CN111233889B - Preparation method of thieno [3,4-b ] -1, 4-dioxin-2-methanol derivative - Google Patents
Preparation method of thieno [3,4-b ] -1, 4-dioxin-2-methanol derivative Download PDFInfo
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Abstract
The invention discloses a preparation method of thieno [3,4-b ] -1, 4-dioxin-2-methanol derivatives, which comprises the following steps: s1, adding a first reaction solvent, a raw material of thieno [3,4-b ] -1, 4-dioxin-2-methanol, a first reactant and a catalyst into a three-neck flask to obtain a first mixed solution; s2, dropwise adding an alkali solution; s3, obtaining a first reaction solution after reaction; s4, standing and layering the first reaction solution to obtain an organic phase and an extraction liquid; s5, combining the organic phase and the extraction liquid and drying; s6, filtering and drying to obtain an intermediate product; s7, adding a second reaction solvent and an intermediate product into a three-neck flask to obtain a mixed solution; s8, concentrating the mixed solution; s9, dropwise adding an alkali solution; s10, extracting and collecting an organic phase; s11, washing the organic phase with water; s12, drying and concentrating the organic phase to obtain a second mixture; and S13, eluting the second mixture, and drying to obtain the target product.
Description
Technical Field
The invention relates to the field of compound preparation, in particular to a preparation method of thieno [3,4-b ] -1, 4-dioxin-2-methanol derivative
Background
The name of the target product is 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid, and the target product is a derivative of 3, 4-ethylenedioxythiophene (EDOT for short). EDOT is a monomer of a conductive polymer found in bayer in germany, which is an electrochemical material. The target product is a conductive compound monomer with stable performance and is also a basic material of a conductive framework, and the target product can be further condensed to prepare carboxylate, and is applied to lithium battery electrolyte. In the prior art, only one synthesis process route (as shown in fig. 1) is provided for the target product, but in the synthesis process, the yield of the finished product of the synthesis process is low, the used reactant 3-bromo-ethyl propionate has photosensitivity, is easily degraded by light and is not easy to treat, and the used sodium hydride has active chemical properties, can be spontaneously combusted in humid air and has great safety hazard in industrial production, so that a new synthesis process is needed to prepare the target product.
Disclosure of Invention
The invention aims to solve the problems and provide a preparation method of thieno [3,4-b ] -1, 4-dioxin-2-methanol derivative with high reaction rate and high yield.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for preparing a thieno [3,4-b ] -1, 4-dioxin-2-methanol derivative, comprising the steps of:
s1, adding a first reaction solvent, a raw material of thieno [3,4-b ] -1, 4-dioxin-2-methanol, a first reactant and a catalyst into a three-neck flask, and continuously stirring under the action of an ice salt bath to obtain a first mixed solution;
s2, dropwise adding an alkali solution with the concentration of 45% when the temperature of the first mixed solution is 0-5 ℃, keeping the temperature of the first mixed solution at 2-6 ℃ for reacting for 1 hour, then removing the ice salt bath, and naturally heating to 18-25 ℃ in the three-neck flask for reacting for 3 hours;
s3, monitoring the reaction in the three-neck flask by using thin-layer chromatography, and stopping the reaction when the reaction of the raw material thieno [3,4-b ] -1, 4-dioxin-2-methanol is finished to obtain a first reaction liquid;
s4, transferring the first reaction solution to a separating funnel, standing for layering, collecting a lower organic phase, extracting an upper aqueous phase twice with an extracting agent, and combining the two extraction solutions;
s5, washing the organic phase with water for four times, combining the washed organic phase with the extraction liquid, and then drying with a drying agent to obtain a first mixture;
s6, filtering the first mixture by using a Buchner funnel, and spin-drying and drying by using a rotary evaporator to obtain a compound 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester;
s7, adding a second reaction solvent and a compound 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -tert-butyl propionate into a three-neck flask, and continuously stirring under the action of an oil bath kettle to obtain a second mixed solution;
s8, placing the second mixed solution on a rotary evaporator at the temperature of 25-30 ℃, concentrating under reduced pressure, evaporating to remove the second reaction solvent, adding an ice-water mixture, continuously stirring under the action of an ice salt bath, and adjusting the pH value to 2-3 by using an acid regulator;
s9, dropwise adding an alkali solution with the concentration of 5% at the temperature of 18-25 ℃, heating to 55 ℃ under the action of an oil bath, carrying out heat preservation reaction for 3 hours, monitoring the reaction in the three-neck flask by using thin-layer chromatography until the compound 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -tert-butyl propionate completely reacts to obtain a second reaction solution;
s10, placing the second reaction solution into a separating funnel, extracting with an extracting agent, standing for layering, discharging an organic phase from the lower opening of the separating funnel, and collecting; extracting for three times repeatedly, and combining the organic phases collected for three times;
s11, washing the combined organic phase for 2 times by using water, standing and separating the organic phase after washing, collecting the washed organic phase again, and combining the organic phase;
s12, drying the washed organic phase by using a drying agent, filtering to remove the drying agent, transferring the organic phase into a pear-shaped bottle, and placing the pear-shaped bottle on a rotary evaporator for reduced pressure concentration to obtain a second mixture;
s13, filling the second mixture into a silica gel column, eluting with an eluent, collecting the effluent, placing the effluent on a rotary evaporator, spin-drying and drying to obtain the 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid.
