CN111018792A - Synthesis method of dicyclanil - Google Patents
Synthesis method of dicyclanil Download PDFInfo
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- CN111018792A CN111018792A CN201911340796.4A CN201911340796A CN111018792A CN 111018792 A CN111018792 A CN 111018792A CN 201911340796 A CN201911340796 A CN 201911340796A CN 111018792 A CN111018792 A CN 111018792A
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Abstract
The invention discloses a synthesis method of dicyclanil. The method comprises the steps of taking dicyandiamide sodium and malononitrile as initial raw materials, carrying out condensation, cyclization and amination reactions to obtain a crude product of dicyclanil, and carrying out decoloration and refining to obtain a refined product of dicyclanil. The synthetic route is short, the process is green and environment-friendly, and methyl mercaptan is not generated; the reaction condition is mild, no pressurization ammoniation is needed, the requirement on equipment is low, the operation is simple and convenient, and the method is suitable for domestic industrial production. The total yield reaches more than 65 percent, and the product purity reaches more than 99 percent.
Description
Technical Field
The invention belongs to the field of chemistry or pharmaceutical chemistry, and particularly relates to a synthesis method of dicyclanil.
Background
Dicyclanil, namely dicyclanil in English, has a chemical name of 4, 6-Diamino-2-cyclopropylamino-5-cyanopyrimidine (4,6-Diamino-2- (cyclo-propyala-min-o) -5-pyrimidinecarbonitrile), is an ecdysone analogue, namely a pyrimidine compound, has strong adhesive force, can effectively control various representative pests in insects and waxes, and is particularly effective on herbivorous insects which harm crops and ectoparasites which harm animals. The pesticide is novel in structure, wide in insecticidal spectrum, high in persistence and safe to crops, has strong market demand as a new-generation veterinary drug, plays an important role in prevention and treatment of animal ectoparasite diseases in future, and has high ecological social effect due to low tolerance and low residue value of the pesticide.
The currently reported synthetic routes for dicyclanil are mainly three as follows:
route 1:
the final product is obtained by taking dimethyl (N-cyanoimino) carbonate as a starting material through condensation, ammoniation, cyclization and substitution. The route has long steps, the total yield is only 32%, and the pressure reaction is needed, so that the potential safety hazard is large, and the method is not suitable for industrial production;
route 2:
2-cyano-3-cyanamido-3-methylthio acrylonitrile is used as a starting material, and a final product is obtained through cyclization, substitution and ammoniation. Despite the short route, the raw material 2-cyano-3-cyanamido-3-methylthio-acrylonitrile is not readily available and is not suitable for industrial production.
Route 3:
in patent CN 104649982B, guanidine hydrochloride and bromocyclopropane undergo substitution reaction, and then undergo ring closure with 2-fluoro malonamide, and finally potassium ferrocyanide is used to provide cyano group, so as to substitute fluorine on the aromatic ring, thereby obtaining the dicyclanil product. But the total yield is only 34.2% -51.7%, the cost is higher, and the market competitiveness is not realized.
Route 4:
at present, a route 4 is adopted for industrial production, N-cyanoimino-S, S-dimethyl dithiocarbonate is taken as a starting material, and a final product is obtained through condensation, cyclization, substitution, oxidation and ammoniation, but the route has long process steps, the total yield is 40%, and foul methyl mercaptan gas is generated during cyclization, so that the pollution is large.
In view of the above disadvantages of the existing dicyclanil synthesis process, the development of a dicyclanil synthesis method which has mild reaction conditions, high yield, high purity, environmental protection and is suitable for production is still pending for further research and study.
