CN114539048B - Carlong anhydride intermediate and preparation method of Carlong anhydride - Google Patents
Carlong anhydride intermediate and preparation method of Carlong anhydride Download PDFInfo
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Abstract
The invention provides a preparation method of a Carlong anhydride intermediate and Carlong anhydride, which utilizes 2-X substituent malonic diester (II) and 2-Y substituent-3-methylbut-2-enoate (III) to obtain dimethyl cyclopropane triester through addition cyclization, and then prepares Carlong acid (IV) through hydrolysis and decarboxylation; and carrying out an anhydration reaction on the obtained caronic acid to obtain the caronic anhydride. The method has the advantages of low-cost and easily-obtained raw materials, low cost, safe and simple operation, small wastewater production amount, environmental protection, high reaction selectivity, few side reactions, high product yield and purity, and suitability for green industrial production.
Description
Technical Field
The invention relates to a Carlong anhydride intermediate and a preparation method of Carlong anhydride, belonging to the technical field of fine chemical engineering.
Background
Carbonic anhydride, chemical name 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane-2, 4-dione, is an important pharmaceutical intermediate; the preparation method can be used for preparing the oral hepatitis C HCV protease inhibitors of bosaprevi and Nirmatrelvir, wherein Nirmatrelvir is the main component of the new coronavirus therapeutic drug Paxlovid of the psicose company, and has large market demand.
There have been reports in the prior art about methods for preparing caronic anhydride and its intermediates, such as:
chinese patent document CN102070575A adopts methyl isobutylene ketone as a starting material, and adopts 3 steps of (ethoxycarbonylmethyl) dimethyl sulfide ylide cyclization, sodium hypochlorite oxidation and acetic anhydride anhydration to obtain the caronic anhydride, wherein the total yield is 67.7%, and the reaction process is described as the following synthetic route 1.
The raw material (ethoxycarbonylmethyl) dimethyl sulfide used in the synthetic route 1 has high ylide price, and the byproduct dimethyl sulfide has bad smell during cyclization and has poor operation environment; sodium hypochlorite is oxidized to generate a large amount of wastewater, so that the environmental protection performance is poor; the yield of the target product is low. The synthesis route 1 is not suitable for industrial production due to high cost of raw materials, poor environmental protection and the like.
Chinese patent document CN102391228A uses ethyl chrysanthemate or ethyl dichlorochrysanthemate, and uses ozone or potassium permanganate to make oxidation so as to obtain the caronic acid, then uses acetic anhydride to make anhydration so as to obtain the caronic anhydride, and its total yield is 65.5%, and the reaction process is described as the following synthetic route 2.
The raw material ethyl chrysanthemate or ethyl dichlorochrysanthemate used in the synthetic route 2 has high price, low yield of target products and is not suitable for industrial production.
The Chinese patent document CN104151279A takes 3-carene as a raw material, and obtains the caronic acid by oxidation of potassium permanganate, and the caronic anhydride is prepared by anhydride, the total yield is 40-45%, the product purity is 90-93%, and the reaction process is described as the following synthetic route 3.
The synthetic route 3 has low total yield and low product purity, and can be used for preparing medicines after purification; meanwhile, a large amount of potassium permanganate is used as an oxidant, so that the operation is dangerous, a large amount of manganese-containing residues are generated, and the environment is polluted.
Chinese patent document CN104163759A uses isopentenol acetate as a starting material and diazoacetic acid ethyl ester to carry out cyclization to generate a three-membered ring key intermediate, then the three-membered ring key intermediate is hydrolyzed and oxidized to obtain caronic acid, and the caronic acid anhydride is obtained through anhydration, wherein the total yield is 17.1%, and the reaction process is described as the following synthetic route 4.
The total yield of the synthetic route 4 is low, and the price of the raw material diazoacetic acid ethyl ester is high; the preparation process involves diazotization reaction, has poor operation safety, and is not suitable for industrial production.
In summary, the existing preparation method of the caronic anhydride and the intermediate thereof has the defects of high raw material price, poor environmental protection, poor operation safety, low product yield and the like, so that the research on the green, safe, low-cost, high-yield and high-purity preparation process of the caronic anhydride has important significance for improving the market supply amount of the caronic anhydride, meeting the production requirement of Nirmatrelvis and resisting the damage of new coronaviruses.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a carpulosic anhydride intermediate and a preparation method of carpulosic anhydride. The method has the advantages of low-cost and easily-obtained raw materials, low cost, safe and simple operation, small wastewater production amount, environmental protection, high reaction selectivity, few side reactions, high product yield and purity, and suitability for green industrial production.
