CN116239468A - Preparation method of 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester - Google Patents

Preparation method of 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester Download PDF

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CN116239468A
CN116239468A CN202310129162.4A CN202310129162A CN116239468A CN 116239468 A CN116239468 A CN 116239468A CN 202310129162 A CN202310129162 A CN 202310129162A CN 116239468 A CN116239468 A CN 116239468A
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diethyl
methylphenyl
acetic acid
methyl
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孙智华
郑慧贇
吴惠屹
杨希辰
陈思远
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Shanghai University of Engineering Science
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/29—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with halogen-containing compounds which may be formed in situ
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Abstract

The invention relates to the field of organic synthesis, in particular to a preparation method of pinoxaden intermediate 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester. The method comprises the following steps: (1) 2, 6-diethyl-4-methyl halogenated benzene and magnesium generate Grignard reagent, and ethylene oxide is added to generate 2- (2, 6-diethyl-4-methylphenyl) -ethanol; (2) 2- (2, 6-diethyl-4-methylphenyl) -ethanol to 2- (2, 6-diethyl-4-methylphenyl) -acetic acid; (3) 2- (2, 6-diethyl-4-methylphenyl) -acetic acid and methanol to form 2- (2, 6-diethyl-4-methylphenyl) -acetic acid methyl ester; (4) Methyl 2- (2, 6-diethyl-4-methylphenyl) -acetate, with a base and dimethyl formate to form dimethyl 2- (2, 6-diethyl-4-methylphenyl) -malonate. The method uses the epoxy hexane as the raw material, has short synthesis steps and high yield in each step, avoids the use of expensive transition metal and ligand, has the advantage of industrial production, and has important significance for the production of pinoxaden.

Description

Preparation method of 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of a pinoxaden key intermediate 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester.
Background
The pinoxaden is a phenyloxazoline herbicide developed by the company Neoprene, is an acetyl coenzyme A Acidylase (ACC) inhibitor and is mainly used for preventing and killing gramineous weeds in a barley field.
In the process of preparing the pesticide, the compound (1) 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester is a key intermediate for synthesizing pinoxaden.
Figure BDA0004083166790000011
The current synthesis of compound (1) is reported according to Pest Manag Sci 201nj. Org. Chem.67,1499 as follows:
1, 3-dibromo-5-methyl-2- (2, 2-trichloroethyl) -benzene is generated from 2, 6-dibromo-4-methylaniline, acetonitrile and tert-butyl nitrite, and then (2, 6-dibromo-4-methyl-phenyl) -acetic acid methyl ester is generated by acetylation and acid treatment of methanol and sodium methoxide.
Reacting (2, 6-dibromo-4-methyl-phenyl) -methyl acetate with ethylene, and refluxing in DMA (direct memory access) by taking bis (triphenylphosphine) palladium (II) chloride and triphenylphosphine as catalysts to generate (2, 6-divinyl-4-methyl-phenyl) -methyl acetate; hydrogenation to generate 2- (2, 6-diethyl-4-methylphenyl) -acetic acid methyl ester, adding NaH into dimethyl carbonate to reflux and react to generate 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester.
Alternatively, methyl (2, 6-dibromo-4-methyl-phenyl) -acetate is added into methyl carbonate, naH is added dropwise into the mixture for reflux reaction to generate 2- (2, 6-dibromo-4-methylphenyl) -malonic acid dimethyl ester, tributylvinyltin is added into the mixture, tetra (triphenylphosphine) palladium is used as a catalyst to generate 2- (2, 6-divinyl-4-methylphenyl) -malonic acid dimethyl ester, and hydrogenation is carried out to generate 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester.
Figure BDA0004083166790000021
Wherein, bromine needs to be replaced by vinyl and then hydrogenation is carried out to obtain a final product, and the required raw materials have high price or toxicity and are difficult to realize industrialized mass production.
There is therefore a need for improvements in the art to reduce costs.
Disclosure of Invention
Aiming at the technical problems, the invention provides a preparation method of a pinoxaden key intermediate.