Disclosure of Invention
Aiming at various defects of the above route, the invention aims to provide a synthesis method of dicyclanil, which has mild reaction conditions, few steps, high yield, environmental protection and is suitable for production, and the specific technical scheme is as follows:
a synthesis method of dicyclanil, which is prepared by the following chemical reaction equation:
the reaction equation is prepared by the following steps:
(1) condensation: adding sodium dicyandiamide into an organic solvent, heating to 105 ℃ under the catalysis of an alkaline catalyst, dropwise adding a malononitrile solution, continuously keeping the temperature and stirring after the dropwise adding is finished, cooling to below 50 ℃, adding a solvent with poor solubility for crystallization, cooling to 10-25 ℃, performing suction filtration, and performing vacuum drying at 65-90 ℃ to obtain a condensation compound;
(2) cyclization: adding the condensation compound obtained in the step (1) into a solvent, dropwise adding hydrochloric acid, keeping the temperature, cooling to below 0 ℃, adjusting the pH value to 7-8 by using 30% liquid alkali, performing suction filtration, washing by using the solvent, and drying at 85-95 ℃ to obtain a cyclic compound;
(3) amination: adding the cyclic compound and cyclopropylamine prepared in the step (2) into a polar solvent, performing heating and heat preservation reaction under the catalysis of inorganic base or organic base, performing HPLC detection reaction completely, cooling to 0-5 ℃, performing suction filtration, washing with water, and drying a filter cake at 90-95 ℃ to obtain a crude product of desinfenile;
(4) refining: and (3) adding the crude product of the dicyclanil obtained in the step (3) and activated carbon into N, N-Dimethylformamide (DMF) or N, N-Dimethylacetamide (DMAC) serving as a solvent, heating to 95-100 ℃, keeping the temperature for decoloring, performing suction filtration, adding water into filtrate for crystallizing, keeping the temperature, cooling to below 5 ℃, performing suction filtration, and obtaining the dicyclanil at 90-95 ℃.
In the reaction step (1), the organic solvent is at least one of N, N-dimethylformamide, N-dimethylacetamide, 1, 3-dimethyl-2-imidazolidinone and N-methylpyrrolidone, and the amount of the organic solvent is 3-6 times of the weight of the dicyandiamide sodium; the alkaline catalyst is at least one of ammonium acetate, sodium acetate, potassium acetate, ammonium formate, sodium formate, pyridine, piperidine, diethylamine and dipotassium hydrogen phosphate, and the dosage of the alkaline catalyst is 0.1-5% of the weight of the dicyandiamide sodium; the feeding molar ratio of the malononitrile to the dicyandiamide sodium is 0.95-1.2: 1, the dropping temperature and the heat preservation reaction temperature of the malononitrile solution are 105-120 ℃, and the heat preservation reaction time is 0.5-1 hour; the poor-solubility solvent is at least one of n-butyl alcohol, 2-butanol, isopropanol, n-propanol, ethanol, methanol, ethyl acetate, ethyl formate, isopropyl acetate, n-hexane and cyclohexane, and the dosage of the poor-solubility solvent is 6-10 times of the weight of the sodium dicyandiamide.
In the reaction step (2), the solvent is at least one of methanol, ethanol and acetonitrile, the dosage of the solvent is 1-3 times of the weight of the condensate, the content of hydrochloric acid is 30% -36%, and the molar ratio of hydrochloric acid to the condensate is 3.5-10: 1, preferably 5 to 7.5: 1; the dropping temperature of the hydrochloric acid is-10 to 15 ℃, and is preferably-5 to 5 ℃; the dropping time is 2 to 12 hours, preferably 3 to 6 hours; the heat preservation temperature is 10-20 ℃, and the heat preservation reaction time is 3-5 hours; the washing solvent is consistent with the reaction solvent and is at least one of methanol, ethanol and acetonitrile, and the dosage of the washing solvent is 0.5-2 times of the weight of the condensation compound.
In the reaction step (3), the polar solvent is at least one of methanol, ethanol, acetonitrile and water, the dosage of the polar solvent is 2-5 times of the weight of the cyclic compound, and the molar ratio of the cyclopropylamine to the cyclic compound is 1.0-2.5: 1, preferably 1.0 to 1.2: 1; the organic base is at least one of triethylamine, 2,4, 6-trimethylpyridine, 4-dimethylaminopyridine, tetramethylethylenediamine, hexamethylenetetramine, N-methylmorpholine, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, butyllithium and tert-butyllithium, preferably at least one of triethylamine, 2,4, 6-trimethylpyridine, 4-dimethylaminopyridine, tetramethylethylenediamine and N-methylmorpholine; the inorganic base is at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and lithium hydroxide, preferably at least one of potassium hydroxide, potassium carbonate, sodium carbonate and lithium hydroxide; the molar ratio of the alkali to the cyclic compound is 1.5-2.5: 1, preferably 1.8-2.3: 1; the reaction temperature in the reaction step (3) is 65-100 ℃, and preferably 80-90 ℃; the reaction time is 3 to 15 hours, preferably 4 to 5 hours. The amount of the washing water is 2-4 times of the weight of the condensation compound.