Description of the terminology:
a compound of formula ii: 2-X substituent malonic acid diester;
a compound of formula iii: 2-Y substituent-3-methylbut-2-enoate;
a compound of formula iv: a caronic anhydride intermediate, i.e., caronic acid;
a compound of formula i: carbonic anhydride.
In the specification, the compound numbers are completely consistent with the structural formula numbers, and have the same reference relationship, and the structural formula is taken as a basis.
The technical scheme of the invention is as follows:
a preparation method of a caronic anhydride intermediate comprises the following steps:
the dimethyl cyclopropane triester is obtained by carrying out addition cyclization reaction on a compound of a formula II and a compound of a formula III; the dimethyl cyclopropane triester is hydrolyzed to obtain dimethyl cyclopropane tricarboxylate; then acidifying and decarboxylating to obtain a compound carpuloic anhydride intermediate shown in the formula IV;
wherein in the compound of formula II, the substituent R 1 Is methyl, ethyl or C 3 H 7 Substituents or C 4 H 9 A substituent, wherein the substituent X is H, cl or Br; in the compounds of formula III, the substituents R 2 Is methyl, ethyl or C 3 H 7 Substituents or C 4 H 9 A substituent, wherein the substituent Y is H, cl or Br; substituent R 1 Substituent R 2 The substituents X and Y are the same or different.
In a preferred compound of formula II according to the invention, the substituents R 1 Methyl or ethyl, and substituent X is H or Cl; in the compounds of formula III, the substituents R 2 Methyl or ethyl, and substituent Y is H, cl or Br.
According to a preferred embodiment of the invention, the compound of formula II is dimethyl malonate, dimethyl 2-chloromalonate or diethyl malonate; the compound of formula III is 2-chloro-3-methylbut-2-enoic acid methyl ester, 2-chloro-3-methylbut-2-enoic acid ethyl ester or 2-bromo-3-methylbut-2-enoic acid methyl ester.
According to the preferred embodiments of the present invention, the compound of formula II wherein the substituent X is Cl or Br may be prepared by halogenating a compound of formula II wherein the substituent X is H with a halogen.
According to the invention, the addition cyclisation of the compounds of the formula II and III is preferably carried out in a solvent A, under the action of a base B.
Preferably, the solvent A is one or more than two of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, acetonitrile, methanol, ethanol, isopropanol, toluene or water; the mass ratio of the solvent A to the compound of the formula III is (5-15): 1.
Preferably, the base B is an organic base or an inorganic base; the organic base is further preferably 1, 8-diazabicycloundec-7-ene (DBU); the inorganic base is further preferably potassium carbonate, sodium methoxide, sodium ethoxide, sodium methoxide methanol solution, sodium ethoxide ethanol solution or potassium tert-butoxide; the molar ratio of the base B to the compound of formula III is (1.0-1.2): 1.
Preferably, the compounds of the formula II and III are added dropwise to a system comprising solvent A and base B; further preferably, the compounds of formula II and III are added dropwise in the form of a mixture to a system comprising solvent A and base B.
According to the invention, the molar ratio of the compounds of the formula II to the compounds of the formula III is preferably (1.0-1.2): 1.
According to the invention, preferably, the temperature of the addition cyclization reaction is 0-100 ℃; preferably, the temperature of the addition cyclization reaction is 30-60 ℃. The time of the addition cyclization reaction is 1-8 hours; preferably, the time of the addition cyclization reaction is 2 to 5 hours.
According to the present invention, preferably, after the completion of the addition cyclization reaction of the compound of formula II and the compound of formula III, the resultant reaction solution is directly subjected to the next step without being treated.
According to the invention, the hydrolysis of the dimethylcyclopropane triester is preferably carried out in the presence of a base C and water.
Preferably, the base C is an inorganic base; the inorganic base is further preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogencarbonate or sodium hydrogencarbonate; the molar ratio of base C to compound of formula III is (3.0-5.0): 1.
Preferably, the mass ratio of water to the compound of formula III is (3-10): 1; the water may be added to the reaction system alone and/or in the form of an aqueous solution of the base C.
According to the invention, preferably, the temperature of the hydrolysis reaction is 40-100 ℃; preferably, the temperature of the hydrolysis reaction is 60-90 ℃. The hydrolysis reaction time is 1-6 hours; preferably, the hydrolysis reaction time is 2 to 4 hours.
According to the invention, preferably, the solvent A is distilled and recovered simultaneously in the hydrolysis reaction process, or the solvent A is recovered from the reaction liquid obtained by distillation after the hydrolysis reaction is completed, and then the next step is carried out; preferably, solvent A is recovered by simultaneous distillation during the hydrolysis reaction.
According to the invention, the acid used for acidification and decarboxylation is hydrochloric acid, sulfuric acid or phosphoric acid, and the pH value of the system is 1.5-2; preferably, the acid used is 15-35wt% hydrochloric acid or 10-50wt% sulfuric acid.