Further, the first reaction solvent is one of dichloromethane, 1, 2-dichloroethane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, and N, N-dimethylformamide.
Further, the first reactant is one of tert-butyl acrylate, methyl acrylate, ethyl acrylate and isopropyl acrylate.
Further, the catalyst is one of tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltriethylammonium chloride, 18-crown-6-ether and 15-crown-5-ether.
Further, the alkali solution is one of a sodium hydroxide solution, a potassium hydroxide solution, a cesium carbonate solution, a cesium fluoride solution, a potassium carbonate solution, and a diazabicyclo solution.
Further, the extractant is one of dichloromethane, 1, 2-dichloroethane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone and N, N-dimethylformamide.
Further, the drying agent is one of anhydrous magnesium sulfate and anhydrous calcium chloride.
Further, the second reaction solvent is one of 95% ethanol, methanol, isopropanol, N-butanol, ethylene glycol, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, and N, N-dimethylformamide.
Further, the acid regulating agent is one of hydrochloric acid, trifluoroacetic acid, oxalic acid, citric acid, potassium dihydrogen phosphate solution, EDTA disodium and acetic acid.
Further, the eluent is a mixed solution of methanol and dichloromethane, wherein the volume ratio of methanol to dichloromethane is 1: 20.
compared with the prior art, the invention has the advantages and positive effects that:
the invention solves the problem of photosensitive visible light decomposition of ethyl bromopropionate in the existing synthesis process by designing a new synthesis process of a target product; meanwhile, the yield of the finished product of the target product is effectively improved, and the defects of flammability and explosiveness of sodium hydride used in the original process are overcome through a new synthesis process, so that the target product is more beneficial to industrial production and has good industrial production value.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a diagram showing the change of molecular structure of a synthetic target product in the prior art;
FIG. 2 is a diagram showing the change of the molecular structure of the target product synthesized by the present invention;
FIG. 3 is a diagram showing a change in molecular structure in the first synthesis step;
FIG. 4 is a diagram showing a change in molecular structure in the second synthesis step;
FIG. 5 is a chromatogram of a target product;
FIG. 6 is a table showing the analysis results of the objective product.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived from the embodiments of the present invention by a person skilled in the art without any creative effort, should be included in the protection scope of the present invention.
Example 1, as shown in fig. 2 and 3, the first step: addition reaction
Preparation of 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester (III);
putting a 1L three-necked bottle in a salt-freezing bath, adding 500mL of Dichloromethane (DCM),20g of raw material thieno [3,4-b ] -1, 4-dioxin-2-methanol (II), 74.4 g of tert-butyl acrylate and 7.48g of tetrabutylammonium bromide (PTC: phase transfer catalyst) under the action of mechanical stirring, dropwise adding 100mL of 45% sodium hydroxide solution at 0 ℃ (preparing and releasing heat, cooling to room temperature and then transferring into a constant pressure dropping funnel), controlling the dropping rate, keeping the temperature of a reaction system at 2 ℃ for reaction for 1h, then removing the salt-freezing bath, naturally heating to 18 ℃ in a reaction bottle for reaction for 3h, monitoring the reaction raw material point and the product point by thin-layer chromatography (TLC), and waiting until the raw material thieno [3,4-b ] -1, 4-dioxin-2-methanol (II) is basically consumed, the reaction was stopped.
