CN110396072B - Method for producing(s) -3-hydroxytetrahydrofuran - Google Patents
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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Abstract
The invention provides a preparation method of(s) -3-hydroxytetrahydrofuran, which comprises the steps of firstly preparing(s) -4-chloro-3-hydroxy-1-butanol by using ethyl 4-chloroacetoacetate as a starting material, dissolving a substrate in a first solvent, adding alkali, carrying out asymmetric hydrogenation reaction with hydrogen under the catalytic action of a first catalyst and a second catalyst to generate the(s) -4-chloro-3-hydroxy-1-butanol, and then preparing chiral 3-hydroxytetrahydrofuran: dissolving the prepared chiral 4-chloro-3-hydroxy-1-butanol in a second solvent, adding acid as a catalyst, and reacting to obtain(s) -3-hydroxytetrahydrofuran, wherein the first catalyst is [ Ir (COD) Cl] 2 The complex is generated by reacting with phosphine-pyridine ligand, the second catalyst is Ru-MACHO complex, the invention has the advantages of short reaction route, simple and convenient process, cheap and easily obtained raw materials, low production cost, small environmental pollution in the reaction process, high optical purity of the product and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of(s) -3-hydroxytetrahydrofuran.
Background
The optically pure (S) -3-hydroxytetrahydrofuran is an important drug intermediate, can be used for synthesizing diabetes drugs Empagliflozin (Empagliflozin), breast cancer drugs Afatinb (Afatinb), anti-AIDS drugs Amprenavir (Amprenavir), Fusavir (Fosamprenavir) and the like, has large market demand and has good application prospect.
Methods for the synthesis of chiral 3-hydroxytetrahydrofuran have been generally reported. In 1983, Tadon first proposed a synthetic route for chiral 3-hydroxytetrahydrofuran (J. org. chem,1983,48, 2767-2769). The route takes chiral malic acid as a starting material, needs a large amount of lithium aluminum hydride, and is not suitable for large-scale production. Many published synthetic methods improve the synthetic route of Tadon, for example, patents CN107935971 and CN109503523 adopt the improved route, chiral malic acid is used as a starting material, chiral malic acid dimethyl ester is generated by methyl esterification, then the chiral malic acid dimethyl ester is reduced to chiral 1,2, 4-butanetriol, and the product chiral 3-hydroxytetrahydrofuran is obtained by dehydration and ring closure under an acidic condition.
The literature (applied chemical industry [ J ],2008,37, 191-charge 194), CN102477019, CN107098872, WO2008093955, WO2000063199, EP761663 and the like adopt optically pure (S) -4-chloro-3-hydroxybutyric acid ethyl ester as a raw material, and the intermediate (S) -4-chloro-3-hydroxybutyric acid is obtained after sodium borohydride reduction, and then (S) -3-hydroxytetrahydrofuran is obtained under acidic conditions. The method has the advantages of expensive raw materials, large amount of sodium borohydride, more waste water and unsuitability for large-scale production.
Patent CN104961711 discloses a preparation method of chiral 3-hydroxytetrahydrofuran. The method takes chiral carnitine as an initial raw material, and obtains corresponding chiral 2, 4-dihydroxy-N, N, N-trimethylbutylamine through reduction. Then acidifying to form salt, and then closing the ring to obtain the chiral 3-hydroxytetrahydrofuran. The method utilizes expensive chiral carnitine as a starting material, and is not suitable for large-scale production.
The literature (Synthesis,2013,45,931 and 935) describes a process for converting (R) -3-hydroxytetrahydrofuran into (S) -3-hydroxytetrahydrofuran by means of a mitsunobu reaction of dimethyl azodicarboxylate. The dimethyl azodicarboxylate used by the method is expensive and is not suitable for large-scale production.
Biological enzyme catalysis is a widely recognized and studied process. The literature (FEBS Journal,2013,280, 3084-. The biological enzymes used in the methods are expensive, long in reaction period and low in yield, and cannot meet the requirement of large-scale production.
Disclosure of Invention
The present invention has been made to solve the above problems, and an object of the present invention is to provide a method for producing(s) -3-hydroxytetrahydrofuran, which is low in raw material cost, short in reaction steps, high in optical purity of the product, efficient, green, and suitable for industrial production.
