CN112441967A - Preparation method of methoxybenzene cry bacterial intermediate - Google Patents
Preparation method of methoxybenzene cry bacterial intermediate Download PDFInfo
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- CN112441967A CN112441967A CN202011291671.XA CN202011291671A CN112441967A CN 112441967 A CN112441967 A CN 112441967A CN 202011291671 A CN202011291671 A CN 202011291671A CN 112441967 A CN112441967 A CN 112441967A
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- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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Abstract
本发明提供一种新的甲氧苯唳菌中间体的制备方法，采用5‑氯‑2‑甲氧基‑4‑甲基烟醛和(2,3,4‑三甲氧基‑6‑甲基苯基)硼酸在镍系催化剂作用下反应，制备得到(5‑氯‑2‑甲氧基‑4‑甲基吡啶‑3‑基)(2,3,4‑三甲氧基‑6‑甲基苯基)甲醇。本发明所述方法为甲氧苯唳菌中间体的制备提供了新的思路；采用的镍系催化剂配合其他反应条件，得到(5‑氯‑2‑甲氧基‑4‑甲基吡啶‑3‑基)(2,3,4‑三甲氧基‑6‑甲基苯基)甲醇的收率更高。The present invention provides a new preparation method of methoxybenzine intermediate, which adopts 5-chloro-2-methoxy-4-methylnicotinaldehyde and (2,3,4-trimethoxy-6-methylnicotinaldehyde) (5-chloro-2-methoxy-4-methylpyridine-3-yl) (2,3,4-trimethoxy-6-methyl) phenyl) methanol. The method of the invention provides a new idea for the preparation of the methoxybenzine intermediate; the adopted nickel-based catalyst cooperates with other reaction conditions to obtain (5-chloro-2-methoxy-4-picoline-3 -yl) (2,3,4-trimethoxy-6-methylphenyl)methanol in higher yields.
Description
Technical Field
The invention relates to the field of pesticides, and particularly relates to a preparation method of a methoxybenzene cry bacterium intermediate.
Background
Methoxybenzene cry bacterium (Pyriofenone), IUPAC chemical name: (5-chloro-2-methoxy-4-methylpyridin-3-yl) -2,3, 4-trimethoxy-6-methylphenyl ketone with CAS number 688046-61-9, belonging to SHID bactericide, and the action mechanism belongs to U8, and the specific action mechanism is unknown. In preventive application, the substance can inhibit the formation of pathogenic bacteria adherent spore and subsequent infiltration of mycelium into plant cells; after the disease appears, the application can inhibit the formation of pathogenic bacteria secondary hypha, mycelium and spore; the bactericidal composition is mainly used for crops such as grains, rice, fruit trees, vegetables and the like, prevents and treats powdery mildew, and has high efficiency on the powdery mildew.
EP1559320 and CN1874680 disclose various methods for the preparation of Pyriofenone.
For example, EP1559320 discloses the following general scheme, which proceeds via a multi-step reaction in which the intermediate (2,3, 4-trimethoxy-6-methylphenyl) (4, 5-dichloro-2-methoxy-3-pyridyl) methanol is obtained by reacting 4, 5-dichloro-2-methoxypyridine with 2,3, 4-trimethoxy-6-methylbenzaldehyde in a low yield of only 51% and Pyriofenone in a yield of 75%.
For example, CN1874680 discloses a plurality of synthetic examples for the preparation of Pyriofenone, and the yield of Pyriofenone is low in most of the synthetic examples, for example, synthetic example 4, although the yield of Pyriofenone is 90%, the intermediate (5-chloro-2-methoxy-4-methylpyridin-3-yl) (2,3, 4-trimethoxy-6-methylphenyl) methanol was prepared as 5-chloro-2-methoxy-4-methyl-3-pyridylmagnesium chloride by 3-bromo-5-chloro-2-methoxy-4-methylpyridine and further reacted with 2,3, 4-trimethoxy-6-methylbenzaldehyde, and the yield was only 70%.