Treatment operation after addition reaction:
1. transferring the reaction solution to a separating funnel, standing and layering, collecting a lower organic phase, extracting an upper aqueous phase twice with dichloromethane, each time with 100ml, and combining dichloromethane phases after extraction;
2. the organic phase was washed four times with 100ml of water, the fourth aqueous phase tested for pH 7;
3. combining the dichloromethane phase and the organic phase, drying with anhydrous magnesium sulfate, and removing water in the organic phase;
4. the sample was filtered through a buchner funnel, and the sample was spin-dried using a rotary evaporator to obtain 26.8 g of 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester (III) in an off-white solid appearance with a calculated yield of 76.81%.
As shown in fig. 2 and 4, the second step: hydrolysis reaction
Preparing 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid (I);
putting a 1L three-necked bottle in an oil bath, adding 260mL 95% ethanol and 26g of compound 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester (III) under the action of mechanical stirring, dropwise adding 130mL 5% sodium hydroxide solution (cooling to room temperature and adding into a constant pressure dropping funnel after preparation) at the room temperature of 18 ℃, heating to 55 ℃ in an oil bath after the sodium hydroxide is added, carrying out heat preservation reaction for 3h, and monitoring the reaction by using Thin Layer Chromatography (TLC) until the compound 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester (III) is completely consumed.
Treatment operation after hydrolysis reaction:
1. at 25 ℃, placing the reaction solution on a rotary evaporator for decompression and concentration, and evaporating most of ethanol;
2. adding 100ml of ice-water mixture into the residual liquid, stirring, and adjusting the pH value to 2 by using 6mol/L hydrochloric acid under the action line of an ice salt bath;
3. the above liquid was put in a separatory funnel, extracted with dichloromethane, allowed to stand for separation, and the organic phase was discharged from the lower mouth of the separatory funnel and collected. Repeating the extraction process for three times, wherein each time the extraction process is performed with 100ml of solvent, and combining the organic phases collected for three times;
4. washing the organic phase with water for 2 times, each time washing 100ml, standing for liquid separation, collecting the organic phase, and combining;
5. drying the organic phase with anhydrous magnesium sulfate, filtering to remove anhydrous magnesium sulfate, transferring the solution into a pear-shaped bottle, and placing the pear-shaped bottle on a rotary evaporator for reduced pressure concentration;
6. mixing the concentrated sample with silica gel, filling the mixture into a column (100-mesh silica gel), and selecting a mixed solvent of methanol and dichloromethane as an eluent. Methanol/dichloromethane ratio 1: 20, collecting the effluent, spin-drying the sample on a rotary evaporator, and drying to obtain 19.6 g of 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid (I) with yield: 92.71% off-white solid.
Example 2, as shown in fig. 2 and 3, the first step: addition reaction
Preparation of 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester (III);
putting a 1L three-necked bottle in an ice salt bath, adding 500mL of Dichloromethane (DCM),20g of raw material thieno [3,4-b ] -1, 4-dioxin-2-methanol (II), 74.4 g of methyl acrylate and 7.48g of tetrabutylammonium iodide (phase transfer catalyst) under the action of mechanical stirring, dropwise adding 100mL of 45% potassium hydroxide solution at the temperature of 2 ℃ (preparing, releasing heat, cooling to room temperature and then transferring to a constant-pressure dropping funnel), controlling the dropping rate, keeping the temperature of a reaction system at 3 ℃ and reacting for 1h, then removing the deicing salt bath, naturally heating to the temperature of 20 ℃ in the reaction flask, reacting for 3 hours, monitoring the reaction raw material point and the product point by using thin-layer chromatography (TLC), and stopping the reaction when the raw material thieno [3,4-b ] -1, 4-dioxin-2-methanol (II) is basically consumed.