According to the invention, preferably, the reaction temperature of the acidification decarboxylation is 10-80 ℃; preferably, the reaction temperature of the acidification decarboxylation is 30-60 ℃. The reaction time of acidification and decarboxylation is 0.5-5 hours; preferably, the reaction time for the acidification decarboxylation is 1-2 hours.
According to the invention, the addition cyclization reaction, hydrolysis reaction and acidification decarboxylation can be carried out preferably via a "one-pot" reaction.
According to the invention, preferably, after the acidification decarboxylation reaction is completed, the obtained reaction liquid is extracted to obtain an organic phase, and the organic phase is washed, dried and distilled to remove the extractant, so that the compound of the formula IV is obtained.
The preparation method of the caronic anhydride comprises the preparation steps of the caronic anhydride intermediate and the steps of: the compound of the formula IV and an anhydration reagent are subjected to an anhydration reaction to obtain the caronic anhydride (I);
according to the invention, the anhydration of the compound of formula IV and the anhydration reagent is preferably carried out in solvent D under the action of a catalyst.
Preferably, the solvent D is one or more of chlorobenzene, o-dichlorobenzene, dimethyl sulfoxide, N-dimethylformamide or N, N-dimethylacetamide; the mass ratio of the solvent D to the compound of the formula IV is (5-10): 1.
Preferably, the catalyst is one or more than two of 4-dimethylaminopyridine, piperidine, morpholine, DBU, sodium acetate or potassium acetate; the mass of the catalyst is (5-20)% of the mass of the compound of formula IV.
According to a preferred embodiment of the present invention, the anhydrating agent is acetic anhydride; the molar ratio of the anhydrating agent to the compound of formula IV is (3-8): 1.
According to the invention, preferably, the temperature of the anhydration reaction is 100-220 ℃; preferably, the temperature of the anhydration reaction is 130-190 ℃. The time for the anhydration is 2 to 18 hours, preferably 6 to 10 hours.
According to a preferred embodiment of the invention, the compound of formula IV and the anhydrating agent are added dropwise to the system containing the catalyst; preferably, the compound of formula IV and the anhydrating agent are added dropwise to the catalyst-containing system in the form of a mixture.
According to the invention, the preparation of the caronic anhydride (I) preferably comprises the steps of: dropwise adding a mixed solution of a compound shown in the formula IV, a solvent D2 and an anhydration reagent into a mixed solution of the solvent D1 and the catalyst, and carrying out an anhydration reaction after the dropwise adding is finished to obtain the carpronic anhydride (I); preferably, the types of the solvent D1 and the solvent D2 are the same as the type of the solvent D, and the mass ratio of the solvent D1 to the solvent D2 is 0.5-2:1.
Preferably, the temperature of the mixture of solvent D1 and catalyst is 80-220 ℃, more preferably 110-190 ℃; the temperature of the mixed solution of the compound of the formula IV, the solvent D2 and the anhydrating agent is 80-100 ℃; the dripping time is 2-5 hours.
According to the invention, the anhydrization reaction is preferably carried out simultaneously with distillation in order to distill off the low fractions.
According to the present invention, preferably, after the completion of the anhydrization reaction, the resultant reaction solution is distilled under reduced pressure, and the residue is recrystallized from petroleum ether to obtain caronic anhydride (I).
The process of the present invention is described as scheme 5 below:
wherein in the compound of formula II, the substituent R 1 Is methyl, ethyl or C 3 H 7 Substituents or C 4 H 9 A substituent, wherein the substituent X is H, cl or Br; in the compounds of formula III, the substituents R 2 Is methyl, ethyl or C 3 H 7 Substituents or C 4 H 9 A substituent, wherein the substituent Y is H, cl or Br; substituent R 1 Substituent R 2 The substituents X and Y are the same or different.
The invention has the technical characteristics and beneficial effects that:
1. the invention provides a novel preparation method of caronic anhydride and a caronic anhydride intermediate. And (3) adding and cyclizing 2-X substituent malonic diester (II) and 2-Y substituent-3-methylbut-2-enoate (III) to obtain dimethyl cyclopropane triester, hydrolyzing the ester group of the dimethyl cyclopropane triester to obtain dimethyl cyclopropane tricarboxylate, and acidifying and decarboxylating to obtain the caronic acid. And carrying out an anhydration reaction on the obtained caronic acid to obtain the caronic anhydride.
2. The route design of the invention fully reflects the reaction characteristics of the reaction materials, the 2-site hydrocarbon of the malonic diester or the 2-X substituent malonic diester has proper activity, the addition cyclization is easy to carry out under the action of alkali, the reaction selectivity is high, and the reaction is easy to carry out. And then decarboxylation is carried out through classical hydrolysis and acidification, the selectivity is specific, and the high selectivity and the high yield of the obtained caronic acid are ensured.