The invention provides a preparation method of(s) -3-hydroxytetrahydrofuran, which is characterized by comprising the following steps: step 1, preparing(s) -4-chloro-3-hydroxy-1-butanol shown as formula II: dissolving 4-chloroacetoacetic acid ethyl ester shown in a formula I in a first solvent, adding alkali, carrying out asymmetric hydrogenation reaction with hydrogen under the catalytic action of a first catalyst and a second catalyst to generate(s) -4-chloro-3-hydroxy-1-butanol shown in a formula II,
step 2, preparing chiral 3-hydroxytetrahydrofuran: dissolving the chiral 4-chloro-3-hydroxy-1-butanol prepared in the step 1 in a second solvent, adding acid as a catalyst, reacting to obtain(s) -3-hydroxytetrahydrofuran shown in a formula V,
wherein the first catalyst is [ Ir (COD) Cl] 2 A complex generated by the reaction with a phosphine-pyridine ligand shown in a formula III,
the second catalyst is a Ru-MACHO complex represented by formula IV.
Further, the method for producing(s) -3-hydroxytetrahydrofuran provided by the present invention may further have the following characteristics: in the step 1, the pressure of hydrogen is 1-8 MPa, the reaction temperature is 20-150 ℃, and the reaction time is 5-6 hours; the reaction temperature in the step 2 is 0-100 ℃, and the reaction time is 3-4 hours.
Further, the method for producing(s) -3-hydroxytetrahydrofuran provided by the present invention may further have the following characteristics: in the step 1, the pressure of hydrogen is 2-4 MPa, and the reaction temperature is 80-120 ℃; the reaction temperature in the step 2 is 50-80 ℃.
Further, the method for producing(s) -3-hydroxytetrahydrofuran provided by the present invention may further have the following characteristics: and 2, dissolving(s) -4-chloro-3-hydroxy-1-butanol in a second solvent, adding acid serving as a catalyst, reacting for 3-4 hours, performing short-path distillation, cooling the distillate, performing rotary distillation to remove the second solvent, and performing reduced pressure distillation to obtain(s) -3-hydroxytetrahydrofuran.
Further, the method for producing(s) -3-hydroxytetrahydrofuran provided by the present invention may further have the following characteristics: in the step 1, before introducing hydrogen, replacing the hydrogen for 3-5 times, after the reaction is finished, slowly releasing the hydrogen, removing the first solvent, and then separating by using a silica gel column to obtain the(s) -4-chloro-3-hydroxy-1-butanol.
Further, inThe method for producing(s) -3-hydroxytetrahydrofuran according to the present invention may further have the following features: the specific method for preparing the first catalyst comprises the following steps: under the protection of nitrogen gas, [ Ir (COD) Cl] 2 And dissolving the mixture and a phosphine-pyridine ligand in a first solvent, and stirring for 8-12 min at room temperature.
Further, the method for producing(s) -3-hydroxytetrahydrofuran provided by the present invention may further have the following characteristics: the volume ratio of the first solvent to the 4-chloroacetoacetic acid ethyl ester in the step 1 is 10: 1-1: 1, wherein the volume of the first solvent comprises the sum of the volumes of the first solvent added into the 4-chloroacetoacetic acid ethyl ester and the first solvent added in the preparation of the first catalyst, the molar ratio of the alkali to the 4-chloroacetoacetic acid ethyl ester is 1: 100-1: 5, the molar ratio of the first catalyst to the 4-chloroacetoacetic acid ethyl ester is 1: 10000-1: 1000 theoretically, and the molar ratio of the second catalyst to the 4-chloroacetoacetic acid ethyl ester is 1: 1000-1: 100;
the volume ratio of the second solvent to the(s) -4-chloro-3-hydroxy-1-butanol prepared in the step (2) is 10: 1-1: 1, and the ratio of the amount of the acid substance to the amount of the(s) -4-chloro-3-hydroxy-1-butanol theoretically prepared in the step (1) is 10: 1-1: 1.
Further, the method for producing(s) -3-hydroxytetrahydrofuran provided by the present invention may further have the following characteristics: the volume ratio of the first solvent to the 4-chloroacetoacetic acid ethyl ester in the step 1 is 5: 1-2: 1, wherein the volume of the first solvent comprises the sum of the volumes of the first solvent added into the 4-chloroacetoacetic acid ethyl ester and the first solvent added in the preparation of the first catalyst, the molar ratio of the alkali to the 4-chloroacetoacetic acid ethyl ester is 1: 20-1: 10, the molar ratio of the first catalyst to the 4-chloroacetoacetic acid ethyl ester is 1: 5000-1: 2000 theoretically, and the molar ratio of the second catalyst to the 4-chloroacetoacetic acid ethyl ester is 1: 500-1: 200;
the volume ratio of the second solvent to the(s) -4-chloro-3-hydroxy-1-butanol prepared in the step (2) is 5: 1-2: 1, and the ratio of the amount of the acid substance to the amount of the(s) -4-chloro-3-hydroxy-1-butanol theoretically prepared in the step (1) is 5: 1-2: 1.