In the reaction step (4), the dosage of DMF or DMAC is 6-10 times of the weight of the crude product of the dicyclanil, the dosage of the active carbon is 3-5% of the weight of the crude product of the dicyclanil, the decoloring temperature is 95-100 ℃, the decoloring time is 0.5-1 hour, the crystallization water addition amount is 1.3-2.5 times of the weight of the crude product of the dicyclanil, the temperature is 50-60 ℃ when water is added, and the heat preservation is carried out for 1-2 hours after the water is added.
The invention has the beneficial effects that:
1) the invention provides a synthesis method of dicyclanil, which has the advantages of short synthesis route, green and environment-friendly process and no generation of methyl mercaptan;
2) the invention provides a synthesis method of dicyclanil, wherein the total yield is more than 65%, and the product purity is more than 99%.
3) The synthesis method of the dicyclanil provided by the invention has the advantages of mild reaction conditions, no need of pressurization and ammoniation, low requirement on equipment, simple and convenient operation and suitability for domestic industrial production.
Drawings
FIG. 1 is the nuclear magnetic hydrogen spectrum of the dicyclanil condensation compound
FIG. 2 is the nuclear magnetic carbon spectrum of the dicyclanil condensation compound.
FIG. 3 is the nuclear magnetic hydrogen spectrum of desinferile cyclic compound
FIG. 4 is the nuclear magnetic carbon spectrum of desinfenile cyclic compound.
Figure 5 is a desinfer nuclear magnetic carbon spectrum.
FIG. 6 is the core magnetic hydrogen spectrum of desinfenile.
Figure 7 is a desinfer mass spectrum.
Detailed Description
The present invention is described in detail by the following specific examples, which are provided for the purpose of illustration and are not to be construed as limiting the invention.
Example 1
1) Preparation of the condensate:
A1L four-necked flask was charged with 89.03g (1mol) of sodium dicyandiamide and 267g of pyridine, N, N-Dimethylacetamide (DMA). Stirring and heating to 105 ℃, dripping 62.76g (0.95mol) of malononitrile in 0.5 hour, and keeping the temperature at 105-110 ℃ for 1 hour. After the heat preservation reaction is finished, cooling to 45 ℃, adding 540g of sec-butyl alcohol, cooling to 10 ℃, carrying out suction filtration, and carrying out vacuum drying on a filter cake at 90 ℃ to obtain 137.1g of light yellow solid with the yield of 88.4%. Purity by HPLC 98.0%.
WNMR-I-500MHz type nuclear magnetic resonance instrument nuclear magnetic hydrogen spectrum detection, the data is as follows:
1H NMR(DMSO-d6,500MHz):δ6.3949(s,2H)；
13C-NMR(DMSO-d6,TMS):δ170.117,120.453,118.638,39.003-40.004。
2) preparation of cyclic compound:
160g of methanol and 155.9g (1mol) of condensation compound are put into a 1L four-mouth bottle, stirring is started, cooling is carried out to-5 ℃, 521.4g (5mol) of 35% hydrochloric acid is dripped, the temperature is controlled to be 5-10 ℃, the dripping time is 6 hours, the temperature is slowly raised to 20 ℃ after the dripping is finished, and the heat preservation reaction is carried out for 4 hours. Cooling to-5 deg.C, adjusting pH to 7-8 with 30% liquid alkali, vacuum filtering to obtain light yellow solid, washing filter cake with 80g methanol, vacuum drying, and oven drying at 90 deg.C to obtain 145.0g dry product. HPLC purity 97.5%, yield 85.5%.