3. The method preferably adopts the steps that the obtained solution of the caronic acid, the solvent and the acetic anhydride is dripped into the solvent and the catalyst, so that the on-line concentration of the caronic acid is reduced, and the decomposition of the caronic acid caused by unstable high temperature is reduced; and preferably, acetic acid with relatively low boiling point is continuously distilled in the reaction process, so that the anhydration equilibrium reaction of the caronic acid and the acetic anhydride is promoted to move to the product caronic anhydride, thereby reducing the decomposition of the caronic acid and promoting the equilibrium reaction, and ensuring the high yield of the caronic anhydride.
4. The method has the advantages of low cost and easy acquisition of raw materials and low cost. The preparation method is simple and convenient, the reaction condition is mild, the implementation is easy, the raw materials and intermediates are stable, and the operation safety is high. The reaction wastewater is small in production amount, easy to treat, environment-friendly and suitable for industrial production. The reaction type related by the invention is classical and concise, the reaction selectivity is high, the side reaction is less, the separation and purification are simple, and the product yield and purity are high; the total yield of the intermediate of the caronic anhydride can reach 92.1 percent, and the purity can reach 99.7 percent; the total yield of the caronic anhydride can reach 83.5 percent and the purity can reach 99.8 percent.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples were all commercially available products.
In the examples, "%" is weight percent unless otherwise specified.
The yields in the examples are all molar yields.
Preparation example 1: 2-chloro-3-methylbut-2-enoic acid methyl ester (III) 2 ) Is prepared from
To a 1000 ml four-necked flask equipped with stirring, thermometer, gas-guide tube, reflux condenser and tail gas absorption with 30% aqueous sodium hydroxide solution were added 450 g of methylene chloride, 114.1 g (1.0 mol) of methyl 3-methylbut-2-enoate (III) 1 ) 80 g of chlorine is introduced under stirring while keeping the internal temperature between 30 and 35 ℃ for about 2 hours. After that, the reaction is stirred for 2 hours at 40-45 ℃, and residual chlorine and byproduct hydrogen chloride are replaced by nitrogen bubbling and bubbling is carried out for 2 hours. Cooling to room temperature, neutralizing with 15wt% sodium carbonate aqueous solution until pH is 7-8, layering, extracting aqueous layer with dichloromethane twice, 100 g each time, mixing organic phases, and using30 g of saturated saline solution is washed, then dried with 5.0 g of anhydrous sodium sulfate, the solvent is removed by rotary evaporation, and then the mixture is distilled under reduced pressure (70-85 ℃ C./5-7 mmHg) to obtain 136.5 g of methyl 2-chloro-3-methylbut-2-enoate (III) 2 ) The yield was 91.9% and the gas phase purity was 99.3%.
Preparation example 2: 2-chloro-3-methylbut-2-enoic acid ethyl ester (III) 3 ) Is prepared from
To a 1000 ml four-necked flask equipped with stirring, thermometer, gas-guide tube, reflux condenser and tail gas absorption by 30% aqueous sodium hydroxide solution, 450 g of methylene chloride, 128.2 g (1.0 mol) of ethyl 3-methylbut-2-enoate were added, the internal temperature was kept at 30-35℃and 80 g of chlorine was introduced under stirring, and the introduction was completed for about 2 hours. After that, the reaction is stirred for 2 hours at 40-45 ℃, and residual chlorine and byproduct hydrogen chloride are replaced by nitrogen bubbling and bubbling is carried out for 2 hours. Cooling to room temperature, then neutralizing with 15wt% sodium carbonate aqueous solution until pH value is 7-8, layering, extracting aqueous layer with dichloromethane twice, 100 g each time, combining organic phase, washing with 30 g saturated saline solution, drying with 5.0 g anhydrous sodium sulfate, rotary evaporating to remove solvent, vacuum distilling (80-90 ℃/5-7 mmHg) to obtain 151.5 g 2-chloro-3-methylbut-2-enoic acid ethyl ester (III) 3 ) The yield was 93.2% and the gas phase purity was 99.1%.
