A preparation method and composition of acetoacetic acid, 6-ethylthio-3-heptene-2-one and intermediates thereof

Abstract

The invention discloses a preparation method and composition of acetoacetic acid, 6-ethylthio-3-heptene-2-one and an intermediate thereof. Diketene is subjected to a hydrolysis reaction in water in the presence of a hydration catalyst to generate acetoacetic acid, wherein the hydration catalyst is soluble in water and is selected from a specific palladium, nickel, ruthenium or rhodium complex; acetoacetic acid and 3-ethylthiobutyraldehyde are subjected to a condensation reaction in the presence of a condensation catalyst to generate 6-ethylthio-4-hydroxy-2-one, and 6-ethylthio-4-hydroxy-3-carboxyl-2-one and 6-ethylthio-3-heptene-2-one may also be generated. The composition comprises the three products generated by the condensation reaction, and the product of the condensation reaction is reacted in a solvent in the presence of a dehydrating agent to prepare 6-ethylthio-3-heptene-2-one. The invention has simple operation, mild reaction conditions, no wastewater pollution to the environment, high atom utilization rate, high overall yield and good purity.

Description

Technical Field

[0001] The invention relates to the technical field of fine chemical synthesis, and in particular to a preparation method and composition of acetoacetic acid, 6-ethylthio-3-heptene-2-one and intermediates thereof. Background Art

[0002] Sethodim belongs to the cyclohexenone stem and leaf herbicide. It is a highly effective, highly selective and low-toxic herbicide that can control annual and perennial grass weeds and has broad market prospects.

[0003] 6-Ethylthio-3-heptene-2-one is a key intermediate for preparing clethodim. The current synthetic routes of 6-Ethylthio-3-heptene-2-one mainly include:

[0004] (1) Using Witting reagent, i.e., triphenylphosphino-2-acetone, and ethylthiobutyraldehyde to synthesize 6-ethylthio-3-heptene-2-one, but in this route, the Witting reagent is an internal phosphorus salt composed of halogenated acetone and triphenylphosphine, the raw material cost of the reagent is high, phosphorus recovery is difficult, the phosphorus wastewater formed pollutes the environment, and the reaction conditions of this route require strict anhydrous conditions;

[0005] (2) Ethyl acetoacetate is first hydrolyzed with sodium hydroxide solution to prepare sodium acetoacetate, and then sodium acetoacetate is reacted with ethylthiobutyraldehyde and then acid is added for dehydration to obtain the target product. However, in this route, an irreversible saponification reaction occurs during the hydrolysis of ethyl acetoacetate, and the alkaline solution used cannot be recycled, and a large amount of sodium acetate wastewater is eventually generated to pollute the environment. Ethyl acetoacetate exhibits two forms of keto hydrolysis and acid hydrolysis in alkaline solutions of different concentrations. The saponification process belongs to the acid hydrolysis process, and the alkaline solution needs to be strictly controlled to be a dilute solution state, which will cause the acetoacetic acid concentration to be too low and the condensation reaction rate to be slow. In addition, after saponification, the pH value of the system needs to be adjusted with acid, and the resulting reaction system has more impurities, and the post-processing operation is more complicated;

[0006] (3) acetone and ethylthiobutyraldehyde undergo aldol condensation under base catalysis to obtain 6-ethylthio-4-hydroxy-2-one, and the product is dehydrated under acidic conditions to obtain the target product;

[0007] Acetone and ethylthiobutyraldehyde react in one step under alkaline conditions to obtain 6-ethylthio-4-hydroxy-2-one;

[0008] Acetone and ethylthiobutyraldehyde react in the presence of a nitrogen-containing organic base or a catalyst formed by a combination of an organic base and an acid to obtain 6-ethylthio-4-hydroxy-2-ketone;

[0009] In the above-mentioned route of synthesizing 6-ethylthio-4-hydroxy-2-one using acetone and ethylthiobutyraldehyde, the reaction system has poor selectivity and low yield. Analysis shows that the main reason for this problem is that the self-condensation reaction between the raw materials and the condensation reaction between the raw materials and the products in the system result in more by-products and lower purity. Summary of the invention

[0010] The object of the present invention is to overcome one or more deficiencies of the prior art and to provide an improved method for preparing a 6-ethylthio-3-heptene-2-one intermediate, namely 6-ethylthio-4-hydroxy-2-one. The method has simple operation, mild reaction conditions, no wastewater pollution to the environment, and the generated products can basically be used to prepare 6-ethylthio-3-heptene-2-one, with high atomic utilization.

[0011] The present invention also provides a composition comprising 6-ethylthio-4-hydroxy-2-ketone, 6-ethylthio-4-hydroxy-3-carboxyl-2-ketone and 6-ethylthio-3-heptene-2-ketone.

[0012] The invention also provides a method for preparing 6-ethylthio-3-heptene-2-one.

[0013] The invention also provides a method for preparing acetoacetic acid.