Treatment operation after addition reaction:
1. transferring the reaction solution to a separating funnel, standing and layering, collecting a lower organic phase, extracting an upper aqueous phase twice with dichloromethane, each time with 100ml, and combining dichloromethane phases after extraction;
2. the organic phase was washed four times with 100ml of water, the fourth aqueous phase tested for pH 7;
3. combining the dichloromethane phase and the organic phase, drying with anhydrous calcium chloride, and removing water in the organic phase;
4. the sample was filtered through a buchner funnel, and the sample was spin-dried using a rotary evaporator to obtain 26.8 g of 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester (III) in an off-white solid appearance with a calculated yield of 76.81%.
As shown in fig. 2 and 4, the second step: hydrolysis reaction
Preparing 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid (I);
putting a 1L three-necked bottle in an oil bath kettle, adding 260mL of ethylene glycol and 26g of compound 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester (III) under the action of mechanical stirring, dropwise adding 130mL of 5% potassium hydroxide solution at the temperature of 20 ℃ at room temperature (cooling to room temperature after preparation and adding a constant-pressure dropping funnel), heating the oil bath to 55 ℃ after potassium hydroxide is added, keeping the temperature for reaction for 3 hours, and monitoring the reaction by using thin-layer chromatography (TLC) until the compound 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester (III) is completely consumed.
Treatment operation after hydrolysis reaction:
1. at the temperature of 28 ℃, placing the reaction solution on a rotary evaporator for decompression and concentration, and evaporating most of glycol;
2. adding 100ml of ice-water mixture into the residual liquid, stirring, and adjusting the pH value to 2 by using 6mol/L oxalic acid under the action line of an ice salt bath;
3. the above liquid was put in a separatory funnel, extracted with dichloromethane, allowed to stand for separation, and the organic phase was discharged from the lower mouth of the separatory funnel and collected. Repeating the extraction process for three times, wherein each time the extraction process is performed with 100ml of solvent, and combining the organic phases collected for three times;
4. washing the organic phase with water for 2 times, each time washing with 100ml, standing, separating, collecting the organic phase, and mixing;
5. drying the organic phase with anhydrous calcium chloride, filtering to remove anhydrous calcium chloride, transferring the solution into a pear-shaped bottle, and concentrating under reduced pressure on a rotary evaporator;
6. mixing the concentrated sample with silica gel, filling the mixture into a column (150-mesh silica gel), and selecting a mixed solvent of methanol and dichloromethane as an eluent. Methanol/dichloromethane ratio 1: 20, collecting the effluent, spin-drying the sample on a rotary evaporator, and drying to obtain 19.6 g of 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid (I) with yield: 92.71% off-white solid.
Example 3, as shown in fig. 2 and 3, the first step: addition reaction
Preparation of 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester (III);
putting a 1L three-necked bottle in an ice salt bath, adding 500mL of Dichloromethane (DCM),20g of raw material thieno [3,4-b ] -1, 4-dioxin-2-methanol (II), 74.4 g of ethyl acrylate and 7.48g of benzyltriethylammonium chloride (phase transfer catalyst) under the action of mechanical stirring, dropwise adding 100mL of 45% sodium hydroxide solution at 5 ℃ (preparing to release heat, cooling to room temperature and then transferring to a constant-pressure dropping funnel), controlling the dropping rate, keeping the temperature of a reaction system at 6 ℃ and reacting for 1h, then removing the deicing salt bath, naturally heating to the temperature of 25 ℃ in the reaction bottle, reacting for 3h, monitoring the reaction raw material point and the product point by using thin-layer chromatography (TLC), and stopping the reaction when the raw material thieno [3,4-b ] -1, 4-dioxin-2-methanol (II) is basically consumed.
Treatment operation after addition reaction:
1. transferring the reaction solution to a separating funnel, standing and layering, collecting a lower organic phase, extracting an upper aqueous phase twice with dichloromethane, each time with 100ml, and combining dichloromethane phases after extraction;
2. the organic phase was washed four times with 100ml of water, the fourth aqueous phase was tested for pH 8;
3. combining the dichloromethane phase and the organic phase, drying with anhydrous magnesium sulfate, and removing water in the organic phase;
4. the sample was filtered through a buchner funnel, and the sample was spin-dried using a rotary evaporator to obtain 26.8 g of 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester (III) in an off-white solid appearance with a calculated yield of 76.81%.