Preparation example 3: 2-bromo-3-methylbut-2-enoic acid methyl ester (III) 4 ) Is prepared from
To a 1000 ml four-necked flask equipped with stirring, thermometer, constant pressure dropping funnel, reflux condenser and tail gas absorption of 30% aqueous sodium hydroxide solution, 300 g of methylene chloride, 114.1 g (1.0 mol) of methyl 3-methylbut-2-enoate were added, the internal temperature was kept between 20 and 25 ℃,170 g of liquid bromine and 200 g of methylene chloride solution were added dropwise under stirring, and the dropwise addition was completed for about 2 hours. After the reaction was stirred at 20 to 30℃for 2 hours, excess bromine was removed by adding 20 g of sodium sulfite, then neutralized with 15% by weight of aqueous sodium carbonate until the pH was 7 to 8, and the layers were separated, the aqueous layer was extracted twice with 100 g of methylene chloride each time, the organic phases were combined, washed with 30 g of saturated brine, then dried over 5.0 g of anhydrous sodium sulfate, and after the solvent was removed by rotary evaporation, 172.9 g of methyl 2-bromo-3-methylbut-2-enoate (III) was obtained by distillation under reduced pressure (105 to 115 ℃ C./5 to 7 mmHg) 4 ) The yield was 89.6%,the purity of the gas phase was 98.9%.
Example 1: preparation of Carlongic acid (IV)
Into a 1000 ml four-necked flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, 300 g of methanol, 30.5 g (0.22 mol) of potassium carbonate and 29.0 g (0.22 mol) of dimethyl malonate (II) were added dropwise while stirring at 40 to 45 ℃were added 1 ) And 29.7 g (0.2 mol) of methyl 2-chloro-3-methylbut-2-enoate (III) 2 ) The mixture is reacted for 4 hours at 50-55 ℃ after dripping. After cooling to room temperature, 150 g of water and 100 g of 25% sodium hydroxide aqueous solution are added for reaction for 3 hours at 80-85 ℃, and methanol is distilled and recovered in the reaction process. Cooling to room temperature, maintaining the temperature between 40 and 45 ℃, acidifying with 25% hydrochloric acid until the pH value of the system is 1.5-2.0, and stirring and reacting for 1 hour at 40-45 ℃. Extraction with ethyl acetate three times, 100 g each, combined organic phases, washing with 30 g saturated brine, then drying with 5.0 g anhydrous sodium sulfate, spin-evaporating to remove solvent gave 28.1 g of caronic acid (IV) in 88.9% yield and 99.6% purity in liquid phase.
The nuclear magnetic data of the product are as follows:
1 HNMR (perdeuterated DMSO, δ, ppm):
1.23-1.40 (3 single peaks, integral 6H), 1.96-2.21 (m, 2H), 11.2 (s, 2H).
Example 2: preparation of Carlongic acid (IV)
Into a 1000 ml four-necked flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, 300 g of methanol, 45.0 g (0.22 mol) of a 27% sodium methoxide methanol solution and 36.6 g (0.22 mol) of dimethyl 2-chloromalonate (II) were added dropwise with stirring at 35 to 40 ℃ 2 ) And 22.8 g (0.2 mol) of methyl 3-methylbut-2-enoate (III) 1 ) The mixture was reacted at 40-45℃for 4 hours after the completion of the dropping. After cooling to room temperature, 150 g of water and 150 g of 25% potassium hydroxide aqueous solution are added, the mixture is reacted for 3 hours at 80-85 ℃, and methanol is distilled and recovered in the reaction process. Cooling to room temperature, maintaining the temperature between 40 and 45 ℃, acidifying with 25% hydrochloric acid until the pH value of the system is 1.5 to 2.0, and stirring and reacting for 1 hour at 40 to 45 ℃. Extraction with ethyl acetate was performed three times, 100 g each, and the organic phases were combined, washed with 30 g of saturated saline, and then with5.0 g of anhydrous sodium sulfate is dried, and after the solvent is removed by rotary evaporation, 29.1 g of caronic acid (IV) is obtained, the yield is 92.1%, and the purity of the liquid phase is 99.5%.
Example 3: preparation of Carlongic acid (IV)
Into a 1000 ml four-necked flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, 300 g of ethanol, 33.5 g (0.22 mol) of DBU (1, 8-diazabicyclo [ 5.4.0)]Undec-7-ene), 35.2 g (0.22 mol) diethyl malonate (II) were added dropwise with stirring at 40-45 ℃ 3 ) And 32.5 g (0.2 mol) of ethyl 2-chloro-3-methylbut-2-enoate (III) 3 ) The mixture is reacted for 4 hours at 50-55 ℃ after dripping. After cooling to room temperature, 150 g of water and 150 g of 25% sodium hydroxide aqueous solution are added for reaction for 3 hours at 85-90 ℃, and ethanol is distilled and recovered in the reaction process. Cooling to room temperature, maintaining the temperature between 40 and 45 ℃, acidifying with 25% hydrochloric acid until the pH value of the system is 1.5 to 2.0, and stirring and reacting for 1 hour at 40 to 45 ℃. Extraction with ethyl acetate three times, 100 g each, combined organic phases, washing with 30 g saturated brine, then drying with 5.0 g anhydrous sodium sulfate, spin-evaporating to remove solvent gave 28.2 g of caronic acid (IV) in 89.2% yield and 99.3% purity in liquid phase.