The technical scheme of the invention is as follows: a method for preparing 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester, which uses ethylene oxide as a raw material to prepare pinoxaden intermediate, wherein the intermediate is 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester, and comprises the following steps:
(1) Grignard reagent is formed by 2, 6-diethyl-4-methyl halogenated benzene (compound (2)) and magnesium, and ethylene oxide is added to form 2- (2, 6-diethyl-4-methylphenyl) -ethanol (compound (3));
Figure BDA0004083166790000022
(2) 2- (2, 6-diethyl-4-methylphenyl) -ethanol to 2- (2, 6-diethyl-4-methylphenyl) -acetic acid (compound (4));
Figure BDA0004083166790000031
(3) 2- (2, 6-diethyl-4-methylphenyl) -acetic acid and methanol to form methyl 2- (2, 6-diethyl-4-methylphenyl) -acetate (compound (5));
Figure BDA0004083166790000032
(4) 2- (2, 6-diethyl-4-methylphenyl) -acetic acid methyl ester with base and dimethyl formate to produce 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester (compound (1)).
Figure BDA0004083166790000033
In the step (1), the Grignard reagent is prepared by mixing magnesium and an initiator in a solvent and adding 2, 6-diethyl-4-methyl halogenated benzene. The reaction is carried out at a temperature of 0 to 100℃and preferably at a temperature of 40 to 60 ℃.
The solvent is diethyl ether, tetrahydrofuran or dioxane; the initiator is at least one of iodine, DMF and dibromoethane, preferably iodine and dibromoethane.
The halogen element on the 2, 6-diethyl-4-methyl halogenated benzene is Cl, br or I, preferably Br.
In step (1), the molar ratio of Grignard reagent to ethylene oxide is 1:0.9-1.1, preferably 1:1, a step of; the reaction temperature is-80 to 20 ℃, preferably-5 to 5 ℃, and in a preferred embodiment of the invention, the reaction temperature is 0 ℃. The solvent used for the reaction of the grignard reagent with ethylene oxide is diethyl ether, tetrahydrofuran or dioxane.
After the Grignard reagent and the ethylene oxide are completely reacted, adding hydrochloric acid solution, and separating an organic phase; the aqueous phase was extracted with ethyl acetate and the organic phases were combined to give the corresponding ring-opened product compound (3) 2- (2, 6-diethyl-4-methylphenyl) -ethanol.
In step (2), the oxidation is carried out with an oxidizing agent which is a peroxy compound, e.g. KOCl, naOCl, KClO 2 、NaClO 2 、NaBrO 2 Swen oxidizer, cr oxidizer, or Mn oxidizer.
The dosage ratio of the 2- (2, 6-diethyl-4-methylphenyl) -ethanol to the oxidant is 1:2-2.5.
Reaction conditions of step (2): adding 2- (2, 6-diethyl-4-methylphenyl) -ethanol into the mixture of acetonitrile and water containing bicarbonate, and slowly adding an oxidant until the reaction is complete. Preferably, tempo (tetramethylpiperidine oxide) is added as catalyst.
In the reaction system, the content of bicarbonate ions is 2% -3.5%; the mass ratio of water to acetonitrile in the reaction system is 1:0.8-1.25.
After the reaction was completed, the organic phase was extracted with water and methylene chloride, and the aqueous phase was extracted with methylene chloride, and the organic phases were combined to obtain compound (4) 2- (2, 6-diethyl-4-methylphenyl) -acetic acid.
Step (3), adding SOCl to the compound (4) 2- (2, 6-diethyl-4-methylphenyl) -acetic acid by a conventional esterification method such as an alcoholic solvent 2 Or concentrated H 2 SO 4 To obtain the compound (5) methyl 2- (2, 6-diethyl-4-methylphenyl) -acetate.
Specifically, SOCl is added into absolute methanol 2 Or concentrated H 2 SO 4 And compound (4), reflux reaction to completion. After the reaction, water and ethyl acetate were added, and the organic phase was washed and dried to remove the solvent.
And (4) extracting hydrogen at the alpha position of the compound (5) by using alkali, reacting with dimethyl formate, and performing alpha-methoxy formylation to obtain the compound (1). The alkali comprises NaH, KOH, KH, liOH, na 2 CO 3 Or K 2 CO 3 。
The reaction condition of the step (4) is that the compound (5) 2- (2, 6-diethyl-4-methylphenyl) -methyl acetate and alkali are respectively dissolved in dimethyl formate to prepare solution A and solution B, and the solution A is dropwise added into the solution B under the protection atmosphere and in a reflux state, so that the reaction is complete. The dosage ratio of the compound (5) 2- (2, 6-diethyl-4-methylphenyl) -acetic acid methyl ester to the alkali is 1:4-5. After the reaction is completed, the reaction is extinguished by methanol, after the dimethyl formate is recovered, the mixture is acidified, water and dichloromethane are used, and an organic phase is taken, washed, dried and purified.