[0014] To achieve the above object, a technical solution adopted by the present invention is: a 6-ethylthio-4-hydroxy-2-ketone (structural formula: ), the preparation method comprising:

[0015] Allow diketene to undergo a hydrolysis reaction in water in the presence of a hydration catalyst to generate acetoacetic acid; the hydration catalyst is soluble in water and is selected from the transition metal complex represented by formula (I) and / or the transition metal complex represented by formula (II);

[0016] R 1 a MR 2 b (I), M(NH3)6R 3 c (II);

[0017] In the formula, R 1 is hydrogen, sodium, potassium, ammonium or barium, R 2 , R 3 are chlorine, sulfate or cyanide respectively; M is palladium, nickel, ruthenium or rhodium, and a, b and c are chemical valence equilibrium numbers respectively;

[0018] Acetoacetic acid and 3-ethylthiobutyraldehyde are subjected to a condensation reaction in the presence of a condensation catalyst to generate 6-ethylthio-4-hydroxy-2-ketone.

[0019] According to some preferred aspects of the present invention, in formula (I) or (II), palladium, nickel and ruthenium are respectively divalent, and rhodium is trivalent.

[0020] According to some preferred and specific aspects of the present invention, the transition metal complex represented by formula (I) is a combination of one or more selected from Na2PdCl4 (sodium tetrachloropalladate), K2PdCl4 (potassium tetrachloropalladate), (NH4)2PdCl4 (ammonium tetrachloropalladate), BaPdCl4 (barium tetrachloropalladate), K2Ni(CN)4 (potassium tetracyanonickelate), Na3RhCl6 (sodium hexachlororhodiumate), and H4PdCl4.

[0021] According to some preferred and specific aspects of the present invention, the transition metal complex represented by formula (II) is a combination of one or more selected from Ni(NH3)6SO4 (hexaamminenickel sulfate), Ni(NH3)6Cl2 (hexaamminenickel chloride), and Ru(NH3)6Cl2 (hexaammineruthenium chloride).

[0022] Furthermore, the hydration catalyst is sodium tetrachloropalladate and / or potassium tetrachloropalladate.

[0023] In the present invention, the amount of hydration catalyst used is relatively small. According to some preferred aspects of the present invention, in the process of preparing acetoacetic acid, the molar ratio of the hydration catalyst to the diketene is 1:20-100.

[0024] Preferably, in the process of preparing acetoacetic acid, the molar ratio of the hydration catalyst to the diketene is 1:25-60.

[0025] More preferably, in the process of preparing acetoacetic acid, the molar ratio of the hydration catalyst to the diketene is 1:30-55.

[0026] According to some preferred aspects of the present invention, in the process of preparing acetoacetic acid, the reaction temperature of the hydrolysis reaction is 0-30°C.

[0027] Preferably, in the process of preparing acetoacetic acid, the reaction temperature of the hydrolysis reaction is 10-30°C.

[0028] More preferably, in the process of preparing acetoacetic acid, the reaction temperature of the hydrolysis reaction is 20-30°C.

[0029] In some preferred embodiments of the present invention, in the process of preparing 6-ethylthio-4-hydroxy-2-ketone, the following embodiments are included: dissolving a hydration catalyst in water until it is completely dissolved to obtain a catalyst solution with a concentration of 8.0wt% to 12.0wt%, then adding diketene for hydrolysis reaction, after the reaction is completed, extracting the generated acetoacetic acid with an organic solvent to obtain an organic phase containing acetoacetic acid, the hydration catalyst and water constitute an aqueous phase, and mixing the organic phase containing acetoacetic acid, the condensation catalyst and 3-ethylthiobutyraldehyde for condensation reaction. In the present invention, the organic phase containing acetoacetic acid can be directly used for reaction with 3-ethylthiobutyraldehyde without separation, the operation is convenient, and the aqueous phase can be recycled.

[0030] According to some specific aspects of the present invention, the organic solvent used for extraction is a low-boiling-point weakly polar solvent selected from diethyl ether, cyclohexane, dichloromethane, chloroform and the like.

[0031] In some embodiments of the present invention, the concentration of the catalyst solution is 10.0 wt% to 11.0 wt%.

[0032] In some embodiments of the present invention, in the process of preparing acetoacetic acid, the reaction time of the hydrolysis reaction is 2-6 hours, and can further be 4-5.5 hours or 4.5-5 hours.

[0033] In some embodiments of the present invention, during the preparation of acetoacetic acid, diketene may be added dropwise.

[0034] According to some preferred aspects of the present invention, in the process of preparing 6-ethylthio-4-hydroxy-2-one, the molar ratio of the 3-ethylthiobutyraldehyde to the diketene is 1:1.1-1.5.

[0035] According to some preferred aspects of the present invention, in the process of preparing 6-ethylthio-4-hydroxy-2-one, the molar ratio of the 3-ethylthiobutyraldehyde to the condensation catalyst is 1: 0.07-0.3. In some embodiments of the present invention, in the process of preparing 6-ethylthio-4-hydroxy-2-one, the molar ratio of the 3-ethylthiobutyraldehyde to the condensation catalyst is 1: 0.07-0.25. In some embodiments of the present invention, in the process of preparing 6-ethylthio-4-hydroxy-2-one, the molar ratio of the 3-ethylthiobutyraldehyde to the condensation catalyst is 1: 0.08-0.23.