Example 4: preparation of Carlongic acid (IV)
Into a 1000 ml four-necked flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, 300 g of methanol, 30.5 g (0.22 mol) of potassium carbonate and 29.0 g (0.22 mol) of dimethyl malonate (II) were added dropwise with stirring at 35-40 ℃ 1 ) And 38.6 g (0.2 mol) of methyl 2-bromo-3-methylbut-2-enoate (III) 4 ) The mixture was reacted at 40-45℃for 3 hours after the completion of the dropping. After cooling to room temperature, 150 g of water and 100 g of 25% sodium hydroxide aqueous solution are added for reaction for 3 hours at 80-85 ℃, and methanol is distilled and recovered in the reaction process. Cooling to room temperature, maintaining the temperature between 40 and 45 ℃, acidifying with 25% hydrochloric acid until the pH value of the system is 1.5-2.0, and stirring and reacting for 1 hour at 40-45 ℃. Extraction with ethyl acetate three times, 100 g each, combined organic phases, washing with 30 g saturated brine, then drying with 5.0 g anhydrous sodium sulfate, spin-evaporating to remove solvent gave 28.9 g of caronic acid (IV) in 91.5% yield and 99.7% purity in liquid phase.
Example 5: preparation of Carlongic acid (IV)
Into a 1000 ml four-necked flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, 300 g of methanol, 30.5 g (0.22 mol) of potassium carbonate, 29.0 g (0.22 mol) of dimethyl malonate (II) 1 ) 29.7 g (0.2 mol) of methyl 2-chloro-3-methylbut-2-enoate (III) 2 ) The reaction is carried out for 4 hours at 50-55 ℃. After cooling to room temperature, 150 g of water and 100 g of 25% sodium hydroxide aqueous solution are added for reaction for 3 hours at 80-85 ℃, and methanol is distilled and recovered in the reaction process. Cooling to room temperature, maintaining the temperature between 40 and 45 ℃, acidifying with 25% hydrochloric acid until the pH value of the system is 1.5-2.0, and stirring and reacting for 1 hour at 40-45 ℃. Insoluble matter was filtered off, the filtrate was extracted three times with ethyl acetate, 100 g each time, the organic phases were combined, washed with 30 g of saturated saline solution, then dried over 5.0 g of anhydrous sodium sulfate, and after removing the solvent by rotary evaporation, 16.3 g of caronic acid (IV) was obtained, the yield was 51.6%, and the purity of the liquid phase was 98.3%.
This example shows dimethyl malonate (II) 1 ) And methyl 2-chloro-3-methylbut-2-enoate (III) 2 ) The addition of (2) affects the reaction yield, and the preferred addition by dripping is advantageous for reducing dimethyl malonate (II) 1 ) And methyl 2-chloro-3-methylbut-2-enoate (III) 2 ) The dripping mode is favorable for the formation of ternary rings, and the high yield is ensured.
Example 6: preparation of Carbonic anhydride (I)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a heat-insulating constant-pressure dropping funnel and a distillation apparatus, 50 g of o-dichlorobenzene, 1.0 g of potassium acetate, heating to 170 to 180℃were added dropwise a hot mixed solution (80 to 100 ℃) of 15.8 g (0.1 mol) of the caronic acid prepared in example 2, 60 g of o-dichlorobenzene and 60.0 g (0.59 mol) of acetic anhydride, after which the reaction was carried out at 180 to 185℃for 8 hours after 3 hours, and at the same time, a low fraction (acetic acid and a small amount of acetic anhydride) was distilled off. Cooling to 60 ℃, distilling under reduced pressure to recover residual acetic acid, excessive acetic anhydride and o-dichlorobenzene, and recrystallizing the residue with 100 g of petroleum ether (boiling range 90-120 ℃) to obtain 12.7 g of caronic anhydride (I), wherein the yield is 90.7%, and the gas phase purity is 99.8%.
The nuclear magnetic data of the product are as follows:
1 HNMR (perdeuterated DMSO, δ, ppm):
1.31(s,3H)，1.41(s，3H)，2.66(s，2H)。
example 7: preparation of Carbonic anhydride (I)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a heat-insulating constant-pressure dropping funnel and a distillation apparatus, 50 g of N, N-dimethylformamide, 1.5 g of DBU, heating at 150 to 160℃were added dropwise a hot mixed solution (80 to 100 ℃) of 15.8 g (0.1 mol) of the caronic acid prepared in example 4, 70 g of N, N-dimethylformamide and 70.0 g (0.69 mol) of acetic anhydride, and after 3 hours the dropping was completed, the reaction was carried out at 180 to 185℃for 8 hours, and at the same time, the low fraction (acetic acid and a small amount of acetic anhydride) was distilled off. Cooling to 60 ℃, distilling under reduced pressure to recover residual acetic acid, excessive acetic anhydride and N, N-dimethylformamide, and recrystallizing the residue with 100 g of petroleum ether (boiling range 90-120 ℃) to obtain 12.5 g of caronic anhydride (I), wherein the yield is 89.3%, and the gas phase purity is 99.6%.
