A kind of preparation process of hexazinone

Abstract

The invention provides a preparation process of cycloazinone. By using a new raw material and an intermediate, the raw material conversion rate and the product purity can be effectively improved, and no special catalyst is needed. The process flow is simple and the production cost can be significantly reduced, so the process has good industrial application value.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a preparation process of cycloazinone. Background Art

[0002] Hexazinone is also known as Wilber, Lincaojing, Feicaojing, and Sentai; its chemical name is 3-cyclohexyl-6-dimethylamino-1-methyl-1,3,5-triazine-2,4-dione. It is a colorless, odorless crystalline solid and belongs to the triazine ketone class of selective, post-emergence contact herbicides. This product is extremely lethal to forest weeds, shrubs, vines and other plants. It can be absorbed by the stems and leaves of plants, and conducted inside the plant using the xylem to directly interfere with the photosynthesis of plants, causing metabolic disorders in plants and leading to plant death; it can also be absorbed by the roots of plants and then conducted to the stems and leaves to interfere with the photosynthesis of plants, causing metabolic disorders and leading to plant death. In addition to its weed control and irrigant activity, hexazinone also has the effect of killing fungi and bacteria in plants. For example, it can effectively prevent and control wheat infections caused by Puccinia.

[0003] At present, the synthesis methods of cycloazinone at home and abroad mainly refer to U.S. Patents US4178448 and US4150225. The synthesis of triazine rings uses a strong base as a cyclization catalyst, so that the alcohol generated by the cyclization exchanges with the dimethylamine group of cycloazinone to generate cyclization side reaction products, which affects the yield.

[0004] The following is a general hexazinone synthesis route:

[0005]

[0006]

[0007] Common catalysts for the cyclization reaction include inorganic strong bases, organic alcohol metal strong bases, etc. The ethanol generated by the reaction undergoes a reversible exchange side reaction of dimethylamine shedding with the cyclization product hexazinone in the presence of a strong base catalyst. The reaction formula is as follows:

[0008]

[0009] There are two common methods for inhibiting the side reaction in the prior art: one is to introduce an equivalent amount of dimethylamine or more to inhibit the dimethylamine from falling off; the other is to remove the alcohol generated by the reaction in time to prevent the side reaction from occurring. Both schemes have disadvantages: in the first scheme, the gaseous dimethylamine introduced must be removed by adding water, and the waste water generated increases the environmental pressure, and the use of dimethylamine has safety hazards. In addition, this scheme cannot completely inhibit the side reaction, and about 10% of the side reaction still occurs.

[0010] In order to avoid the occurrence of cyclization side reactions, CN104402837A discloses a new synthesis route of hexazinone, which includes two steps of reaction: in the first step, guanidine is reacted with cyclohexylamine to generate a guanidinyl urea intermediate and an alcohol, and after the reaction is completed, the alcohol is removed; and then a photochemical cyclization reaction is performed. However, this route requires the use of phosgene, which poses a safety hazard in industrial production and is prone to pollution.

[0011] CN117343022A uses an amide compound or a cyclic urea compound as a catalyst to prepare hexazinone through a cyclization reaction, wherein the amide compound or the cyclic urea compound is preferably N', N-dimethylformamide or N', N-dimethylimidazolidinone. This method can greatly reduce the generation of ethoxy impurities and improve the purity of the product. However, this process requires the use of a catalyst, which increases the production cost.

[0012] In view of the above-mentioned defects existing in the prior art, developing a new hexazinone preparation has good economic value. Summary of the invention

[0013] The invention provides a new preparation process of cycloazinone. By using a new raw material and an intermediate, the raw material conversion rate and the product purity can be effectively improved, and no special catalyst is needed. The process flow is simple and the production cost can be significantly reduced. The process has good industrial application value.