Therefore, it is a problem to be solved to increase the yield of Pyriofenone intermediate, particularly (5-chloro-2-methoxy-4-methylpyridin-3-yl) (2,3, 4-trimethoxy-6-methylphenyl) methanol.
Disclosure of Invention
The present invention has been made to solve the above problems and an object of the present invention is to achieve a high yield of Pyriofenone by increasing the yield of (5-chloro-2-methoxy-4-methylpyridin-3-yl) (2,3, 4-trimethoxy-6-methylphenyl) methanol.
In one aspect, the invention provides a preparation method of a novel methoxybenzene cry bacterial intermediate, wherein the intermediate M3 is prepared by the following reaction:
wherein:
the reaction is carried out in an alkaline system under the action of a catalyst.
The chemical names of M1, M2 and M3 are respectively as follows:
m1: 5-chloro-2-methoxy-4-methylnicotinaldehyde;
m2: (2,3, 4-trimethoxy-6-methylphenyl) boronic acid;
m3: (5-chloro-2-methoxy-4-methylpyridin-3-yl) (2,3, 4-trimethoxy-6-methylphenyl) methanol.
The arylboronic acid M2 is used as a reaction material, and has the advantages of good thermal stability, functional group compatibility, insensitivity to air and water and the like.
In some embodiments, the molar ratio of M1 to M2 is 1 (0.8-5). For example, the molar ratio of M1 to M2 is 1:0:8, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, and so forth.
In some embodiments, the catalyst of the present invention is one or more of rhodium-based catalyst, palladium-based catalyst, nickel-based catalyst, copper-based catalyst, and iron-based catalyst.
In still other embodiments, the rhodium-based catalyst is selected from [ RhCl (cod) ]]2、RhCl3 .3H2O、Rh(PPh3)3Cl、Rh2(OAc)4And one or more of Rh-NHC complex.
In still other embodiments, the palladium-based catalyst is selected from Pd (OAc)2、PdCl2/P(1-Nap)3、[Pd(allyl)Cl]2、PdCl2(PPh3)2One or more of (a).
In still other embodiments, the nickel-based catalyst is selected from the group consisting of Ni (cod)2、NiCl2 .6H2O、Ni(OAc)2 .4H2O、Ni(acac)2 .2H2O、NiCl2(PPh3)2One or more of (a).
In still other embodiments, the copper-based catalyst is selected from cuprous iodide and/or cupric acetate.
In still other embodiments, the iron-based catalyst is selected from ferric chloride.
In the prior art, noble metals such as rhodium, palladium and the like are used for similar reactions; the invention adopts the nickel catalyst, and can obtain good catalytic effect while reducing the cost.
Preferably, the first and second electrodes are formed of a metal,the nickel catalyst is NiCl2(PPh3)2Are commercially available or can be prepared by methods conventional in the art.
For example, NiCl2(PPh3)2The preparation method of (A) can be as follows: dissolving nickel chloride hexahydrate in absolute ethyl alcohol, dripping absolute ethyl alcohol containing triphenylphosphine, stirring and refluxing in nitrogen atmosphere to obtain dark green solution, cooling, standing, precipitating solid, filtering, washing, and vacuum drying.
In some embodiments, the molar ratio of M1 to the catalyst is 1 (0.01-0.10). For example, M1 may be used in a molar ratio to the catalyst of 1:0.01, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.10, and the like.
In some of these embodiments, the base is one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, sodium acetate.
Preferably, the base is potassium phosphate.
Further, the amount of the base used is not particularly limited; for example, the molar ratio of M1 to base is 1 (1-2), specifically, 1:1, 1:1.2, 1:1.25, 1:1.3, 1:1.4, 1:1.5, 1:2, etc.
In still other embodiments, the reaction is carried out in a solvent system that is one or more of dimethyl sulfoxide (DMSO), toluene, acetonitrile, Tetrahydrofuran (THF), methyl tert-butyl ether (MTBE), 1, 4-dioxane, ethanol, isopropanol, tert-butanol, acetone, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), water.