Example 8: preparation of Carbonic anhydride (I)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a heat-insulating constant-pressure dropping funnel and a distillation apparatus, 110 g of o-dichlorobenzene, 1.0 g of potassium acetate, 60.0 g of acetic anhydride, 15.8 g (0.1 mol) of the caronic acid prepared in example 2 were charged, and reacted at 180℃to 185℃for 8 hours while distilling off a low fraction (acetic acid and a small amount of acetic anhydride). Cooling to 60 ℃, distilling under reduced pressure to recover residual acetic acid, excessive acetic anhydride and o-dichlorobenzene, and recrystallizing the residue with 100 g of petroleum ether (boiling range 90-120 ℃) to obtain 10.1 g of caronic anhydride (I), wherein the yield is 72.1%, and the gas phase purity is 99.2%.
This example shows that the manner of adding the caronic acid has an important effect on the reaction yield, and that the caronic acid has poor high temperature stability and is easy to decompose under high heat conditions. According to the embodiment of the invention, a mode of dropwise adding the caronic acid solution is adopted, the caronic acid is gradually added into a reaction system conforming to the anhydration reaction condition, the reaction is completed in time, and the decomposition loss of the caronic acid is reduced. Acetic acid with a lower boiling point is continuously distilled, so that the equilibrium reaction of the acetic anhydride and the acetic acid generated by the caronic acid and the acetic anhydride is promoted, the generation of the caronic anhydride product is promoted, and the high yield of the caronic anhydride is ensured.
Claims (15)
1. A preparation method of a caronic anhydride intermediate comprises the following steps:
the dimethyl cyclopropane triester is obtained by carrying out addition cyclization reaction on a compound of a formula II and a compound of a formula III; the dimethyl cyclopropane triester is hydrolyzed to obtain dimethyl cyclopropane tricarboxylate; then acidifying and decarboxylating to obtain a compound carpuloic anhydride intermediate shown in the formula IV;
the addition cyclization reaction of the compound of the formula II and the compound of the formula III is carried out in a solvent A under the action of a base B; the solvent A is one or more than two of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, acetonitrile, methanol, ethanol, isopropanol, toluene or water; the alkali B is organic alkali or inorganic alkali; the compound of the formula II and the compound of the formula III are added into a system containing a solvent A and a base B in a dropwise manner;
the hydrolysis reaction of the dimethyl cyclopropane triester is carried out in the presence of a base C and water; the alkali C is inorganic alkali;
wherein in the compound of formula II, the substituent R 1 Is methyl, ethyl or C 3 H 7 Substituents or C 4 H 9 A substituent, wherein the substituent X is H, cl or Br; in the compounds of formula III, the substituents R 2 Is methyl, ethyl or C 3 H 7 Substituents or C 4 H 9 A substituent, wherein the substituent Y is H, cl or Br; substituent R 1 Substituent R 2 The substituents X and Y are the same or different.
2. A process for the preparation of a carbaryl anhydride intermediate as claimed in claim 1, wherein,
the compound of the formula II is dimethyl malonate, dimethyl 2-chloromalonate or diethyl malonate; the compound of formula III is 2-chloro-3-methylbut-2-enoic acid methyl ester, 2-chloro-3-methylbut-2-enoic acid ethyl ester or 2-bromo-3-methylbut-2-enoic acid methyl ester.
3. A process for the preparation of a caronic anhydride intermediate according to claim 1, characterized in that it comprises one or more of the following conditions:
i. the mass ratio of the solvent A to the compound of the formula III is (5-15): 1;
ii. The organic base is 1, 8-diazabicyclo undec-7-ene (DBU), sodium methoxide, sodium ethoxide, sodium methoxide methanol solution, sodium ethoxide ethanol solution or potassium tert-butoxide; the inorganic base is potassium carbonate or sodium carbonate; the molar ratio of the base B to the compound of formula III is (1.0-1.2): 1;
iii, the compound of formula II and the compound of formula III are added dropwise in the form of a mixture to a system comprising solvent A and base B;
iv, the molar ratio of the compound of formula II to the compound of formula III being (1.0-1.2): 1;
v, the temperature of the addition cyclization reaction is 0-100 ℃;
after completion of the addition cyclization reaction of vi, the compound of formula II and the compound of formula III, the reaction solution obtained is directly subjected to the next step without treatment.