[0036] According to some preferred aspects of the present invention, the condensation catalyst comprises an alkaline organic substance, and the alkaline organic substance comprises at least one of triethylamine, diethylamine, dimethylamine, pyridine and pyrrole.

[0037] According to some preferred aspects of the present invention, the reaction temperature of the condensation reaction is 10-40°C, preferably 20-35°C.

[0038] In some embodiments of the present invention, the reaction time of the condensation reaction is 4-8 h, or 5-7.5 h or 5.5-6 h.

[0039] According to some preferred aspects of the present invention, in the process of preparing 6-ethylthio-4-hydroxy-2-ketone, the acetoacetic acid and the condensation catalyst are co-dropped into 3-ethylthiobutyraldehyde for condensation reaction, or 3-ethylthiobutyraldehyde is dropwise added into a mixture of the acetoacetic acid and the condensation catalyst. In some embodiments of the present invention, the dripping time is controlled to be 30-90 min, or 40-60 min.

[0040] Another technical solution provided by the present invention is: a composition, in the process of preparing 6-ethylthio-4-hydroxy-2-one by the above-mentioned preparation method, 6-ethylthio-4-hydroxy-3-carboxyl-2-one and 6-ethylthio-3-heptene-2-one are also generated respectively, and the composition contains 6-ethylthio-4-hydroxy-2-one, 6-ethylthio-4-hydroxy-3-carboxyl-2-one and 6-ethylthio-3-heptene-2-one.

[0041] According to the present invention, in the composition, the mass percentage of 6-ethylthio-4-hydroxy-2-ketone is more than 50%.

[0042] According to some specific aspects of the present invention, the preparation method of the composition comprises: preparing 6-ethylthio-4-hydroxy-2-ketone by the preparation method described above, and after the reaction is completed, removing the light components under reduced pressure to obtain 6-ethylthio-4-hydroxy-2-ketone, 6-ethylthio-4-hydroxy-3-carboxy-2-ketone (structural formula: ) and 6-ethylthio-3-heptene-2-one (structural formula: )'s composition.

[0043] Another technical solution provided by the present invention is a method for preparing 6-ethylthio-3-heptene-2-one, the method comprising:

[0044] Using 6-ethylthio-4-hydroxy-2-ketone prepared by the above-mentioned preparation method as a raw material, reacting the raw material in the presence of a dehydrating agent in a solvent to generate 6-ethylthio-3-heptene-2-ketone;

[0045] or,

[0046] The above-mentioned composition is used as a raw material, and the raw material, a dehydrating agent and a solvent are mixed. The 6-ethylthio-4-hydroxy-2-ketone in the raw material removes water in the solvent in the presence of a dehydrating agent to generate 6-ethylthio-3-heptene-2-ketone; the 6-ethylthio-4-hydroxy-3-carboxy-2-ketone in the raw material removes carbon dioxide and water respectively in the solvent in the presence of a dehydrating agent to generate 6-ethylthio-3-heptene-2-ketone.

[0047] According to some preferred aspects of the present invention, the dehydrating agent is a combination of one or more selected from oxalic acid, phosphoric acid, concentrated hydrochloric acid, and concentrated sulfuric acid, the mass percentage of the concentrated hydrochloric acid is 20%-38%, and the mass percentage of the concentrated sulfuric acid is 70%-99%.

[0048] According to some preferred aspects of the present invention, the solvent is a combination of one or more selected from toluene, xylene, and cyclohexane.

[0049] According to some preferred aspects of the present invention, the volume ratio of the raw material to the solvent is 1: 0.8-1.3. In some embodiments of the present invention, the volume ratio of the raw material to the solvent is 1: 0.90-1.25. In some embodiments of the present invention, the volume ratio of the raw material to the solvent is 1: 0.95-1.2.

[0050] According to some preferred aspects of the present invention, the molar ratio of the 3-ethylthiobutyraldehyde to the dehydrating agent is 1:0.1-0.4. In some embodiments of the present invention, the molar ratio of the 3-ethylthiobutyraldehyde to the dehydrating agent is 1:0.15-0.35. In some embodiments of the present invention, the molar ratio of the 3-ethylthiobutyraldehyde to the dehydrating agent is 1:0.2-0.3.

[0051] According to some preferred aspects of the present invention, the dehydration temperature is 70-110°C.

[0052] Furthermore, the dehydration temperature of the dehydration is 80-100°C.

[0053] Furthermore, the dehydration temperature of the dehydration is 80-90°C.

[0054] In some embodiments of the present invention, the dehydration time is 4-7 hours, or 5-7 hours.