Further, the method for producing(s) -3-hydroxytetrahydrofuran provided by the present invention may further have the following characteristics: the first solvent is any one of anhydrous dichloromethane, anhydrous dichloroethane, methanol, ethanol, anhydrous tetrahydrofuran and anhydrous toluene;
the second solvent is any one of deionized water, methanol, ethanol, isopropanol, tetrahydrofuran and dioxane;
the alkali is any one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, sodium bicarbonate and potassium carbonate;
the acid is any one of hydrochloric acid, sulfuric acid, phosphoric acid and p-toluenesulfonic acid.
Further, the method for producing(s) -3-hydroxytetrahydrofuran provided by the present invention may further have the following characteristics: the first solvent is methanol or ethanol; the second solvent is deionized water or methanol; the alkali is sodium methoxide or potassium tert-butoxide; the acid is hydrochloric acid or sulfuric acid.
The present invention provides the following advantages:
the invention relates to a preparation method of(s) -3-hydroxytetrahydrofuran, which adopts cheap and easily obtained ethyl 4-chloroacetoacetate as a starting raw material, generates asymmetric hydrogenation reaction under the catalytic action of a catalyst under an alkaline condition to generate(s) -4-chloro-3-hydroxy-1-butanol, and then cyclizes the(s) -4-chloro-3-hydroxy-1-butanol under the catalytic action of an acidic catalyst to generate the(s) -3-hydroxytetrahydrofuran.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the preparation method of the(s) -3-hydroxytetrahydrofuran of the invention is specifically described below with reference to the examples.
< example one >
Step 1, preparation of(s) -4-chloro-3-hydroxy-1-butanol:
step 1-1, under the protection of nitrogen gas, [ Ir (COD) Cl] 2 Dissolving chiral phosphine-pyridine ligand in ethanol at room temperatureThe mixture was stirred for 10 minutes to obtain a first catalyst.
Step 1-2, taking the substrate of ethyl 4-chloroacetoacetate and dissolving the substrate in ethanol according to the amount of the first catalyst substance theoretically prepared in the step 1-1 and the ratio of the amount of the first catalyst substance to the amount of the ethyl 4-chloroacetoacetate substance of 1: 3000. Wherein the volume ratio of the total volume of the ethanol used in the step 1-1 and the ethanol used in the step 1-2 to the substrate ethyl 4-chloroacetoacetate is 3: 1. Then, the above-mentioned ethanol solution of ethyl 4-chloroacetoacetate was added to the first catalyst prepared in the step 1-1.
Step 1-3, according to the molar ratio of potassium tert-butoxide to ethyl 4-chloroacetoacetate of 1:15 and the molar ratio of Ru-MACHO complex to ethyl 4-chloroacetoacetate of 1:300, placing the potassium tert-butoxide and the Ru-MACHO complex in a high-pressure reaction kettle, replacing 3 times with hydrogen, introducing hydrogen to 2MPa while keeping the pressure unchanged, reacting for 5 hours at 100 ℃, then slowly releasing the hydrogen, removing the solvent ethanol, and separating by using a silica gel column to obtain the chiral 4-chloro-3-hydroxy-1-butanol.
Step 2, preparing chiral 3-hydroxytetrahydrofuran:
dissolving the chiral 4-chloro-3-hydroxy-1-butanol prepared in the step 1 into ethanol according to the volume ratio of 3:1 of the ethanol to the chiral 4-chloro-3-hydroxy-1-butanol, adding concentrated hydrochloric acid as a catalyst according to the volume ratio of 3:1 of the hydrochloric acid to the chiral 4-chloro-3-hydroxy-1-butanol theoretically prepared in the step 1, reacting for 3 hours at 60 ℃, performing short-path distillation on the reaction liquid, cooling the distillate, performing rotary evaporation to remove ethanol, and finally performing reduced pressure distillation to obtain(s) -3-hydroxytetrahydrofuran. The total yield of(s) -3-hydroxytetrahydrofuran was 91.3%. The chemical purity of the prepared(s) -3-hydroxytetrahydrofuran is 98.5%, and the optical purity is 99%.
< example two >
Step 1, preparation of(s) -4-chloro-3-hydroxy-1-butanol:
step 1-1, under the protection of nitrogen, adding [ Ir (COD) Cl] 2 And dissolving the chiral phosphine-pyridine ligand in methanol, and stirring for 10 minutes at room temperature to prepare the first catalyst.