The overall reaction steps are as follows:
Figure BDA0004083166790000051
the yield of 2- (2, 6-diethyl-4-methylphenyl) -acetic acid methyl ester obtained by taking 2, 6-diethyl-4-methyl halogenated benzene as a raw material is about 57.5%, and the total yield of 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester is about 45%.
The invention adopts bromobenzene Grignard reagent to react with ethylene oxide to form 2- (2, 6-diethyl-4-methylphenyl) -ethanol, and then the target compound 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester is generated through oxidation, esterification and alpha-methoxy formylation reaction. The process provided by the invention adopts ethylene oxide as a raw material, has the advantages of short synthesis steps and high yield in each step, avoids the use of expensive transition metal and ligand, has the advantage of industrial production, and has important significance for the production of pinoxaden.
Detailed Description
The technical features of the technical solutions provided in the present invention will be further clearly and completely described in connection with the specific embodiments, but the scope of the present invention is not limited by these examples.
It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1 Synthesis of dimethyl 2- (2, 6-diethyl-4-methylphenyl) -malonate using ethylene oxide (Compound 1)
The first step: synthesis of 2- (2, 6-diethyl-4-methylphenyl) -ethanol (Compound 3)
Figure BDA0004083166790000061
2.46 g (0.103 mol) of magnesium turnings are added into 80 ml of dry tetrahydrofuran under the protection of nitrogen, 0.11 g (0.0004 mol) of iodine and 0.88 g (0.0044 mol) of 1, 2-dibromoethane are added, the reaction solution is heated to 50 ℃,20 g (0.088 mol) of 2, 6-diethyl-4-methyl bromobenzene is slowly added into the reaction solution in a dropwise manner, the internal temperature is not more than 60 ℃, after the dropwise addition, the reaction solution is continuously reacted at 50 ℃ for 2 hours, and the reaction solution is cooled to room temperature. 3.87 g (0.088 mol) of ethylene oxide is dissolved in 100 ml of tetrahydrofuran, the temperature is reduced to 0 ℃, the prepared Grignard reagent is dripped into the reaction liquid under the protection of nitrogen, the reaction liquid is naturally cooled to room temperature after dripping, stirring is continued for 12 hours until the raw materials disappear, then 100 ml of 1M hydrochloric acid is added, an organic phase is separated, an aqueous phase is extracted with 200 ml of ethyl acetate, the organic phases are combined, dried and purified, and 12 g of compound (3) is obtained, and the yield is 72%.
1 HNMR(CDCl 3 ，400MHz)δ:1.22(6H,t,J＝7.7Hz),2.29.(3H,s),2.66(4H,q,J＝7.7Hz),2.95(2H,t,J＝7.7Hz),3.7 4(2H,t,J＝7.7Hz),6.88(2H,s).
And a second step of: synthesis of 2- (2, 6-diethyl-4-methylphenyl) -acetic acid (4)
Figure BDA0004083166790000062
1.8 g of sodium bicarbonate was dissolved in 17.5 g of water, 20 g of acetonitrile was further added, 1.92 g (10 mmol) of compound (4) and 0.1 g (0.2 mmol) of TEMPO were added to the above solution, cooled to 0℃and 0.14 g (0.2 mmol) of 11% aqueous sodium hypochlorite solution was slowly added dropwise for 30 minutes, under this reaction condition, 2.4 g (21 mmol) of aqueous sodium hypochlorite solution was continuously added again, the reaction was detected to be completed, 100 ml of water and 200 ml of methylene chloride were added, the organic phase was separated, the aqueous phase was once again extracted with methylene chloride, the organic phase was combined, washed with water, dried, the solvent was recovered under reduced pressure, and silica gel was separated and purified to obtain 1.77 g of compound (4) in 86% yield.
1 HNMR(CDCl 3 ，400MHz)δ:1.19(6H,t,J＝7.6Hz),2.30(3H,s),2.62(4H,q,J＝7.6Hz),3.73(2H,s),6.90(2H,s).
And a third step of: synthesis of methyl 2- (2, 6-diethyl-4-methylphenyl) -acetate (5)
Figure BDA0004083166790000071
To 30 ml of anhydrous methanol, 0.2 ml of concentrated sulfuric acid and 2.06 g (10 mmol) of compound (4) were added, and the mixture was refluxed for 3 hours, and after the completion of the reaction, cooling, water and ethyl acetate were added, the organic phase was washed with saturated sodium carbonate, water, and the organic phase was dried, the solvent was recovered under reduced pressure, and silica gel was separated and purified to give 2.05 g of compound (5) with a yield of 93%.