[0055] Another technical solution provided by the present invention is a method for preparing acetoacetic acid, which comprises: hydrolyzing diketene in water in the presence of a hydration catalyst to generate acetoacetic acid; the hydration catalyst is soluble in water and is selected from the transition metal complex represented by formula (I) and / or the transition metal complex represented by formula (II);

[0056] R1 a MR 2 b (I), M(NH3)6R 3 c (II);

[0057] In the formula, R 1 is sodium, potassium, ammonium or barium, R 2 , R 3 are chloride, sulfate or cyanide respectively; M is palladium, nickel, ruthenium or rhodium, and a, b, c are the chemical valence equilibrium numbers respectively.

[0058] In the present invention, the mechanism of preparing acetoacetic acid by hydrolysis of diketene is roughly as follows (wherein for ease of description, the hydration catalyst is represented by MLn, M is palladium, nickel, ruthenium or rhodium, L is R 2 or R 3 ):

[0059]

[0060] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0061] The present invention is based on the defects of poor selectivity of the reaction system, low yield, low purity, large pollution problem, complicated operation, etc. in the process of preparing 6-ethylthio-3-heptene-2-one in the prior art, and innovatively provides a process route of preparing acetoacetic acid by hydrolyzing diketene, and then reacting with 3-ethylthiobutyraldehyde to prepare 6-ethylthio-3-heptene-2-one intermediate, i.e., 6-ethylthio-4-hydroxy-2-one. The route uses a specific transition metal complex as a catalyst, which can not only obtain acetoacetyl acetate with high efficiency and high yield, but also has mild reaction conditions, and overcomes the problems of saponification wastewater and the need to use acid to adjust the pH value in the preparation process of the prior art, no wastewater is generated, the environmental protection is good, the operation is simpler, and the transition metal complex catalyst can be recycled and reused, and the cost is relatively lower. In addition, the product obtained when the intermediate 6-ethylthio-4-hydroxy-2-one is prepared by the present invention can be directly used as the process of preparing 6-ethylthio-3-heptene-2-one in the next step, so that the atomic utilization rate is high, the overall yield is high, and the purity is good. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 This is a gas chromatogram of acetoacetic acid obtained in Example 1 of the present invention;

[0063] Figure 2 This is a gas chromatogram of the crude 6-ethylthio-4-hydroxy-2-ketone intermediate obtained in Example 7 of the present invention;

[0064] Figure 3This is the mass spectrum of 6-ethylthio-3-heptene-2-one prepared in Example 7 of the present invention;

[0065] Figure 4 6-ethylthio-3-heptene-2-one prepared in Example 7 of the present invention 1 H NMR (nuclear magnetic resonance hydrogen spectrum) chart. DETAILED DESCRIPTION

[0066] The above scheme is further described below in conjunction with specific embodiments; it should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments; the implementation conditions adopted in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0067] Unless otherwise specified in the following examples, all raw materials are commercially available or prepared by conventional methods in the art.

[0068] Example 1 Preparation of acetoacetic acid

[0069] Weigh 4.0g of sodium tetrachloropalladate into a two-necked flask, add 36.1g of water, stir and heat to 30°C, and continue stirring after the temperature is constant until the sodium tetrachloropalladate is completely dissolved. Add 42.0g of diethyl ketone into the flask. During the addition, the color of the solution changes from dark red to yellow. Keep the temperature to react, and track the raw material status with TLC. After about 5.0h, TLC tracking shows that no diethyl ketone is detected, and the reaction is over. Extract the reaction solution three times with 50g of dichloromethane, and combine the organic phases to obtain 96.7g. The organic phase contains the generated acetoacetic acid, and its gas chromatogram is as shown below. Figure 1 As shown (Note: a small amount of diketene raw material is added to show the relative positions of the substances), the gas phase content of acetoacetic acid is 45.04%, and the calculated yield is 85.32%. The aqueous phase contains the catalyst sodium tetrachloropalladate, which can be recycled.

[0070] Example 2 Preparation of acetoacetic acid

[0071] Weigh 3.6g of potassium tetrachloropalladate in a two-necked flask, add 36.0g of water, stir and heat to 25°C, and continue stirring until the potassium tetrachloropalladate is completely dissolved after the temperature is constant. Add 46.2g of diethylene ketone to the flask, and the color of the solution changes from brownish red to yellow during the dropwise addition. Keep the reaction warm and track the raw material situation with TLC. After 4.5h, TLC tracking shows that diethylene ketone is not detected, and the reaction is completed. The reaction solution is extracted three times with 50g of cyclohexane, and the organic phase is combined to obtain 98.1g, the gas phase content of acetoacetic acid is 48.3%, and the calculated yield is 84.42%. The aqueous phase contains the catalyst sodium tetrachloropalladate, which can be recycled.