4. A process for the preparation of a carbaryl anhydride intermediate according to claim 3 wherein the temperature of the addition cyclization reaction is 30-60 ℃.
5. A process for the preparation of a caronic anhydride intermediate according to claim 1, characterized in that it comprises one or more of the following conditions:
i. the inorganic base is sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate; the molar ratio of base C to compound of formula III is (3.0-5.0): 1;
ii. The mass ratio of the water to the compound of the formula III is (3-10): 1; the water may be added to the reaction system alone and/or in the form of an aqueous solution of the base C;
iii, the temperature of the hydrolysis reaction is 40-100 ℃;
and iv, simultaneously distilling and recovering the solvent A in the hydrolysis reaction process, or distilling the obtained reaction liquid after the hydrolysis reaction is finished to recover the solvent A, and then carrying out the next step.
6. The process for preparing a carbaryl anhydride intermediate as claimed in claim 5, wherein the hydrolysis reaction is carried out at a temperature of 60 to 90 ℃.
7. A process for the preparation of a caronic anhydride intermediate according to claim 1, characterized in that it comprises one or more of the following conditions:
i. the acid used for acidification and decarboxylation is hydrochloric acid, sulfuric acid or phosphoric acid, and the pH value of the system is 1.5-2;
ii. The reaction temperature of the acidification decarboxylation is 10-80 ℃;
iii, addition cyclization, hydrolysis and acidification decarboxylation can be performed via a "one-pot" reaction;
and iv, after the acidification decarboxylation reaction is finished, extracting the obtained reaction liquid to obtain an organic phase, and washing, drying and distilling the organic phase to remove the extractant to obtain the compound of the formula IV.
8. The process for preparing a caronic anhydride intermediate according to claim 7, comprising one or more of the following conditions:
i. the acid is 15-35wt% hydrochloric acid or 10-50wt% sulfuric acid;
ii. The reaction temperature of the acidification decarboxylation is 30-60 ℃.
9. A process for the preparation of a caronic anhydride comprising the steps of preparing a caronic anhydride intermediate according to any one of claims 1-8, further comprising the steps of: the compound of the formula IV and an anhydration reagent are subjected to an anhydration reaction to obtain the caronic anhydride (I);
10. the process for preparing caron anhydride according to claim 9, wherein the anhydration of the compound of formula iv with the anhydration reagent is carried out in solvent D under the action of a catalyst.
11. The process for preparing caronic anhydride of claim 10, comprising one or more of the following conditions:
i. the solvent D is one or more of chlorobenzene, o-dichlorobenzene, dimethyl sulfoxide, N-dimethylformamide or N, N-dimethylacetamide, and the mass ratio of the solvent D to the compound of the formula IV is (5-10): 1;
ii. The catalyst is one or the combination of more than two of 4-dimethylaminopyridine, piperidine, morpholine, DBU, sodium acetate or potassium acetate; the mass of the catalyst is (5-20)% of the mass of the compound of formula IV;
iii, the anhydration reagent is acetic anhydride; the molar ratio of the anhydrating agent to the compound of formula IV is (3-8): 1;
iv, the temperature of the anhydration reaction is 100-220 ℃;
v, the compound of formula IV and the anhydrating agent are added into the system containing the catalyst in a dropwise manner;
vi, carrying out distillation at the same time of the anhydration reaction so as to distill out low-fraction;
and vii, after the anhydration reaction is finished, the obtained reaction liquid is distilled under reduced pressure, and the residue is recrystallized by petroleum ether to obtain the caronic anhydride (I).
12. The process for preparing caronic anhydride of claim 11, comprising one or more of the following conditions:
i. the temperature of the anhydration reaction is 130-190 ℃;
ii. The compound of formula IV and the anhydrating agent are added dropwise to the system containing the catalyst in the form of a mixture.
13. The process for preparing caronic anhydride according to claim 10, characterized in that the preparation of caronic anhydride (i) comprises the steps of: and (3) dropwise adding a mixed solution of the compound shown in the formula IV, the solvent D2 and the anhydration reagent into a mixed solution of the solvent D1 and the catalyst, and carrying out anhydration reaction after the dropwise adding is finished to obtain the caronic anhydride (I).
14. The method for preparing the caronic anhydride according to claim 13, wherein the solvent D1 and the solvent D2 are the same in kind and the mass ratio of the solvent D1 to the solvent D2 is 0.5-2:1.
15. The method for preparing the caronic anhydride according to claim 13, wherein the temperature of the mixture of the solvent D1 and the catalyst is 80-220 ℃; the temperature of the mixed solution of the compound of the formula IV, the solvent D2 and the anhydrating agent is 80-100 ℃; the dripping time is 2-5 hours.
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