1 HNMR(CDCl 3 ,400MHz):δ＝1.20(t,6H),2.32(s,3H),2.62(1,4H),3.67(s,3H),2.72(s,2H),6.93(s,2H).
Fourth step: synthesis of dimethyl 2- (2, 6-diethyl-4-methylphenyl) -malonate (1)
Figure BDA0004083166790000072
2.2 g (0.01 mol) of compound (5) is dissolved in 20 ml of dimethyl formate to prepare solution A, 1.71 g (0.044 mol) of NaH is suspended in 120 ml of dimethyl formate to prepare solution B, the solution A is dropwise added into the solution B under the protection of nitrogen under the reflux state, after the dropwise addition, the mixture is kept at reflux for 10 hours, the reaction is detected, the temperature is reduced to 0 ℃ and 20 ml of absolute methanol is slowly dropwise added to extinguish the reaction, most of dimethyl formate is recovered, then diluted hydrochloric acid is acidified, water and dichloromethane are added, an organic phase is washed by saturated sodium carbonate, the water is dried, the solvent is recovered under reduced pressure, silica gel is separated and purified, and 2.17 g of compound (1) is obtained, and the yield is 78%.
1HNMR (400 MHz, CDCl 3) delta ppm:1.18 (t, J=7.5 Hz, 6H), 2.30 (s, 3H), 2.64 (q, J=7.5 Hz, 4H), 3.73 (s, 6H), 5.06 (s, 1H), 6.93 (s, 2H), 13CNMR (101 MHz, CDCl 3) delta ppm:15.2,21.1,26.6,51.5,52.6,126.4,127.9,137.9,143.6,169.3 MS (ES+) m/z 279 (C16H 22O4 +H) +,301 (C16H 22O4 +Na) +HRMS (H-ESI+) m/z: calcd for (C16H 22O4 +Na) + 301.1410; found 301.1411 example 2
Synthesis of I.8- (2, 6-diethyl-4-methylphenyl) tetrahydropyrrole [1,2-d ] [1,4,5] oxydiaza-7, 9-dione heptane (Compound 7)
Figure BDA0004083166790000081
27.8 g (0.1 mol) of dimethyl 2- (2, 6-diethyl-4-methylphenyl) maleate are dissolved in 200 ml of xylene, 19 g (0.11 mol) of 1,4, 5-oxydiazepane dihydrochloride are added at room temperature, 22 g (0.21 mol) of triethylamine are heated to 60℃and reacted for 1 hour, after 1,4, 5-oxydiazepane is converted to the free state, the reaction is further heated to reflux, the ethanol produced by the reaction can be removed in the middle, the reaction is no longer produced until the ethanol is produced, approximately the reflux (alcohol removal) is required for 5 hours, the reaction is ended, cooled to room temperature, triethylamine hydrochloride is filtered off, xylene is recovered, the crude product is purified by reprecipitation of sodium salt, hydrochloric acid conditioning recovery is carried out, specifically, 300 ml of 1N sodium hydroxide solution is added, the crude product is dissolved, then washed 2 times with dichloromethane (discarding), the basic aqueous solution is adjusted to pH 2 to 3 with 4N brine, white solid is precipitated) and dried to obtain 29 g of white powder, the yield is 98%, purity is 98%.
1 H NMR(CDCl 3 ):δ2.06(s,3H),2.25(s,3H),2.39(s,3H),3.81(ddd,2H),3.92–4.02(m,4H),4.22(ddd,2H),4.72(s,1H),6.83(s,1H),6.93(s,1H). 13 CNMR(CDCl 3 ):δ20.0,20.9,21.0,46.1,48.3,70.5,125.9,129.5,130.0,136.1,138.2,138.4,165.5.MS(ES + )m/z:289(C16H20N2O3+H) + .