[0014] The first aspect of the present invention provides a process for preparing hexazinone, which comprises the following steps:

[0015] 1) subjecting benzyloxycarbonyl cyanamide or its salt to methylation reaction to obtain intermediate 1;

[0016] 2) reacting intermediate 1 with dimethylamine or its salt to obtain intermediate 2;

[0017] 3) reacting intermediate 2 with cyclohexyl isocyanate to obtain intermediate 3;

[0018] 4) The intermediate 3 is subjected to a ring-closing reaction in the presence of a base to obtain hexazinone;

[0019] The reaction route is as follows:

[0020]

[0021] Wherein: M is selected from H, alkali metals, and alkaline earth metals.

[0022] Preferably, M is selected from H, K, Na, Mg or Ca.

[0023] Preferably, the methylating agent used in the methylation reaction of step 1) is selected from one or more of dimethyl sulfate, methyl iodide, methyl p-toluenesulfonate, and methyl trifluoromethanesulfonate.

[0024] Preferably, step 1) is carried out in the presence of a solvent, and the solvent is selected from one or more of aliphatic, alicyclic and aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, toluene, xylene; ethers, such as diethyl ether, dimethyl ether, tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane; alcohols, such as methanol, ethanol, propanol; esters, such as ethyl acetate, tert-butyl acetate; more preferably, the solvent is selected from one or more of acetonitrile, propionitrile, toluene, xylene, ethyl acetate.

[0025] Preferably, the reaction temperature in step 1) is 40-100°C, more preferably 65-70°C.

[0026] Preferably, in step 1), the molar ratio of benzyloxycarbonyl cyanamide or its salt to the methylating agent is 1:1-1.5, more preferably 1:1-1.2.

[0027] Preferably, in step 2), the dimethylamine salt is selected from one or more of dimethylamine hydrochloride, dimethylamine hydrobromide, and dimethylamine hydroiodide; the dimethylamine salt is fed in the form of an aqueous solution, and the concentration of the dimethylamine salt aqueous solution is 30% to 90%, more preferably 40% to 70%.

[0028] Preferably, in step 2), the molar ratio of intermediate 1 to dimethylamine or its salt is 1:1-2, more preferably 1:1.2-1.5.

[0029] Preferably, step 2) is carried out in the presence of a phase transfer catalyst, and more preferably, the phase transfer catalyst in step 2) is selected from benzyltriethylammonium chloride, hexadecyltrimethylammonium bromide, tetramethylammonium bromide, and PEG.

[0030] Preferably, the reaction temperature in step 2) is 40-100°C, more preferably 65-70°C.

[0031] Preferably, the reaction in step 3) is carried out in the presence of a solvent, and the solvent is selected from one or more of aliphatic, alicyclic and aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, toluene, xylene; ethers, such as diethyl ether, dimethyl ether, tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane; alcohols, such as methanol, ethanol, propanol; esters, such as ethyl acetate, tert-butyl acetate; more preferably, the solvent is selected from one or more of acetonitrile, propionitrile, toluene, xylene, ethyl acetate.

[0032] Preferably, the reaction temperature of step 3) is 0-80°C, more preferably 20-60°C, most preferably 38-42°C.

[0033] Preferably, in step 3), the molar ratio of the intermediate 2 to cyclohexyl isocyanate is 1:1 to 1.5, more preferably 1:1 to 1.2.

[0034] Preferably, dimethylamine is also added in step 4), and the molar ratio of intermediate 3 to dimethylamine is 1:1-2, more preferably 1:1.1-1.5;

[0035] Preferably, in step 4), the base is selected from an inorganic base or an organic base;

[0036] Preferably, the inorganic base is selected from alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, alkaline earth metal hydroxides, including but not limited to potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide; the organic base includes but is not limited to aliphatic amines, aromatic amines, alkali metal salts of alcohols or alkyl lithiums, such as triethylamine, tripropylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, sodium methoxide, sodium ethoxide, phenyllithium, diisopropylamide lithium, hexamethyldisilazide lithium; most preferably, the base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide.

[0037] Preferably, the reaction of step 4) is carried out in the presence of a solvent, and the solvent is selected from one or more of aliphatic, alicyclic and aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, toluene, xylene; ethers, such as diethyl ether, dimethyl ether, tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, alcohols, such as methanol, ethanol, esters, such as ethyl acetate, tert-butyl acetate. More preferably, the organic solvent is selected from one or more of toluene, xylene, methanol, ethanol, and ethyl acetate.