WNMR-I-500MHz type nuclear magnetic resonance instrument nuclear magnetic hydrogen spectrum detection, the data is as follows:
1H NMR(DMSO-d6,500MHz):δ7.6094(s,4H)；
13C-NMR(DMSO-d6,TMS):δ165.236,161.442,114.946,65.713，39.04-40.000。
3) preparation of crude product of dicyclanil:
adding 169.57g (1mol) of cyclic compound, 500g of acetonitrile, 159g (1.5mol) of sodium carbonate and 57.09g (1.0mol) of cyclopropylamine into a 1L four-necked bottle, stirring, heating to reflux, keeping reflux for 6 hours, detecting complete reaction by HPLC, cooling to 0-5 ℃, carrying out suction filtration, draining, and drying in an oven (90 ℃) to obtain 172.1g of white solid. HPLC purity 98.1%, yield 90.5%. m.P.: 249.8-250.5 ℃ (document value of 249-251 ℃). WNMR-I-500MHz type nuclear magnetic resonance instrument nuclear magnetic hydrogen spectrum detection, the data is as follows:
1H NMR(DMSO-d6,500MHz)δ:0.4349-0.4652,0.5652-0.6023(m,4H,-CH2-CH2-),δ:2.7046-2.7568(m,1H,CH),δ:6.44985(s,4H,-NH2),δ:67837,6.7921(d,1H,-NH-)。
13C-NMR(500MHz，DMSO),δ:6.265(-CH2-CH2-),δ:23.676(CH),δ:59.855(-CN),δ:117.639(C),δ:163.068(-C-N＝C-N＝C-)。
[M+1]:191.10。
4) preparation of a dicyclanil refined product:
adding 300g of N, N-Dimethylacetamide (DMAC), 50g of crude dicyclanil and 1.2g of activated carbon into a 500ml four-mouth bottle, heating to 95-100 ℃, keeping the temperature and decoloring for 0.5 hour, performing suction filtration, cooling to 50 ℃, adding 65g of water into filtrate for crystallization, keeping the temperature for 1 hour, cooling to below 5 ℃, performing suction filtration, and obtaining 47.75g of refined dicyclanil at 90-95 ℃ with the yield of 95.5%. HPLC purity 99.8%, other single impurity less than 0.1%.
The total yield is as follows: 88.4% × 85.5% × 90.5% × 95.5% ═ 65.3%
Example 2:
1) preparation of the condensate:
A1L four-necked flask was charged with 89.03g (1mol) of sodium dicyandiamide, 1.2g of piperidine, and 300g of N, N-Dimethylformamide (DMF). Stirring and heating to 105 ℃, dripping 62.76g (0.95mol) of malononitrile in 0.5 hour, and keeping the temperature at 105-110 ℃ for 1 hour. After the reaction is finished, cooling to 45 ℃, adding 540g of methanol, cooling to 15 ℃, performing suction filtration, and performing vacuum drying on a filter cake at 90 ℃ to obtain 136.5g of light yellow solid with the yield of 88.0%. Purity by HPLC 98.5%.
2) Preparation of cyclic compound:
160g of acetonitrile and 155.9g (1mol) of condensation compound are put into a 1L four-mouth bottle, stirring is started, cooling is carried out to-5 ℃, 405.6g (3.5mol) of 31.5% hydrochloric acid is dripped, the temperature is controlled to be-5-0 ℃, the dripping time is 10 hours, the temperature is slowly raised to 20 ℃ after the dripping is finished, and the heat preservation reaction is carried out for 4 hours. Cooling to-5 deg.C, adjusting pH to 7-8 with 30% liquid alkali, vacuum filtering to obtain light yellow solid, washing filter cake with 80g acetonitrile, vacuum drying, and oven drying in oven (90 deg.C) to obtain dry product 148.2 g. HPLC purity 97.0%, yield 87.3%.
3) Preparation of crude product of dicyclanil:
169.57g (1mol) of cyclic compound, 500g of acetonitrile, 182.1g (1.8mol) of triethylamine and 62.80g (1.1mol) of cyclopropylamine are added into a 1L four-mouth bottle, the mixture is stirred, heated to reflux, kept for reflux reaction for 4 hours, completely detected by HPLC, cooled to 0-5 ℃, filtered, drained and dried in an oven (90 ℃) to obtain 176.1g of white solid. HPLC purity 98.1%, yield 92.6%.