II Synthesis of pinoxaden (Compound 8)
Figure BDA0004083166790000091
Under the protection of nitrogen, 20 g of 8- (2, 6-diethyl-4-methylphenyl) tetrahydropyrrole [1,2-d ] [1,4,5] oxydiaza-7, 9-dione heptane is dissolved in 200 ml of dry tetrahydrofuran, cooled to 20 ℃,16 g of triethylamine and 0.2 g of 4-dimethylaminopyridine are added under stirring, 50 g of pivaloyl chloride is dropwise added, the reaction temperature is kept at 20-25 ℃ until the reaction is finished, the reaction solution is washed with 20% of saline, the organic phase is dried and concentrated, the crude product is recrystallized in methyl tertiary butyl ether, and the dried product is obtained, wherein 19 g of pinoxaden with the purity of 98.1% and the yield is 75%.
Mp：122-123℃. 1 H NMR(CDCl 3 ):δ1.03(s,9H),1.12(t,6H),2.29(s,3H),2.35-2.63(m,4H),3.81-3.90(m,4H),3.93(m,2H),4.26(m,2H),6.88(s,2H). 13 C NMR(CDCl 3 ):δ14.7,21.3,26.3,26.4,39.1,45.6,49.5,69.4,70.6,97.3,122.7,126.0,137.7,144.3,149.1,162.0,174.1.FD-MS m/z:400(C23H32N2O4) + .HRMS(EI+)m/z:Calcd for(C23H32N2O4) + :400.2362；Found:400.2361.

Claims (9)

  1. The preparation method of the 2- (2, 6-diethyl-4-methylphenyl) -acetic acid methyl ester is characterized by comprising the following steps:
    (1) 2, 6-diethyl-4-methyl halogenated benzene and magnesium generate Grignard reagent, and ethylene oxide is added to generate 2- (2, 6-diethyl-4-methylphenyl) -ethanol;
    (2) 2- (2, 6-diethyl-4-methylphenyl) -ethanol to 2- (2, 6-diethyl-4-methylphenyl) -acetic acid;
    (3) 2- (2, 6-diethyl-4-methylphenyl) -acetic acid and methanol to form 2- (2, 6-diethyl-4-methylphenyl) -acetic acid methyl ester;
    (4) Methyl 2- (2, 6-diethyl-4-methylphenyl) -acetate, with a base and dimethyl formate to form dimethyl 2- (2, 6-diethyl-4-methylphenyl) -malonate.
  2. 2. The preparation method according to claim 1, wherein in the step (1), the grignard reagent is prepared by mixing magnesium with an initiator in a solvent and adding 2, 6-diethyl-4-methyl halogenated benzene.
  3. 3. The method according to claim 2, wherein the halogen element on the 2, 6-diethyl-4-methyl halogenated benzene is Cl, br or I.
  4. 4. The method of claim 1, wherein the reaction conditions of step (2): adding 2- (2, 6-diethyl-4-methylphenyl) -ethanol into the mixed solution of acetonitrile and water containing bicarbonate, and slowly adding an oxidant until the reaction is complete;
    the dosage ratio of the 2- (2, 6-diethyl-4-methylphenyl) -ethanol to the oxidant is 1:2-2.5; the oxidizing agent used is a peroxy compound.
  5. 5. The method of claim 4, wherein the peroxy compound comprises hydrogen peroxide, hypochlorous acid, naOCl, KOCl, naClO 2 、NaBrO 2 、KClO 2 Swern oxidant, m-chloroperoxybenzoic acid, peracetic acid, cr-based oxidant or Mn-based oxidant.
  6. 6. The preparation method according to claim 4, wherein the content of bicarbonate ions in the reaction system is 2% -3.5%; the mass ratio of water to acetonitrile in the reaction system is 1:0.8-1.25.
  7. 7. The process of claim 1, wherein the reaction conditions in step (3) are that SOCl is added to anhydrous methanol 2 Or concentrated H 2 SO 4 And 2- (2, 6-diethyl-4-methylphenyl) -acetic acid, and refluxing to completion.
  8. 8. The preparation method according to claim 1, wherein the reaction condition of the step (4) is that 2- (2, 6-diethyl-4-methylphenyl) -acetic acid methyl ester and alkali are respectively dissolved in dimethyl formate to prepare solution A and solution B, and the solution A is dropwise added into the solution B under the protection atmosphere and in a reflux state, so that the reaction is complete.
  9. 9. The process according to claim 1 or 7, wherein the ratio of methyl 2- (2, 6-diethyl-4-methylphenyl) -acetate to base is 1:4-5.
CN202310129162.4A 2023-02-17 2023-02-17 Preparation method of 2- (2, 6-diethyl-4-methylphenyl) -malonic acid dimethyl ester Pending CN116239468A (en)

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