Research shows that the solvent system has great influence on the reaction; preferably, the solvent is one or two of toluene or tetrahydrofuran; further preferably, the solvent is a mixture of toluene and tetrahydrofuran.
More preferably, the volume ratio of toluene to tetrahydrofuran is (3-10):1 or (6-9): 1. For example, the volume ratio of toluene to tetrahydrofuran is 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, and so forth.
Most preferably, the volume ratio of toluene to tetrahydrofuran is 9: 1.
Furthermore, the total volume of the solvent is not particularly required, and the reaction can be carried out smoothly, for example, the ratio of M1 to the total volume of the solvent may be 1mmol (10 to 30) mL, based on M1.
In some embodiments, the reaction temperature is 70-130 ℃, for example, the reaction temperature is 70 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃, 100 ℃, 110 ℃, 120 ℃, 130 ℃, etc.
In some embodiments, the reaction is carried out for a reaction time of 6 to 20 hours, e.g., the reaction is carried out for a reaction time of 6 hours, 8 hours, 9 hours, 10 hours, 12 hours, 16 hours, 20 hours, etc.
In still other embodiments, the present invention provides a novel process for preparing an intermediate of methoxybenzene cry bacterium, said intermediate M3 being prepared by reacting M1 with M2:
wherein:
the reaction is carried out in a solvent under the action of a catalyst and an alkaline environment;
the solvent is toluene and tetrahydrofuran, wherein the volume ratio of toluene to tetrahydrofuran is (3-10) to 1 or (6-9) to 1; specifically, the volume ratio of toluene to tetrahydrofuran is 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10: 1;
the base is potassium phosphate;
the catalyst is NiCl2(PPh3)2；
The molar using amount ratio of the M1 to the M2 is 1 (0.8-5); specifically, the molar ratio of M1 to M2 is 1:0:8, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4 or 1: 5;
the molar using amount ratio of the M1 to the catalyst is 1 (0.01-0.10); specifically, the molar ratio of the M1 to the catalyst is 1:0.01, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09 or 1: 0.10.
On the other hand, the invention provides a preparation method of methoxybenzene cry bacteria, which comprises the step of carrying out oxidation reaction on the intermediate M3 to obtain the methoxybenzene cry bacteria.
Preferably, the oxidizing agent of the oxidation reaction is activated manganese dioxide, chromic acid or tert-butyl peroxide.
Specifically, for example, the intermediate (5-chloro-2-methoxy-4-methylpyridin-3-yl) (2,3, 4-trimethoxy-6-methylphenyl) methanol of the present invention is dissolved in a toluene solution, activated manganese dioxide is added, the mixture is stirred under heating reflux, filtered, and the solvent is removed under reduced pressure, so that a methoxybenzene cry bacterial product can be obtained.
Compared with the prior art, the invention has the beneficial effects that: (1) the (5-chloro-2-methoxy-4-methylpyridin-3-yl) (2,3, 4-trimethoxy-6-methylphenyl) methanol is prepared by adopting a new synthetic route, and a new thought is provided for the preparation of a methoxybenzene cry bacterium intermediate; (2) using NiCl as a nickel-based catalyst2(PPh3)2And other reaction conditions are matched to obtain a better catalytic effect, and compared with the prior art, the yield of (5-chloro-2-methoxy-4-methylpyridin-3-yl) (2,3, 4-trimethoxy-6-methylphenyl) methanol can be obviously improved.
Detailed Description
The present invention will be described in detail below by way of examples. In the following examples, various starting materials used are either commercially available or may be prepared by methods conventional in the art, unless otherwise specified. The following examples are not all-inclusive and other examples that may be obtained by one of ordinary skill in the art without making any inventive step are within the scope of the present invention.