4) Preparation of a dicyclanil refined product:
adding 400g of N, N-Dimethylacetamide (DMAC), 50g of crude dicyclanil and 1.2g of activated carbon into a 1L four-mouth bottle, heating to 95-100 ℃, keeping the temperature and decoloring for 0.5 hour, performing suction filtration, cooling to 50 ℃, adding 80g of water into filtrate for crystallization, keeping the temperature for 1 hour, cooling to below 5 ℃, performing suction filtration, and obtaining 47.4g of refined dicyclanil at 90-95 ℃ with the yield of 94.8%. HPLC purity 99.8%, other single impurity less than 0.1%.
The total yield is as follows: 85.5% × 87.3% × 91.9% × 94.8% ═ 65.02%
Example 3:
1) preparation of the condensate:
A2L four-necked flask was charged with 89.03g (1mol) of sodium dicyandiamide, 4.45g of diethylamine, and 500g of N, N-Dimethylacetamide (DMA). Stirring and heating to 110 ℃, dripping 62.76g (0.95mol) of malononitrile in 0.5 hour, and keeping the temperature at 110-115 ℃ for 1 hour. After the reaction is finished, cooling to 45 ℃, adding 540g of isopropyl acetate, cooling to 20 ℃, performing suction filtration, and performing vacuum drying on a filter cake at 90 ℃ to obtain 134.6g of light yellow solid with the yield of 86.8%. Purity by HPLC 98.0%.
2) Preparation of cyclic compound:
160g of ethanol and 155.9g (1mol) of condensation compound are put into a 2L four-mouth bottle, stirring is started, cooling is carried out to-5 ℃, 973.3g (8mol) of 30% hydrochloric acid is dripped, the temperature is controlled to be-5-0 ℃, the dripping time is 12 hours, the temperature is slowly raised to 20 ℃ after the dripping is finished, and the heat preservation reaction is carried out for 5 hours. Cooling to-5 deg.C, adjusting pH to 7-8 with 30% liquid alkali, vacuum filtering to obtain light yellow solid, washing filter cake with 80g ethanol, vacuum drying, and oven drying in oven (90 deg.C) to obtain dry product 146.2 g. HPLC purity 96.8%, yield 86.2%.
3) Preparation of crude product of dicyclanil:
169.57g (1mol) of cyclic compound, 500g of ethanol, 158.8g (1.3mol) of 4-dimethylaminopyridine and 59.94g (1.05mol) of cyclopropylamine are added into a 1L four-neck bottle, the mixture is stirred, heated to reflux, kept for reflux reaction for 6 hours, completely detected by HPLC, cooled to 0-5 ℃, filtered, drained, and dried in an oven (90 ℃) to obtain 176.7g of white solid. HPLC purity 98.0%, yield 92.9%.
4) Preparation of a dicyclanil refined product:
adding 350g of N, N-Dimethylformamide (DMF), 50g of crude product of desinfer and 2.0g of activated carbon into a 500ml four-mouth bottle, heating to 95-100 ℃, keeping the temperature and decoloring for 1 hour, performing suction filtration, cooling to 50 ℃, adding 100g of water into filtrate for crystallization, keeping the temperature for 1 hour, cooling to below 5 ℃, performing suction filtration, and obtaining 47.9g of refined product of desinfer at 90-95 ℃, wherein the yield is 95.8%. HPLC purity 99.7%, other single impurity less than 0.1%.
The total yield is as follows: 86.8% × 86.2% × 92.9% × 95.8% ═ 66.6%
Example 4:
1) preparation of the condensate:
into a 1L four-necked flask, 89.03g (1mol) of sodium dicyandiamide and 3.6g of diethylamine, 250g of 1, 3-dimethyl-2-imidazolidinone were put. Stirring and heating to 115 ℃, dripping 62.76g (0.95mol) of malononitrile in 0.5 hour, and keeping the temperature at 115 ℃ and 120 ℃ for 1 hour. After the reaction is finished, cooling to 45 ℃, adding 540g of cyclohexane, cooling to 25 ℃, performing suction filtration, and performing vacuum drying on a filter cake at 90 ℃ to obtain 137.9g of light yellow solid with the yield of 88.9%. Purity by HPLC 98.6%.
