is potassium hydroxide, and the mass ratio of the reaction product of the bromination reaction to the alkaline substance is (2.5-6.5): 1.
Further preferably, the mass ratio of the reaction product of the bromination reaction to the alkaline substance is (4.5-5.5): 1.
Preferably, the reaction solvent of Favorskii rearrangement reaction is ethanol.
Preferably, the temperature of Favorskii rearrangement reaction is 55-90 ℃ and the reaction time is 3-7 h.
Preferably, the feeding mass ratio of the 5-nitro-8-carboxyl-benzonorbornene to the phosphorus pentachloride is 1 (1-3).
Further preferably, the feeding mass ratio of the 5-nitro-8-carboxyl-benzonorbornene to the phosphorus pentachloride is 1 (1.5-2).
Preferably, the 5-nitro-8-carboxy-benzonorbornene and the phosphorus pentachloride are reacted in diphenyl ether.
Preferably, the reaction temperature of the 5-nitro-8-carboxyl-benzonorbornene and the phosphorus pentachloride is 175 ℃ to 225 ℃ and the reaction time is 7h to 11h.
Further preferably, the reaction temperature of the 5-nitro-8-carboxy-benzonorbornene and the phosphorus pentachloride is 205 ℃ to 215 ℃.
Preferably, raney nickel is used as a catalyst in the hydrogenation reduction reaction, and the feeding mass ratio of the 9-dichloromethylene-5-nitro-benzonorbornene to the Raney nickel is 1 (0.01-0.5).
Further preferably, raney nickel is used as a catalyst in the hydrogenation reduction reaction, and the feeding mass ratio of the 9-dichloromethylene-5-nitro-benzonorbornene to the Raney nickel is 1 (0.05-0.25).
Preferably, the reaction solvent of the hydrogenation reduction reaction is 2-methyltetrahydrofuran.
Preferably, the hydrogen pressure of the hydrogenation reduction reaction is 2-10bar.
Preferably, the reaction temperature of the hydrogenation reduction reaction is 40-50 ℃ and the reaction time is 2-3h.
Preferably, the mass concentration of the isoamyl nitrite is 95% or more.
Preferably, the mass concentration of the 6-nitroanthranilic acid is 90% or more.
Preferably, the anisole has a mass concentration of 90% and above.
Preferably, the mass concentration of the liquid bromine used in the bromination reaction is 90% or more.
Preferably, the mass concentration of phosphorus pentachloride is 95% or more.
The invention provides a preparation method of 9-dichloromethylene-5-amino-benzonorbornene, which comprises the following steps:
step one, isoamyl nitrite, 6-nitroanthranilic acid and anisole react for 2h to 3h at 25 ℃ to 35 ℃ in 2-methyltetrahydrofuran in the presence of trifluoroacetic acid;
step two, reacting the reaction product of the step one with liquid bromine in 2-methyltetrahydrofuran at 5-35 ℃ for 2-3 h;
Step three, reacting the reaction product of the step two in ethanol at 55-90 ℃ for 3-7 h in the presence of potassium hydroxide to obtain 5-nitro-8-carboxyl-benzonorbornene;
Step four, reacting the 5-nitro-8-carboxyl-benzonorbornene and phosphorus pentachloride in diphenyl ether at 175-225 ℃ for 7-11 h to obtain 9-dichloromethylene-5-nitro-benzonorbornene;
Step five, reacting the 9-dichloromethylene-5-nitro-benzonorbornene of the step four with 2-10bar hydrogen in 2-methyltetrahydrofuran at 40-50 ℃ for 2-3h in the presence of Raney nickel to obtain the 9-dichloromethylene-5-amino-benzonorbornene.
Specifically, the first step, the second step, the third step and the fourth step are all performed under the protection of inert gas.
Specifically, in the first step, the 6-nitroanthranilic acid and the anisole are mixed with part of 2-methyltetrahydrofuran and then are fed in a dropwise manner, wherein the dropwise temperature is controlled to be 40-55 ℃, and the dropwise is controlled to be completed within 30-60 minutes.
Specifically, in the second step, the liquid bromine and part of 2-methyltetrahydrofuran are mixed and then are added in a dropwise manner, the dropwise adding temperature is controlled to be 15-25 ℃, and the dropwise adding is controlled to be completed within 30-60 minutes.
Specifically, the first step and the second step. And step three, step four and step five respectively comprise post-treatment.
The post-treatment of the first step, the second step and the third step is to mix the reacted reaction liquid with water and ethyl acetate, adjust the pH value to 7-8, concentrate the organic phase and obtain the required compound through column chromatography.