Preparation of intermediate (5-chloro-2-methoxy-4-methylpyridin-3-yl) (2,3, 4-trimethoxy-6-methylphenyl) methanol
Example 1
A50 mL three-necked flask was charged with potassium phosphate (1mmol,212mg) and NiCl2(PPh3)2(0.04mmol,26.16mg) followed by the addition of 5-chloro-2-methoxy-4-methylnicotinaldehyde (E1mmol,185.6mg) and (2,3, 4-trimethoxy-6-methylphenyl) boronic acid (1.5mmol,339mg), followed by addition of dimethyl sulfoxide (17.5mL), heating the mixture to 80 ℃ under nitrogen atmosphere for reaction for 8h, cooling to room temperature, filtering, removing the solvent under reduced pressure, and purifying by silica gel column chromatography (eluent: ethyl acetate: petroleum ether is 1: 4) 121.4mg of a pale yellow oil are obtained in 33% yield and 98.3% purity.
1H NMR(CDCl3,300MHz)δ2.24(s,3H),2.27(s,3H),3.56(s,3H),3.80(s,3H),3.84(s,3H),3.95(s,3H),5.34(d,J＝9.0Hz,1H),6.10(d,J＝9.0Hz,1H),6.50(s,1H),8.02(s,1H).
Examples 2-16 below were prepared in a similar manner to example 1 to provide intermediate M3 according to the present invention.
TABLE 1
From the results in Table 1, it can be seen that:
(1) under the same other reaction conditions, the solvent system has an influence on the yield of the intermediate, and when a toluene/THF system is used and the volume ratio of the toluene/THF system to the intermediate is in the range of 6/1-9/1, the intermediate is obtained in higher yield;
(2) under the same other reaction conditions, the type of the base has an influence on the yield of the intermediate of the invention, and when potassium phosphate is used, the yield of the intermediate of the invention is higher;
(3) under the same other reaction conditions, the type of the catalyst has an influence on the yield of the intermediate of the invention, and the nickel-based catalyst of the invention can be used for obtaining the intermediate of the invention with higher yield.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.
Claims (10)
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| CN101822253A (en) * | 2003-10-31 | 2010-09-08 | 石原产业株式会社 | Fungicide composition and method for preventing and controlling plant diseases |
| JP2011098909A (en) * | 2009-11-06 | 2011-05-19 | Sagami Chemical Research Institute | Method for producing alcohols |
| CN102584511A (en) * | 2011-01-05 | 2012-07-18 | 郑建鸿 | Preparation method of secondary alcohol |
| CN109265319A (en) * | 2017-07-17 | 2019-01-25 | 中国科学院化学研究所 | The preparation method of two (miscellaneous) aryl first alcohol compounds |
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2020
- 2020-11-18 CN CN202011291671.XA patent/CN112441967B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010031777A1 (en) * | 2000-02-11 | 2001-10-18 | Dyke Hazel Joan | Heterocyclic compounds and their therapeutic use |
| CN1440389A (en) * | 2000-07-05 | 2003-09-03 | 石原产业株式会社 | Benzoylpyridine drivative or its salt, fungicide containing it as active ingredient, its production process and intermediate for producing it |
| JP2004143152A (en) * | 2002-10-03 | 2004-05-20 | Canon Inc | Method for producing halogenated aromatic amine compound |
| US20060089390A1 (en) * | 2002-10-31 | 2006-04-27 | Ishihara Sangyo Kaisha, Ltd. | 3-benzoyl-2,4,5-substituted pyridine derivatives or salts thereof and bactericides containing the same |
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| CN101456790A (en) * | 2008-11-04 | 2009-06-17 | 大连理工大学 | Method for preparing diaryl alcohol by catalyzing addition reaction of aryl boric acid and aldehyde by nickel |
| JP2011098909A (en) * | 2009-11-06 | 2011-05-19 | Sagami Chemical Research Institute | Method for producing alcohols |
| CN102584511A (en) * | 2011-01-05 | 2012-07-18 | 郑建鸿 | Preparation method of secondary alcohol |
| CN109265319A (en) * | 2017-07-17 | 2019-01-25 | 中国科学院化学研究所 | The preparation method of two (miscellaneous) aryl first alcohol compounds |
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