[0072] Example 3 Preparation of acetoacetic acid

[0073] Weigh 3.6g of potassium tetracyanonickelate into a two-necked flask, add 38.7g of water, stir and heat to 20°C, and continue stirring until the potassium tetracyanonickelate is completely dissolved after the temperature is constant. Add 50.4g of diethylene ketone into the flask. During the addition, the color of the solution changes from blue-green to light yellow. Keep the reaction warm and track the raw material situation by TLC. After 5.0h, TLC tracking shows that no diethylene ketone is detected, and the reaction is over. Extract the reaction solution three times with 50g of cyclohexane, combine the organic phases to obtain 105.7g, the acetoacetic acid gas phase content is 41.4%, and the calculated yield is 71.4%. The aqueous phase contains the catalyst sodium tetrachloropalladate, which can be recycled.

[0074] Example 4 Preparation of acetoacetic acid

[0075] Weigh 4.1g of hexaammineruthenium chloride into a two-necked flask, add 37.2g of water, stir and heat to 20°C, and continue stirring after the temperature is constant until the hexaammineruthenium chloride is completely dissolved. Add 50.1g of diethylene ketone to the flask. During the addition, the color of the solution changes from dark blue to yellow-green. Keep the reaction warm and track the raw material situation by TLC. After 4.5h, TLC tracking shows that no diethylene ketone is detected, and the reaction is over. Extract the reaction solution three times with 50g of cyclohexane, combine the organic phases to obtain 93.3g, the acetoacetic acid gas phase content is 50.5%, and the calculated yield is 77.4%. The aqueous phase contains the catalyst sodium tetrachloropalladate, which can be recycled.

[0076] Example 5 Preparation of acetoacetic acid

[0077] Weigh 7.5g of sodium hexachlororhodiumate in a two-necked flask, add 67.5g of water, stir and heat to 20°C, and continue stirring until the sodium hexachlororhodiumate is completely dissolved after the temperature is constant. Add 84.0g of diethylene ketone to the flask. During the dropwise addition, the solution color changes from milky white to light yellow. Keep the reaction warm and track the raw material situation with TLC. After 5.5h, TLC tracking shows that diethylene ketone is not detected, and the reaction is completed. The reaction solution is extracted three times with 100g of cyclohexane, and the organic phase is combined to obtain 203.1g, the acetoacetic acid gas phase content is 39.7%, and the calculated yield is 79.8%. The aqueous phase contains the catalyst sodium tetrachloropalladate, which can be recycled.

[0078] Example 6 Preparation of acetoacetic acid

[0079] The method is basically the same as Example 1, except that sodium tetrachloropalladate is replaced by an equal molar amount of chloropalladic acid (H4PdCl4). The gas phase content of acetoacetic acid is 35.2%, and the calculated yield is 69.1%.

[0080] Comparative Example 1

[0081] The method is basically the same as Example 1, except that sodium tetrachloropalladate is replaced by an equal molar amount of palladium acetate. The gas phase content of acetoacetic acid is 32.3%, and the calculated yield is 52.3%.

[0082] Comparative Example 2

[0083] The method is basically the same as Example 1, except that sodium tetrachloropalladate is replaced by an equal molar amount of tetrakis(triphenylphosphine)palladium. The gas phase content of acetoacetic acid is 30.3%, and the calculated yield is 56.4%.

[0084] Example 7 Preparation of 6-ethylthio-3-heptene-2-one

[0085] Weigh 4.0g of sodium tetrachloropalladate into a two-necked flask, add 36.1g of water, stir and heat to 30°C, and continue stirring until the sodium tetrachloropalladate is completely dissolved after the temperature is constant. Add 42.0g of diethyl ketone into the flask. During the addition, the color of the solution changes from dark red to yellow. Keep the reaction warm and track the raw material by TLC. After about 5.0h, TLC tracking shows that no diethyl ketone is detected, and the reaction is over. Extract the reaction solution three times with 50g of dichloromethane, combine the organic phase to obtain 96.7g, the aqueous phase, the aqueous phase contains the catalyst sodium tetrachloropalladate, which can be recycled.

[0086] Weigh 54.8 g of 3-ethylthiobutyraldehyde into a three-necked flask, stir and heat up. Place the organic phase obtained after the hydrolysis of diketene into an acetoacetic acid constant-pressure dropping funnel, and weigh 4.2 g of triethylamine into an alkaline catalyst constant-pressure dropping funnel. After the temperature is constant at 30°C, adjust the ratio of the two constant-pressure dropping funnels and start dripping into the three-necked flask. The dripping time is 40 minutes. After the addition is completed, keep the temperature for the reaction, and during this period, gas phase detection is used to track the ethylthiobutyraldehyde raw material. After 4.5 hours of gas phase detection, 0.34 wt% of ethylthiobutyraldehyde remains, and the reaction is completed. Vacuum rotary evaporation is used to remove light components to obtain 110.35 g of a crude 6-ethylthio-4-hydroxy-2-ketone intermediate (see its gas chromatogram for details). Figure 2 As shown), in the intermediate crude product, the content of undehydrated, undecarboxylated intermediate β-keto acid (6-ethylthio-4-hydroxy-3-carboxy-2-one) is 31.81wt%, the content of undehydrated intermediate 6-ethylthio-4-hydroxy-2-one is 43.04wt%, and the content of 6-ethylthio-3-heptene-2-one is 12.5wt%.