As shown in fig. 2 and 4, the second step: hydrolysis reaction
Preparing 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid (I);
putting a 1L three-necked bottle in an oil bath kettle, adding 260mL of methanol and 26g of compound 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester (III) under the action of mechanical stirring, dropwise adding 130mL of 5% sodium hydroxide solution at the room temperature of 25 ℃ (cooling to room temperature after preparation and adding a constant-pressure dropping funnel), heating the oil bath to 55 ℃ after the sodium hydroxide is completely added, keeping the temperature for reaction for 3h, and monitoring the reaction by thin-layer chromatography (TLC) until the compound 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester (III) is completely consumed.
Treatment operation after hydrolysis reaction:
1. at the temperature of 30 ℃, placing the reaction solution on a rotary evaporator for decompression and concentration, and evaporating most of methanol;
2. adding 100ml of ice-water mixture into the residual liquid, stirring, and adjusting the pH value to 3 by using 6mol/L citric acid under the action line of an ice salt bath;
3. the above liquid was put in a separatory funnel, extracted with dichloromethane, allowed to stand for separation, and the organic phase was discharged from the lower mouth of the separatory funnel and collected. Repeating the extraction process for three times, wherein each time the extraction process is performed with 100ml of solvent, and combining the organic phases collected for three times;
4. washing the organic phase with water for 2 times, each time washing with 100ml, standing, separating, collecting the organic phase, and mixing;
5. drying the organic phase with anhydrous magnesium sulfate, filtering to remove anhydrous magnesium sulfate, transferring the solution into a pear-shaped bottle, and placing the pear-shaped bottle on a rotary evaporator for reduced pressure concentration;
6. mixing the concentrated sample with silica gel, filling the mixture into a column (200-mesh silica gel), and selecting a mixed solvent of methanol and dichloromethane as an eluent. Methanol/dichloromethane ratio 1: 20, collecting the effluent, spin-drying the sample on a rotary evaporator, and drying to obtain 19.6 g of 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid (I) with yield: 92.71% off-white solid.
As shown in fig. 5 and 6, the obtained target product 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid (I) is examined and analyzed, and it is confirmed that the purity is high, and the yield is significantly higher than that of the target product in the prior art, thereby bringing a step-by-step progress in the production of the target product.
The invention solves the problem of photosensitive visible light decomposition of ethyl bromopropionate in the existing synthesis process by designing a new synthesis process of a target product; meanwhile, the yield of the finished product of the target product is effectively improved, and the defects of flammability and explosiveness of sodium hydride used in the original process are overcome through a new synthesis process, so that the target product is more beneficial to industrial production and has good industrial production value.
Claims (8)
1. A process for producing a thieno [3,4-b ] -1, 4-dioxin-2-methanol derivative, characterized in that: the method comprises the following steps:
s1, adding a first reaction solvent, a raw material of thieno [3,4-b ] -1, 4-dioxin-2-methanol, a first reactant and a catalyst into a three-neck flask, and continuously stirring under the action of an ice salt bath to obtain a first mixed solution;
s2, dropwise adding an alkali solution with the concentration of 45% when the temperature of the first mixed solution is 0-5 ℃, keeping the temperature of the first mixed solution at 2-6 ℃ for reacting for 1 hour, then removing the ice salt bath, and naturally heating to 18-25 ℃ in the three-neck flask for reacting for 3 hours;
s3, monitoring the reaction in the three-neck flask by using thin-layer chromatography, and stopping the reaction when the reaction of the raw material thieno [3,4-b ] -1, 4-dioxin-2-methanol is finished to obtain a first reaction liquid;
s4, transferring the first reaction solution to a separating funnel, standing for layering, collecting a lower organic phase, extracting an upper aqueous phase twice with an extracting agent, and combining the two extraction solutions;
s5, washing the organic phase with water for four times, combining the washed organic phase with the extraction liquid, and then drying with a drying agent to obtain a first mixture;