And step four, the post-treatment is to mix the reacted reaction liquid with ice water, adjust the pH value to 7-8, add ethyl acetate for extraction, concentrate the organic phase and obtain the required compound through column chromatography.
And step five, the post-treatment is to mix the reacted reaction liquid with water and ethyl acetate, concentrate an organic phase and obtain a required compound through column chromatography.
The present invention also provides an intermediate compound for preparing 9-dichloromethylene-5-amino-benzonorbornene, which isAnd/orOr the intermediate compound is
One or more of the following.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
The 9-dichloromethylene-5-amino-benzonorbornene prepared by the method has a shorter reaction route and shorter reaction time, so that the overall yield of the reaction is greatly increased. And the cost is reduced, the three wastes are reduced, the practical value is high, and the method is suitable for industrial production.
Detailed Description
Hereinafter, only certain exemplary embodiments are briefly described. As will be recognized by those of skill in the pertinent art, the described embodiments may be modified in numerous different ways without departing from the spirit or scope of the embodiments of the present invention. Accordingly, the drawings and description are to be regarded as illustrative in nature and not as restrictive.
In the present invention, various processes and methods, which are not described in detail, are conventional methods well known in the art.
In the invention, all the raw materials can be obtained by commercial purchase or/and preparation by adopting known means, and all the raw materials meet the requirements of standard chemical products when not specifically described.
Example 1
This example provides a process for the preparation of 9-dichloromethylene-5-amino-benzonorbornene, which comprises the following steps:
The preparation method comprises the following steps:
1. Synthesis of intemmedate 1 (intermediate 1)
Under the protection of N 2, 8.4g of isoamyl nitrite and 20g of 2-methyltetrahydrofuran are sequentially added into a reaction bottle, stirring is carried out at the temperature of 40-50 ℃, 10g of 6-nitroanthranilic acid, 10g of anisole and 0.6g of trifluoroacetic acid are dissolved in 25g of 2-methyltetrahydrofuran, the mixture is slowly dripped into the reaction bottle, the dripping is completed for about 60min, then the temperature is increased to 75 ℃, the reaction is carried out for 3h, after the TLC detection reaction is completed, ethyl acetate and purified water are added into the reaction liquid for extraction, the solvent and unreacted raw materials are removed under the condition of organic coherence and decompression, 9.7g of intemedia 1 oily substance is obtained, the mixture is directly thrown into the next step for use without purification, and the yield is 82.2%.
MS-EI(m/z,%):216(M++H+)。
2. Synthesis of intemmedate 2 (intermediate 2)
Under the protection of N 2, 9.7g of intermedate 1 and 20g of 2-methyltetrahydrofuran are sequentially added into a reaction bottle, stirring is carried out, the temperature is kept at 15 ℃, 8.7g of liquid bromine and 20g of mixed liquid of 2-methyltetrahydrofuran are slowly added into the reaction system in a dropwise manner, after 60 minutes of adding is finished, the reaction is carried out for 3 hours at 15 ℃, after TLC detection is finished, ethyl acetate and purified water are added into the reaction liquid, the pH value is regulated to be about 7-8, organic phase is dried and concentrated, 11.7g of intermedate 2 oily matter is obtained, the reaction liquid is directly added to the next step without purification, and the yield is 88.7%.
MS-EI(m/z,%):293(M+);295(M++2H+)。
3. Synthesis of 5-nitro-8-carboxy-benzonorbornenes
Under the protection of N 2, sequentially adding 11.7g of intermedate 2, 30g of ethanol and 2.4g of potassium hydroxide into a reaction bottle, stirring, reacting for 5h at the temperature of 70 ℃, adding ethyl acetate and purified water into the reaction liquid after the TLC detection reaction is completed, adjusting the pH to about 7-8, organically drying and concentrating, separating by column chromatography (300 meshes of silica gel 150 g), and carrying out linear gradient elution on an eluent, wherein the eluent is petroleum ether, namely ethyl acetate (v/v) =1:3-1:1, so as to finally obtain 6.5g of product, and the yield is 70.5%.
The synthesized compound was subjected to structural detection and identified as 5-nitro-8-carboxy-benzonorbornene, and the data of hydrogen spectrum and mass spectrum were as follows:
Bruker model is selected for nuclear magnetic resonance apparatus ,1HNMR(300MHz,DMSO)11.019(s,1H),8.092-8.052(d,1H,J＝12Hz),7.621-7.581(d,1H,J＝12Hz),7.441-7.399(t,1H),5.620-5.580(d,2H,J＝12Hz),4.175-4.135(d,2H,J＝12Hz),2.877(q,1H,).