2) Preparation of cyclic compound:
160g of acetonitrile and 155.9g (1mol) of condensation compound are put into a 2L four-mouth bottle, stirring is started, the temperature is reduced to-5 ℃, 798.4g (7mol) of 32% hydrochloric acid is dripped, the temperature is controlled to be-5-0 ℃, the dripping time is 8 hours, the temperature is slowly raised to 20 ℃ after the dripping is finished, and the heat preservation reaction is carried out for 4 hours. Cooling to-5 deg.C, adjusting pH to 7-8 with 30% liquid alkali, vacuum filtering to obtain light yellow solid, washing filter cake with 100g acetonitrile, vacuum drying, and oven drying at 90 deg.C to obtain 143.6g dried product. HPLC purity 97.2%, yield 84.7%.
3) Preparation of crude product of dicyclanil:
adding 169.57g (1mol) of cyclic compound, 500g of acetonitrile, 174.3g (1.5mol) of tetramethylethylenediamine and 142.73g (2.5mol) of cyclopropylamine into a 1L four-necked bottle, stirring, heating to reflux, keeping reflux reaction for 15 hours, detecting complete reaction by HPLC, cooling to 0-5 ℃, carrying out suction filtration, carrying out suction drying, and drying in an oven (90 ℃) to obtain 174.0g of white solid. HPLC purity 98.1%, yield 91.5%.
4) Preparation of a dicyclanil refined product:
adding 400g of N, N-Dimethylacetamide (DMAC), 50g of crude dicyclanil and 1.5g of activated carbon into a 1L four-mouth bottle, heating to 95-100 ℃, keeping the temperature and decoloring for 0.5 hour, performing suction filtration, cooling to 50 ℃, adding 125g of water into filtrate for crystallization, keeping the temperature for 1 hour, cooling to below 5 ℃, performing suction filtration, and obtaining 48.5g of refined dicyclanil at 90-95 ℃ with the yield of 97.0%. HPLC purity 99.4%, other single impurity less than 0.2%.
The total yield is as follows: 88.9% × 84.7% × 91.5% × 97.0% ═ 66.8%
Example 5:
1) preparation of the condensate:
A1L four-necked flask was charged with 89.03g (1mol) of sodium dicyandiamide, 0.1g of pyridine, and 190g of N-methylpyrrolidone. The mixture is stirred and heated to 115 ℃, 79.27g (1.2mol) of malononitrile is added dropwise in 1.5 hours, and the reaction is carried out at the temperature of 115 ℃ and 120 ℃ for 1 hour. After the reaction is finished, cooling to 45 ℃, adding 540g of n-hexane, cooling to 15 ℃, carrying out suction filtration, and carrying out vacuum drying on a filter cake at 90 ℃ to obtain 139.3g of light yellow solid with the yield of 89.8%. Purity by HPLC 98.3%.
2) Preparation of cyclic compound:
160g of water and 155.9g (1mol) of condensation compound are put into a 1L four-mouth bottle, stirring is started, cooling is carried out to-5 ℃, 521.4g (6mol) of 36% hydrochloric acid is dripped, the temperature is controlled to be 0-5 ℃, the dripping time is 6 hours, the temperature is slowly raised to 20 ℃ after the dripping is finished, and the acetonitrile is reacted for hours under heat preservation. Cooling to-5 deg.C, adjusting pH to 7-8 with 30% liquid alkali, vacuum filtering to obtain light yellow solid, washing filter cake with 120g water, vacuum drying, and oven drying at 90 deg.C to obtain 145.8g dry product. HPLC purity 97.5%, yield 86.0%.