[0038] Preferably, the reaction temperature in step 4) is 20-80°C, preferably 30-60°C, more preferably 40-50°C.

[0039] Preferably, the reaction time of step 4) is 0.5 to 12 hours, more preferably 1 to 3 hours, and most preferably 1.5 to 2 hours.

[0040] By adopting the above technical solution, the present invention has the following beneficial effects:

[0041] 1) The process of the present invention has high reaction conversion rate and selectivity, improves the yield and purity of the product, and has good industrial prospects.

[0042] 2) The present invention does not require the addition of a catalyst or a complicated process flow, thereby reducing production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is the H NMR spectrum of intermediate 1.

[0044] Figure 2 This is the H NMR spectrum of intermediate 2.

[0045] Figure 3This is the H NMR spectrum of intermediate 3.

[0046] Figure 4 This is the H NMR spectrum of cyclozinone. DETAILED DESCRIPTION

[0047] The following specific implementation methods are used to clearly and completely describe the technical solutions of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0048] Example 1 Preparation of Intermediate 1 (Benzyl N-cyano-N-methylcarbamate)

[0049] In a 500ml four-necked flask equipped with a mechanical stirrer, 60g (280mmol) of self-made potassium benzyloxycarbonylaminocyanide and 245ml of acetonitrile were added, stirring was started while heating was maintained at 65-70°C, 35.3g (280mmol) of dimethyl sulfate was added dropwise using a constant pressure dropping funnel for 0.5-1 hour, and the temperature was kept for 1 hour after the addition was completed. The reaction solution was rotary evaporated to obtain a colorless oil, 400ml of dichloromethane was added, and then 100g of 1% potassium hydroxide aqueous solution was added. The mixture was stirred at room temperature for 1 hour, the liquids were separated, and the organic phase was rotary evaporated to obtain 51.9g of a colorless oil (i.e., intermediate 1) with a yield of 97.5%. 1 HNMR (CDCl3, 400MHz): δ7.39-7.31(m,5H), δ5.234(s,2H), δ3.133(s,3H). HRMS(ESI) 189.0758[M-1] (Cal. 190.07).

[0050] Example 2 Preparation of Intermediate 2 (N,N,N'-trimethyl-N'-carboxylic acid benzyl guanidine)

[0051] In a 250ml four-necked flask equipped with a mechanical stirrer, 51.9g (273mmol) of intermediate 1, 2.06g (8.9mmol) of benzyltriethylammonium chloride and 41.32g (355mmol) of 70% aqueous dimethylamine hydrochloride solution were added and stirred. A 40% aqueous dimethylamine solution was added dropwise while the temperature was raised to adjust the pH value to 9. The mixture was kept at 65-70℃ for 1h and then cooled to room temperature. A 40% aqueous dimethylamine solution was added to adjust the pH value to above 12. The mixture was extracted with 450ml (150ml*3) of dichloromethane. The dichloromethane phases were combined and washed with 90ml of process water, and the dichloromethane phase was retained. 15g of anhydrous sodium sulfate was added for drying, and the mixture was filtered with suction. The filtrate was rotary evaporated to obtain 52.8g of a light yellow oil (i.e., intermediate 2) with a yield of 82.2%. 1HNMR (CDCl3, 400MHz): δ7.25-7.17 (d, 5H), δ5.08-5.04 (s, 2H), δ3.1-2.9 (s, 3H), δ2.83-2.80 (s, 1H), δ2.80-2.65 (m, 6H). HRMS (ESI) 236.1388[M+1] (Cal. 235.13).