MS-EI(m/z,%):230(M+-H+);232(M++H+)。
4. Synthesis of 9-dichloromethylene-5-nitro-benzonorbornene
Under the protection of N 2, 6.5g of 5-nitro-8-carboxyl-benzonorbornene, 20g of diphenyl ether and 11.7g of phosphorus pentachloride are sequentially added into a reaction bottle, stirring is carried out, the reaction is carried out for 9h at the temperature of 205 ℃, after TLC detection of the disappearance of the reactant, the reaction liquid is poured into ice water, the pH is regulated to be about 7-8, ethyl acetate is added for extraction, organic phase is dried and concentrated, column chromatography (150 g of 300-mesh silica gel) is carried out for separation, the eluent is petroleum ether and ethyl acetate (v/v) =1:3-1:1, 4.62g is obtained through separation, and the yield is 61.7%.
The synthesized compound was subjected to structural detection and identified as 9-dichloromethylene-5-nitro-benzonorbornene, and the hydrogen spectrum and mass spectrum were as follows:
Bruker model is selected for nuclear magnetic resonance apparatus ,1HNMR(300MHz,CDCl3)7.947-7.907(d,1H,J＝12Hz),7.482-7.442(d,1H,J＝12Hz),7.359-7.301(t,1H),4.823-4.715(m,1H),4.051-3.932(m,1H),2.229-2.121(m,2H),1.480-1.397(m,1H),1.351-1.221(m,1H),.
MS-EI(m/z,%):268(M++H+)。
5. Synthesis of 9-dichloromethylene-5-amino-benzonorbornene
4.0G of 9-dichloromethylene-5-nitro-benzonorbornene, 30g of 2-methyltetrahydrofuran and 0.5g of Raney nickel are sequentially added into a high-pressure reaction kettle, the high-pressure reaction kettle is closed, stirring is started, nitrogen is used for purging three times to remove oxygen, nitrogen is replaced by hydrogen for 3 times, the reactor is pressurized to 5bar by hydrogen, the reaction kettle is heated to 40 ℃ for reaction for 3 hours, after TLC detection reaction is completed, ethyl acetate and purified water are added into the reaction liquid, organic phase is dried and concentrated, column chromatography (150 g of 300-mesh silica gel) is separated, eluent is petroleum ether: ethyl acetate (v/v) =1:3-1:1, 3.45g is obtained through separation, and the yield is 96.2%.
The synthesized compound was subjected to structural detection and identified as 9-dichloromethylene-5-amino-benzonorbornene, and the data of hydrogen spectrum and mass spectrum were as follows:
bruker model is selected for nuclear magnetic resonance apparatus ,1HNMR(300MHz,CDCl3)6.972-6.851(t,1H),6.663-6.623(d,1H,J＝12Hz),6.623(d,1H,J＝12Hz),3.912-3.901(m,1H),3.872-3.832(m,1H),3.597(br,2H,),2.061-1.965(m,2H),1.375-1.321(m,2H),.
MS-EI(m/z,%):240(M++H+);262(M++Na+)。
Example 2
This example provides a process for the preparation of 9-dichloromethylene-5-amino-benzonorbornene according to the same route as in example 1. The preparation method comprises the following steps:
1. Synthesis of intemmedate 1 (intermediate 1)
Under the protection of N 2, 8.4g of isoamyl nitrite and 20g of 2-methyltetrahydrofuran are sequentially added into a reaction bottle, stirring is carried out at 50-55 ℃ under the condition of heat preservation, 10g of 6-nitroanthranilic acid, 10g of anisole and 0.6g of trifluoroacetic acid are dissolved in 25g of 2-methyltetrahydrofuran, the mixture is slowly dripped into the reaction bottle, the dripping is completed for about 30min, then the temperature is raised to 85 ℃, the reaction is carried out for 2h, after the TLC detection reaction is completed, ethyl acetate and purified water are added into the reaction liquid for extraction, the solvent and unreacted raw materials are removed under the condition of organic coherence and decompression, 10.9g of intemedia 1 oily substance is obtained, the mixture is directly used in the next step without purification, and the yield is 92.3%.
MS-EI(m/z,%):216(M++H+)。
2. Synthesis of intemmedate 2 (intermediate 2)
Under the protection of N 2, sequentially adding 9.7g of intermedate 1 and 20g of 2-methyltetrahydrofuran into a reaction bottle, stirring, keeping the temperature at 25 ℃, slowly dropwise adding 8.7g of liquid bromine and 20g of mixed liquid of 2-methyltetrahydrofuran into the reaction system for about 30min, then reacting for 2h at 25 ℃, after TLC detection reaction is completed, adding ethyl acetate and purified water into the reaction solution, regulating the pH value to about 7-8, and organically drying and concentrating to obtain 12.3g of intermedate 2 oily matter, wherein the mixed liquid is directly used in the next step without purification, and the yield is 93.4%.