[0087] Take the crude intermediate product of the previous step into a two-necked flask, add 100mL of toluene solvent, add 10.5g of oxalic acid, stir and heat to 90°C, keep warm for reaction, and track the reaction with gas phase detection. After 7 hours of reaction, the content of the intermediate 6-ethylthio-4-hydroxy-2-one is ≤1%, and the reaction is completed. Neutralize the acid with 10% sodium carbonate solution, wash twice with water until neutral, and vacuum distill the organic phase at a vacuum degree of 960Pa. Take the 103-106°C fraction to obtain a light yellow liquid 6-ethylthio-3-heptene-2-one (see its mass spectrum Figure 3 As shown, 1 H NMR (nuclear magnetic resonance hydrogen spectrum) Figure 4 As shown) 59.9g, product content 94.6%, overall yield 79.19%.

[0088] Example 8 Preparation of 6-ethylthio-3-heptene-2-one

[0089] Weigh 3.6g of potassium tetrachloropalladate into a two-necked flask, add 36.0g of water, stir and heat to 25°C, and continue stirring until the potassium tetrachloropalladate is completely dissolved after the temperature is constant. Add 46.2g of diethylene ketone into the flask. During the addition, the color of the solution changes from brown-red to yellow. Keep the reaction warm and track the raw material situation with TLC. After 4.5h, TLC tracking shows that no diethylene ketone is detected, and the reaction is over. Extract the reaction solution three times with 50g of cyclohexane, combine the organic phase to obtain 98.1g, the aqueous phase, the aqueous phase contains the catalyst sodium tetrachloropalladate, which can be recycled.

[0090] Weigh 55.8g of 3-ethylthiobutyraldehyde in a three-necked flask, stir and heat. Place the organic phase obtained after the hydrolysis of diketene in an acetoacetic acid constant pressure dropping funnel, and weigh 4.3g of pyridine in an alkaline catalyst constant pressure dropping funnel. After the temperature is constant at 25°C, adjust the ratio of the two constant pressure dropping funnels and start dripping into the three-necked flask. The dripping time is 45min. After the dripping is completed, keep warm for reaction, and the gas phase detection is used to track the ethylthiobutyraldehyde raw material during the period. 5.0h gas phase detection shows that ethylthiobutyraldehyde remains 0.48wt%, and the reaction is completed. The light components were removed by vacuum rotary evaporation to obtain 110.76 g of a crude 6-ethylthio-4-hydroxy-2-ketone intermediate, of which the content of undehydrated, undecarboxylated intermediate β-keto acid (6-ethylthio-4-hydroxy-3-carboxy-2-ketone) was 6.34 wt%, the content of undehydrated intermediate 6-ethylthio-4-hydroxy-2-ketone was 48.04 wt%, and the content of 6-ethylthio-3-heptene-2-one was 14.33 wt%.

[0091] Take the above intermediate crude product in a two-necked flask, add 100mL of solvent cyclohexane, add 8.5g of concentrated sulfuric acid (98wt%), stir and heat to 80°C, keep warm and reflux reaction, and track the reaction by gas phase detection. After 5.5h of reaction, the content of intermediate 6-ethylthio-4-hydroxy-2-one is ≤1%, and the reaction is completed. Neutralize the acid with 10% sodium carbonate solution, wash twice with water to neutrality, and vacuum distill the organic phase with a vacuum degree of -0.1MPa. Take the 103-106°C fraction to obtain 63.1g of light yellow liquid 6-ethylthio-3-heptene-2-one, with a product content of 95.6% and an overall yield of 82.91%.

[0092] Example 9 Preparation of 6-ethylthio-3-heptene-2-one

[0093] Weigh 3.6g of potassium tetracyanonickelate into a two-necked flask, add 38.7g of water, stir and heat to 20°C, and continue stirring until the potassium tetracyanonickelate is completely dissolved after the temperature is constant. Add 50.4g of diethylene ketone into the flask. During the addition, the color of the solution changes from blue-green to light yellow. Keep the reaction warm and track the raw material situation with TLC. After 5.0h, TLC tracking shows that no diethylene ketone is detected, and the reaction is over. Extract the reaction solution three times with 50g of cyclohexane, combine the organic phase to obtain 105.7g, and the aqueous phase contains the catalyst sodium tetrachloropalladate, which can be recycled.

[0094] The organic phase was placed in a three-necked flask, 5.1 g of dimethylamine was added thereto, and the mixture was stirred and heated to 25 ° C. After the temperature was constant, 66.0 g of 3-ethylthiobutyraldehyde was added dropwise with a constant pressure dropping funnel for 40 min. After the addition was completed, the reaction was kept warm, and the ethylthiobutyraldehyde raw material was tracked by gas phase detection during the period. 6.0 h gas phase detection showed that 0.50 wt% of ethylthiobutyraldehyde remained, and the reaction was completed. Vacuum rotary evaporation was used to remove light components to obtain 128.4 g of a crude intermediate of 6-ethylthio-4-hydroxy-2-ketone. In the crude intermediate, the content of the undehydrated and undecarboxylated intermediate β-keto acid (6-ethylthio-4-hydroxy-3-carboxy-2-ketone) was 16.40 wt%, the content of the undehydrated intermediate 6-ethylthio-4-hydroxy-2-ketone was 51.79 wt%, and the content of 6-ethylthio-3-heptene-2-ketone was 5.36 wt%.