[0052] Example 3 Preparation of Intermediate 3 (Benzyl N-methyl-N-(N',N'-dimethyl-N''-cyclohexylaminocarbonylamidino)carbamate)

[0053] In a 250ml four-necked flask equipped with mechanical stirring, add 20g (85.0mmol) of intermediate 2 and 120ml of dried toluene, raise the temperature to 38~42℃, and use a constant pressure dropping funnel to drop 21.3g (85.0mmol) of 50% cyclohexyl isocyanate toluene solution. Add for about 1h, keep warm for 2h after the addition is completed, cool to room temperature, add 50g of process water for washing, retain the organic phase, and rotary evaporate the organic phase to obtain 29.4g of white solid (i.e., intermediate 3) with a yield of 96.0%. 1 HNMR (CDCl3, 400MHz): δ7.39-7.26(m,5H), δ5.3-4.85(m,3H), δ3.56-3.48(m,1H), δ3.1- 2.75(m,9H), δ1.95-1.75(d,2H), δ1.7-1.5(m,3H), δ1.35-1.2(m,2H), δ1.15-0.9(m,3H). HRMS(ESI) 361.2234[M+1](Cal.360.22).

[0054] Example 4 Preparation of Hexazinone

[0055] In a 100ml three-necked flask equipped with mechanical stirring, add 21.0g (58.3mmol) of intermediate 3, 60ml of toluene and 3.02g (67.1mmol) of dimethylamine, start stirring, heat to 50℃, add 0.84g (4.5mmol) of 29% sodium methoxide methanol solution, keep warm for 1.5 hours, add 40ml (20ml*2) of process water for washing, add 30ml of toluene to extract after combining the aqueous phases, combine the organic phases and desolventize under negative pressure until the content of cycloazinone is about 50%, add 20ml of n-hexane at 60~65℃, slowly cool to 0~5℃, a white solid precipitates, filter, and dry the filter cake to obtain 14.2g of cycloazinone with a yield of 96.5% and a purity of 99.2%. 1HNMR(CDCl3,400MHz):δ4.5-4.3(m,1H),δ3.4-3.2(s,3H),δ3.0-2.8(s,6H),δ2.3-2.1(m,2H),δ1.8-1.7(d,2H),δ1.65-1.5(m,3H),δ1.3-1.2(m,2H),δ1.2-1.1(m,1H)。

Claims

1. A process for preparing hexazinone, comprising the following steps: 1) subjecting benzyloxycarbonyl cyanamide or its salt to methylation reaction to obtain intermediate 1; 2) reacting intermediate 1 with dimethylamine or its salt to obtain intermediate 2; 3) reacting intermediate 2 with cyclohexyl isocyanate to obtain intermediate 3; 4) The intermediate 3 is subjected to a ring-closing reaction in the presence of a base to obtain hexazinone; The reaction route is as follows: in: M is selected from H, alkali metals, and alkaline earth metals; Step 2) The molar ratio of intermediate 1 to dimethylamine or its salt is 1:1-2; The reaction temperature of step 2) is 40-100°C; Step 2) is carried out in the presence of a phase transfer catalyst, wherein the phase transfer catalyst is selected from benzyltriethylammonium chloride, hexadecyltrimethylammonium bromide, tetramethylammonium bromide, and PEG; The reaction temperature of step 3) is 20-60°C; In step 3), the molar ratio of the intermediate 2 to cyclohexyl isocyanate is 1:1 to 1.5; In step 4), dimethylamine is also added, and the molar ratio of intermediate 3 to dimethylamine is 1:1-2; Step 4) The reaction temperature is 20-80°C; Step 4) The reaction time is 0.5-12 hours.

2. The process for preparing hexazinone according to claim 1, characterized in that: The methylating agent used in the methylation reaction of step 1) is selected from one or more of dimethyl sulfate, methyl iodide, methyl p-toluenesulfonate, and methyl trifluoromethanesulfonate.

3. The process for preparing hexazinone according to claim 1 or 2, characterized in that: The reaction temperature of step 1) is 40-100°C; In step 1), the molar ratio of benzyloxycarbonyl cyanamide or its salt to the methylating agent is 1:1-1.

5.

4. The process for preparing hexazinone according to claim 1 or 2, characterized in that: M is selected from H, K, Na, Mg or Ca.

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