MS-EI(m/z,%):293(M+);295(M++2H+)。
3. Synthesis of 5-nitro-8-carboxy-benzonorbornenes
Under the protection of N 2, sequentially adding 11.7g of intermedate 2, 30g of ethanol and 2.4g of potassium hydroxide into a reaction bottle, stirring, reacting for 4h at the temperature of 85 ℃, adding ethyl acetate and purified water into the reaction liquid after the TLC detection reaction is completed, adjusting the pH to about 7-8, organically drying and concentrating, separating by column chromatography (300 meshes of silica gel 150 g), and performing linear gradient elution on an eluent, wherein the eluent is petroleum ether, namely ethyl acetate (v/v) =1:3-1:1, so as to obtain 7.9g of a product, and the yield is 85.5%.
The synthesized compound was subjected to structural detection and identified as 5-nitro-8-carboxy-benzonorbornene, and the data of hydrogen spectrum and mass spectrum were as follows:
Bruker model is selected for nuclear magnetic resonance apparatus ,1HNMR(300MHz,DMSO)11.019(s,1H),8.092-8.052(d,1H,J＝12Hz),7.621-7.581(d,1H,J＝12Hz),7.441-7.399(t,1H),5.620-5.580(d,2H,J＝12Hz),4.175-4.135(d,2H,J＝12Hz),2.877(q,1H,).
MS-EI(m/z,%):230(M+-H+);232(M++H+)。
4. Synthesis of 9-dichloromethylene-5-nitro-benzonorbornene
Under the protection of N 2, 6.5g of 5-nitro-8-carboxyl-benzonorbornene, 20g of diphenyl ether and 11.7g of phosphorus pentachloride are sequentially added into a reaction bottle, stirred, reacted for 8 hours at the temperature of 215 ℃, after TLC detection of the disappearance of the reactant, the reaction liquid is poured into ice water, the pH is regulated to be about 7-8, ethyl acetate is added for extraction, organic phase is dried and concentrated, column chromatography (150 g of 300-mesh silica gel) is separated, eluent is petroleum ether and ethyl acetate (v/v) =1:3-1:1, 6.5g is obtained through separation, and the yield is 86.9%.
The synthesized compound was subjected to structural detection and identified as 9-dichloromethylene-5-nitro-benzonorbornene, and the hydrogen spectrum and mass spectrum were as follows:
Bruker model is selected for nuclear magnetic resonance apparatus ,1HNMR(300MHz,CDCl3)7.947-7.907(d,1H,J＝12Hz),7.482-7.442(d,1H,J＝12Hz),7.359-7.301(t,1H),4.823-4.715(m,1H),4.051-3.932(m,1H),2.229-2.121(m,2H),1.480-1.397(m,1H),1.351-1.221(m,1H),.
MS-EI(m/z,%):268(M++H+)。
5. Synthesis of 9-dichloromethylene-5-amino-benzonorbornene
4.0G of 9-dichloromethylene-5-nitro-benzonorbornene, 30g of 2-methyltetrahydrofuran and 0.5g of Raney nickel are sequentially added into a high-pressure reaction kettle, the high-pressure reaction kettle is closed, stirring is started, nitrogen is used for purging three times to remove oxygen, nitrogen is replaced by hydrogen for 3 times, the reactor is pressurized to 3bar by hydrogen, the reaction kettle is heated to 50 ℃ for reaction for 2 hours, after TLC detection reaction is completed, ethyl acetate and purified water are added into the reaction liquid, organic phase is dried and concentrated, column chromatography (150 g of 300-mesh silica gel) is separated, eluent is petroleum ether: ethyl acetate (v/v) =1:3-1:1, 3.5g is obtained through separation, and the yield is 97.9%.
The synthesized compound was subjected to structural detection and identified as 9-dichloromethylene-5-amino-benzonorbornene, and the data of hydrogen spectrum and mass spectrum were as follows:
bruker model is selected for nuclear magnetic resonance apparatus ,1HNMR(300MHz,CDCl3)6.972-6.851(t,1H),6.663-6.623(d,1H,J＝12Hz),6.623(d,1H,J＝12Hz),3.912-3.901(m,1H),3.872-3.832(m,1H),3.597(br,2H,),2.061-1.965(m,2H),1.375-1.321(m,2H),.
MS-EI(m/z,%):240(M++H+);262(M++Na+)。
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