[0095] Take the above intermediate crude product in a two-necked flask, add 120mL of solvent cyclohexane, add 10.0g of concentrated sulfuric acid (98wt%), stir and heat to 80°C, keep warm for reaction, and track the reaction by gas phase detection. After 6.0h of reaction, the content of intermediate 6-ethylthio-4-hydroxy-2-one is ≤1%, and the reaction is completed. Neutralize the acid with 10% sodium carbonate solution, wash twice with water to neutrality, and vacuum distill the organic phase with a vacuum degree of -0.1MPa. Take the 103-106°C fraction to obtain 70.3g of light yellow liquid 6-ethylthio-3-heptene-2-one, with a product content of 94.8% and an overall yield of 77.49%.

[0096] Example 10 Preparation of 6-ethylthio-3-heptene-2-one

[0097] Weigh 4.1g of hexaammineruthenium chloride into a two-necked flask, add 37.2g of water, stir and heat to 20°C, and continue stirring after the temperature is constant until the hexaammineruthenium chloride is completely dissolved. Add 50.1g of diethylene ketone to the flask. During the addition, the color of the solution changes from dark blue to yellow-green. Keep the reaction warm and track the raw material situation with TLC. After 4.5h, TLC tracking shows that no diethylene ketone is detected, and the reaction is over. Extract the reaction solution three times with 50g of cyclohexane, combine the organic phase to obtain 93.3g, and the aqueous phase contains the catalyst sodium tetrachloropalladate, which can be recycled.

[0098] The organic phase was placed in a three-necked flask, 4.9 g of diethylamine was added thereto, and the mixture was stirred and heated to 25 ° C. After the temperature was constant, 65.6 g of 3-ethylthiobutyraldehyde was added dropwise with a constant pressure dropping funnel for 40 min. After the addition was completed, the reaction was kept warm, and the ethylthiobutyraldehyde raw material was tracked by gas phase detection during the period. 6.0 h gas phase detection showed that 0.38 wt% of ethylthiobutyraldehyde remained, and the reaction was completed. Vacuum rotary evaporation was used to remove light components to obtain 121.6 g of 6-ethylthio-4-hydroxy-2-ketone crude intermediate, in which the undehydrated and undecarboxylated intermediate β-keto acid (6-ethylthio-4-hydroxy-3-carboxy-2-ketone) content was 17.33 wt%, the undehydrated intermediate 6-ethylthio-4-hydroxy-2-ketone content was 56.12 wt%, and the 6-ethylthio-3-heptene-2-ketone content was 4.69 wt%.

[0099] Take the above intermediate crude product in a two-necked flask, add 120mL of solvent toluene, add 10.0g of concentrated sulfuric acid (98%wt), stir and heat to 80°C, keep warm for reaction, and track the reaction by gas phase detection. After 6.0h of reaction, the content of intermediate 6-ethylthio-4-hydroxy-2-one is ≤1%, and the reaction is completed. Neutralize the acid with 10% sodium carbonate solution, wash twice with water to neutrality, and vacuum distill the organic phase with a vacuum degree of -0.1MPa. Take the 103-106°C fraction to obtain 74.23g of light yellow liquid 6-ethylthio-3-heptene-2-one, with a product content of 93.77% and an overall yield of 86.7%.

[0100] Example 11 Preparation of 6-ethylthio-3-heptene-2-one

[0101] Weigh 7.5g of sodium hexachlororhodiumate into a two-necked flask, add 67.5g of water, stir and heat to 20°C, and continue stirring until the sodium hexachlororhodiumate is completely dissolved after the temperature is constant. Add 84.0g of diethylene ketone into the flask. During the dropwise addition, the solution color changes from milky white to light yellow. Keep the reaction warm and track the raw material situation with TLC. After 5.5h, TLC tracking shows that no diethylene ketone is detected, and the reaction is over. Extract the reaction solution three times with 100g of cyclohexane, combine the organic phase to obtain 203.1g, and the aqueous phase contains the catalyst sodium tetrachloropalladate, which can be recycled.