s6, filtering the first mixture by using a Buchner funnel, and spin-drying and drying by using a rotary evaporator to obtain a compound 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid tert-butyl ester;
s7, adding a second reaction solvent and a compound 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -tert-butyl propionate into a three-neck flask, and continuously stirring under the action of an oil bath kettle to obtain a second mixed solution;
s8, placing the second mixed solution on a rotary evaporator at the temperature of 25-30 ℃, concentrating under reduced pressure, evaporating to remove the second reaction solvent, adding an ice-water mixture, continuously stirring under the action of an ice salt bath, and adjusting the pH value to 2-3 by using an acid regulator;
s9, dropwise adding an alkali solution with the concentration of 5% at the temperature of 18-25 ℃, heating to 55 ℃ under the action of an oil bath, carrying out heat preservation reaction for 3 hours, monitoring the reaction in the three-neck flask by using thin-layer chromatography until the compound 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -tert-butyl propionate completely reacts to obtain a second reaction solution;
s10, placing the second reaction solution into a separating funnel, extracting with an extracting agent, standing for layering, discharging an organic phase from the lower opening of the separating funnel, and collecting; extracting for three times repeatedly, and combining the organic phases collected for three times;
s11, washing the combined organic phase for 2 times by using water, standing and separating the organic phase after washing, collecting the washed organic phase again, and combining the organic phase;
s12, drying the washed organic phase by using a drying agent, filtering to remove the drying agent, transferring the organic phase into a pear-shaped bottle, and placing the pear-shaped bottle on a rotary evaporator for reduced pressure concentration to obtain a second mixture;
s13, filling the second mixture into a silica gel column, eluting with an eluent, collecting the effluent, placing the effluent on a rotary evaporator, spin-drying and drying to obtain 3- [ (2, 3-dihydrothieno [3,4-b ] -1, 4-dioxin-2-yl) methoxy ] -propionic acid;
the first reactant is one of tert-butyl acrylate, methyl acrylate, ethyl acrylate and isopropyl acrylate; the catalyst is one of tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltriethylammonium chloride, 18-crown-6-ether and 15-crown-5-ether.
2. The process for producing a thieno [3,4-b ] -1, 4-dioxin-2-methanol derivative according to claim 1, characterized in that: the first reaction solvent is one of dichloromethane, 1, 2-dichloroethane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone and N, N-dimethylformamide.
3. The process for producing a thieno [3,4-b ] -1, 4-dioxin-2-methanol derivative according to claim 1, characterized in that: the alkali solution is one of sodium hydroxide solution, potassium hydroxide solution, cesium carbonate solution, cesium fluoride solution, potassium carbonate solution and diazabicyclo solution.
4. The process for producing a thieno [3,4-b ] -1, 4-dioxin-2-methanol derivative according to claim 1, characterized in that: the extractant is one of dichloromethane, 1, 2-dichloroethane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone and N, N-dimethylformamide.
5. The process for producing a thieno [3,4-b ] -1, 4-dioxin-2-methanol derivative according to claim 1, characterized in that: the drying agent is one of anhydrous magnesium sulfate and anhydrous calcium chloride.
6. The process for producing a thieno [3,4-b ] -1, 4-dioxin-2-methanol derivative according to claim 1, characterized in that: the second reaction solvent is one of 95% ethanol, methanol, isopropanol, N-butanol, ethylene glycol, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone and N, N-dimethylformamide.
7. The process for producing a thieno [3,4-b ] -1, 4-dioxin-2-methanol derivative according to claim 1, characterized in that: the acid regulating agent is one of hydrochloric acid, trifluoroacetic acid, oxalic acid, citric acid, potassium dihydrogen phosphate solution, EDTA disodium and acetic acid.
8. The process for producing a thieno [3,4-b ] -1, 4-dioxin-2-methanol derivative according to claim 1, characterized in that: the eluent is a mixed solution of methanol and dichloromethane, wherein the volume ratio of the methanol to the dichloromethane is 1: 20.
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| PCT/CN2020/111603 WO2021174775A1 (en) | 2020-03-02 | 2020-08-27 | Method for preparing 3-[(2,3-dihydrothieno[3,4-b]-1,4-dioxin-2-yl)methoxy]-propionic acid |
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