3) Preparation of crude product of dicyclanil:
169.57g (1mol) of cyclic compound, 500g of acetonitrile, 117.6g (2.1mol) of potassium hydroxide and 131.3g (2.3mol) of cyclopropylamine are added into a 1L four-mouth bottle, the mixture is stirred, the temperature is raised to reflux, the reflux reaction is kept for 5 hours, the HPLC detection reaction is complete, the mixture is cooled to 0-5 ℃, the suction filtration is carried out, the drying is carried out in an oven (90 ℃) after the drying, and 175.4g of white solid is obtained. HPLC purity 98.6%, yield 92.2%.
4) Preparation of a dicyclanil refined product:
adding 350g of N, N-Dimethylacetamide (DMAC), 50g of crude dicyclanil and 2.5g of activated carbon into a 500ml four-mouth bottle, heating to 95-100 ℃, keeping the temperature and decoloring for 0.5 hour, performing suction filtration, cooling to 50 ℃, adding 75g of water into filtrate for crystallization, keeping the temperature for 2 hours, cooling to below 5 ℃, performing suction filtration, and obtaining 48.3g of refined dicyclanil at 90-95 ℃, wherein the yield is 96.6%. HPLC purity 99.9%, other single impurity less than 0.1%.
The total yield is as follows: 89.8% × 86.0% × 92.2% × 96.6% ═ 68.7%
The present invention is not limited to the above-described embodiments, and any simple, equivalent changes or modifications made to the above-described embodiments in accordance with the technical spirit of the present invention fall within the technical scope of the present invention.
Claims (7)
1. A synthesis method of dicyclanil, which is characterized by comprising the following chemical reaction equations:
the reaction equation is prepared by the following steps:
(1) condensation: adding sodium dicyandiamide into an organic solvent, heating to 105 ℃ under the catalysis of an alkaline catalyst, dropwise adding a malononitrile solution, continuously keeping the temperature and stirring after the dropwise adding is finished, cooling to below 50 ℃, adding a solvent with poor solubility for crystallization, cooling to 10-25 ℃, performing suction filtration, and performing vacuum drying at 65-90 ℃ to obtain a condensation compound;
(2) cyclization: adding the condensation compound obtained in the step (1) into a solvent, dropwise adding hydrochloric acid, keeping the temperature, cooling to below 0 ℃, adjusting the pH value to 7-8 by using 30% liquid alkali, performing suction filtration, washing by using the solvent, and drying at 85-95 ℃ to obtain a cyclic compound;
(3) amination: adding the cyclic compound and cyclopropylamine prepared in the step (2) into a polar solvent, performing heating and heat preservation reaction under the catalysis of inorganic base or organic base, performing HPLC detection reaction completely, cooling to 0-5 ℃, performing suction filtration, washing with water, and drying a filter cake at 90-95 ℃ to obtain a crude product of desinfenile;
(4) refining: and (3) adding the crude product of the dicyclanil obtained in the step (3) and activated carbon into N, N-Dimethylformamide (DMF) or N, N-Dimethylacetamide (DMAC) serving as a solvent, heating to 95-100 ℃, keeping the temperature for decoloring, performing suction filtration, adding water into filtrate for crystallizing, keeping the temperature, cooling to below 5 ℃, performing suction filtration, and obtaining the dicyclanil at 90-95 ℃.
2. The method for synthesizing dicyclanil according to claim 1, wherein: in the reaction step (1), the organic solvent is at least one of N, N-dimethylformamide, N-dimethylacetamide, 1, 3-dimethyl-2-imidazolidinone and N-methylpyrrolidone, and the amount of the organic solvent is 3-6 times of the weight of the dicyandiamide sodium; the alkaline catalyst is at least one of ammonium acetate, sodium acetate, potassium acetate, ammonium formate, sodium formate, pyridine, piperidine, diethylamine and dipotassium hydrogen phosphate, and the dosage of the alkaline catalyst is 0.1-5% of the weight of the dicyandiamide sodium; the feeding molar ratio of the malononitrile to the dicyandiamide sodium is 0.95-1.2: 1, the dropping temperature and the heat preservation reaction temperature of the malononitrile solution are 105-120 ℃, and the heat preservation reaction time is 0.5-1 hour; the poor-solubility solvent is at least one of n-butyl alcohol, 2-butanol, isopropanol, n-propanol, ethanol, methanol, ethyl acetate, ethyl formate, isopropyl acetate, n-hexane and cyclohexane, and the dosage of the poor-solubility solvent is 6-10 times of the weight of the sodium dicyandiamide.