[0102] The organic phase was placed in a three-necked flask, 8.2 g of triethylamine was added thereto, and the mixture was stirred and heated to 25 ° C. After the temperature was constant, 101.5 g of 3-ethylthiobutyraldehyde was added dropwise with a constant pressure dropping funnel for 40 min. After the addition was completed, the reaction was kept warm, and the ethylthiobutyraldehyde raw material was tracked by gas phase detection during the period. 6.5 h gas phase detection showed that 0.32 wt% of ethylthiobutyraldehyde remained, and the reaction was completed. Vacuum rotary evaporation was used to remove light components to obtain 121.6 g of 6-ethylthio-4-hydroxy-2-ketone crude intermediate, in which the undehydrated and undecarboxylated intermediate β-keto acid (6-ethylthio-4-hydroxy-3-carboxy-2-ketone) content was 14.65 wt%, the undehydrated intermediate 6-ethylthio-4-hydroxy-2-ketone content was 58.54 wt%, and the product 6-ethylthio-3-heptene-2-ketone content was 3.98 wt%.

[0103] Take the above intermediate crude product in a two-necked flask, add 200mL of solvent xylene, add 15.0g of concentrated hydrochloric acid (98wt%), stir and heat to 80°C, keep warm for reaction, and track the reaction by gas phase detection. After 7.0h of reaction, the content of intermediate 6-ethylthio-4-hydroxy-2-one is ≤1%, and the reaction is completed. Neutralize the acid with 10% sodium carbonate solution, wash twice with water to neutrality, and vacuum distill the organic phase with a vacuum degree of -0.1MPa. Take the 103-106°C fraction to obtain 116.58g of light yellow liquid 6-ethylthio-3-heptene-2-one, with a product content of 94.74% and an overall yield of 83.5%.

[0104] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

[0105] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

Claims

1. A method for preparing 6-ethylthio-3-heptene-2-one, characterized in that: The preparation method comprises: Allow diketene to undergo a hydrolysis reaction in water in the presence of a hydration catalyst to generate acetoacetic acid; wherein the generated acetoacetic acid is extracted with an organic solvent to obtain an organic phase containing acetoacetic acid, and the hydration catalyst and water constitute an aqueous phase, wherein the hydration catalyst is soluble in water and is selected from a combination of one or more of Ni(NH3)6Cl2 and Ru(NH3)6Cl2, and the reaction temperature of the hydrolysis reaction is 20-30°C; The organic phase containing acetoacetic acid, a condensation catalyst and 3-ethylthiobutyraldehyde are mixed to carry out a condensation reaction. After the reaction is completed, light components are removed under reduced pressure to obtain a composition containing 6-ethylthio-4-hydroxy-2-ketone, 6-ethylthio-4-hydroxy-3-carboxy-2-ketone and 6-ethylthio-3-heptene-2-ketone; wherein, during the mixing process, 3-ethylthiobutyraldehyde is added dropwise to the mixture of acetoacetic acid and the condensation catalyst, and the condensation catalyst is diethylamine; The composition is used as a raw material, and the raw material, a dehydrating agent and a solvent are mixed; in the presence of a dehydrating agent, 6-ethylthio-4-hydroxy-2-ketone in the raw material removes water in the solvent to generate 6-ethylthio-3-heptene-2-ketone; in the presence of a dehydrating agent, 6-ethylthio-4-hydroxy-3-carboxyl-2-ketone in the raw material removes carbon dioxide and water respectively in the solvent to generate 6-ethylthio-3-heptene-2-ketone; wherein the dehydrating agent is concentrated sulfuric acid, the mass percentage of the concentrated sulfuric acid is 70%-99%, and the solvent is toluene.

2. The method for preparing 6-ethylthio-3-heptene-2-one according to claim 1, characterized in that: The molar ratio of the hydration catalyst to the diketene is 1:20-100.

3. The method for preparing 6-ethylthio-3-heptene-2-one according to claim 2, characterized in that: The molar ratio of the hydration catalyst to the diketene is 1:25-60.

4. The method for preparing 6-ethylthio-3-heptene-2-one according to claim 3, characterized in that: The molar ratio of the hydration catalyst to the diketene is 1:30-55.

5. The method for preparing 6-ethylthio-3-heptene-2-one according to claim 1, characterized in that: The preparation method includes the following implementation: dissolving a hydration catalyst in water until it is completely dissolved to obtain a catalyst solution with a concentration of 8.0wt% to 12.0wt%, and then adding diketene to carry out a hydrolysis reaction.

6. The method for preparing 6-ethylthio-3-heptene-2-one according to claim 1, characterized in that: The molar ratio of the 3-ethylthiobutyraldehyde to the diketene is 1:1.1-1.5; and / or the molar ratio of the 3-ethylthiobutyraldehyde to the condensation catalyst is 1:0.07-0.3; and / or the reaction temperature of the condensation reaction is 10-40°C.

7. The method for preparing 6-ethylthio-3-heptene-2-one according to claim 1, characterized in that: The reaction temperature of the condensation reaction is 20-35°C.

8. The method for preparing 6-ethylthio-3-heptene-2-one according to claim 1, characterized in that: The molar ratio of the 3-ethylthiobutyraldehyde to the dehydrating agent is 1:0.1-0.4; and / or the dehydration temperature of the dehydration is 70-110°C.

9. The method for preparing 6-ethylthio-3-heptene-2-one according to claim 1, characterized in that: The dehydration temperature of the dehydration is 80-100°C.

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