3. The method for synthesizing dicyclanil according to claim 1, wherein: in the reaction step (2), the solvent is at least one of methanol, ethanol and acetonitrile, the dosage of the solvent is 1-3 times of the weight of the condensate, the content of hydrochloric acid is 30% -36%, and the molar ratio of hydrochloric acid to the condensate is 3.5-10: 1, dripping hydrochloric acid at-10 to 15 ℃ for 2 to 12 hours; the heat preservation temperature is 10-20 ℃, and the heat preservation reaction time is 3-5 hours; the washing solvent is consistent with the reaction solvent and is at least one of methanol, ethanol and acetonitrile, and the dosage of the washing solvent is 0.5-2 times of the weight of the condensation compound.
4. The method of synthesis according to claim 3, characterized in that: the molar ratio of hydrochloric acid to condensate is preferably 5 to 7.5: 1, the dripping temperature of the hydrochloric acid is preferably-5 ℃, and the dripping time is preferably 3-6 hours.
5. The method for synthesizing dicyclanil according to claim 1, wherein: in the reaction step (3), the polar solvent is at least one of methanol, ethanol, acetonitrile and water, and the dosage of the polar solvent is 2-5 times of the weight of the cyclic compound; the mol ratio of the cyclopropylamine to the cyclic compound is 1.0-2.5: 1; the organic base is at least one of triethylamine, 2,4, 6-trimethylpyridine, 4-dimethylaminopyridine, tetramethylethylenediamine, hexamethylenetetramine, N-methylmorpholine, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, butyl lithium and tert-butyl lithium, the inorganic base is at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and lithium hydroxide, and the molar ratio of the base to the cyclic compound is 1.5-2.5: 1; the reaction temperature of the reaction step (3) is 65-100 ℃, and the reaction time is 3-15 hours; the amount of the washing water is 2-4 times of the weight of the condensation compound.
6. The method of synthesis according to claim 5, characterized in that: the mol ratio of the cyclopropylamine to the cyclic compound is preferably 1.0-1.2: 1, the organic base is preferably at least one of triethylamine, 2,4, 6-trimethylpyridine, 4-dimethylaminopyridine, tetramethylethylenediamine, N-methylmorpholine, sodium tert-butoxide and potassium tert-butoxide, the inorganic base is preferably at least one of potassium hydroxide, potassium carbonate, sodium carbonate and lithium hydroxide, and the molar ratio of the base to the cyclic compound is preferably 1.8-2.3: 1; the reaction temperature in the reaction step (3) is preferably 80-90 ℃, and the reaction time is preferably 4-5 hours.
7. The method for synthesizing dicyclanil according to claim 1, wherein: in the reaction step (4), the dosage of DMF or DMAC is 6-10 times of the weight of the crude product of the dicyclanil; the dosage of the active carbon is 3-5% of the weight of the crude product of the dicyclanil, the decoloring temperature is 95-100 ℃, and the decoloring time is 0.5-1 hour; the water adding amount for crystallization is 1.3-2.5 times of the weight of the crude product of the dicyclanil, the temperature is 50-60 ℃ when water is added, and the temperature is kept for 1-2 hours after the water is added.
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| CN102250017A (en) * | 2011-06-15 | 2011-11-23 | 扬州天和药业有限公司 | Synthesizing method of dicyclanil |
| CN104130197A (en) * | 2014-07-29 | 2014-11-05 | 华中农业大学 | Chemical synthetic method of 2,4,6-triamido-5-cyano pyrimidine |
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| CN102250017A (en) * | 2011-06-15 | 2011-11-23 | 扬州天和药业有限公司 | Synthesizing method of dicyclanil |
| CN104130197A (en) * | 2014-07-29 | 2014-11-05 | 华中农业大学 | Chemical synthetic method of 2,4,6-triamido-5-cyano pyrimidine |
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