Step 1-2, taking the substrate ethyl 4-chloroacetoacetate and dissolving the substrate in methanol according to the amount of the first catalyst substance theoretically prepared in the step 1-1 and the ratio of the amount of the first catalyst substance to the amount of the ethyl 4-chloroacetoacetate substance of 1: 2000. Wherein the volume ratio of the total volume of the methanol used in the step 1-1 and the methanol used in the step 1-2 to the substrate ethyl 4-chloroacetoacetate is 5: 1. Then, the above-mentioned methanol solution of ethyl 4-chloroacetoacetate was added to the first catalyst prepared in the step 1-1.
Step 1-3, according to the molar ratio of sodium methoxide to 4-ethyl chloroacetoacetate of 1:20 and the molar ratio of Ru-MACHO complex to 4-ethyl chloroacetoacetate of 1:500, putting the sodium methoxide and the Ru-MACHO complex into a high-pressure reaction kettle, replacing with hydrogen for 5 times, then introducing hydrogen to 3MPa and keeping the pressure unchanged, reacting for 5 hours at 80 ℃, then slowly releasing the hydrogen, removing the solvent methanol, and separating with a silica gel column to obtain the chiral 4-chloro-3-hydroxy-1-butanol.
Step 2, preparing chiral 3-hydroxytetrahydrofuran:
dissolving the chiral 4-chloro-3-hydroxy-1-butanol prepared in the step 1 into methanol according to the volume ratio of 5:1 of the methanol to the chiral 4-chloro-3-hydroxy-1-butanol, adding concentrated hydrochloric acid as a catalyst according to the volume ratio of 2:1 of the hydrochloric acid to the chiral 4-chloro-3-hydroxy-1-butanol theoretically prepared in the step 1, reacting for 4 hours at 50 ℃, performing short-path distillation on the reaction liquid, cooling the distillate, performing rotary distillation to remove the methanol, and finally performing reduced pressure distillation to obtain(s) -3-hydroxytetrahydrofuran. The total yield of(s) -3-hydroxytetrahydrofuran was 94.6%. The chemical purity of the prepared(s) -3-hydroxytetrahydrofuran is 98.3%, and the optical purity is 99%.
< example three >
Step 1, preparation of(s) -4-chloro-3-hydroxy-1-butanol:
step 1-1, under the protection of nitrogen gas, [ Ir (COD) Cl] 2 And dissolving the chiral phosphine-pyridine ligand in anhydrous dichloromethane, and stirring at room temperature for 10 minutes to prepare the first catalyst.
Step 1-2, taking the substrate ethyl 4-chloroacetoacetate and dissolving the substrate in anhydrous dichloromethane according to the amount of the first catalyst substance theoretically prepared in the step 1-1 and the ratio of the amount of the first catalyst substance to the amount of the ethyl 4-chloroacetoacetate being 1: 5000. Wherein the volume ratio of the total volume of the anhydrous dichloromethane used in the step 1-1 and the anhydrous dichloromethane used in the step 1-2 to the substrate ethyl 4-chloroacetoacetate is 2: 1. Then, the above-mentioned solution of ethyl 4-chloroacetoacetate in anhydrous dichloromethane was added to the first catalyst prepared in the step 1-1.
Step 1-3, according to the molar ratio of sodium ethoxide to ethyl 4-chloroacetoacetate of 1:10 and the molar ratio of Ru-MACHO complex to ethyl 4-chloroacetoacetate of 1:200, placing the sodium ethoxide and the Ru-MACHO complex in a high-pressure reaction kettle, replacing 4 times with hydrogen, introducing hydrogen to 4MPa, keeping the pressure unchanged, reacting at 120 ℃ for 5 hours, slowly releasing the hydrogen, removing solvent anhydrous dichloromethane, and separating by using a silica gel column to obtain the chiral 4-chloro-3-hydroxy-1-butanol.
Step 2, preparing chiral 3-hydroxytetrahydrofuran:
dissolving the chiral 4-chloro-3-hydroxy-1-butanol prepared in the step 1 into deionized water according to the volume ratio of the deionized water to the chiral 4-chloro-3-hydroxy-1-butanol of 2:1, adding concentrated hydrochloric acid as a catalyst according to the use amount of 5:1 of the hydrochloric acid to the chiral 4-chloro-3-hydroxy-1-butanol theoretically prepared in the step 1, reacting at 80 ℃ for 3.5 hours, performing short-range distillation on a reaction liquid, cooling a liquid-cooled distillate, performing rotary evaporation to remove the deionized water, and finally performing reduced pressure distillation to obtain(s) -3-hydroxytetrahydrofuran. The total yield of(s) -3-hydroxytetrahydrofuran was 90%. The chemical purity of the prepared(s) -3-hydroxytetrahydrofuran is 98.9%, and the optical purity is 99%.
< example four >
Step 1, preparation of(s) -4-chloro-3-hydroxy-1-butanol:
step 1-1, under the protection of nitrogen gas, [ Ir (COD) Cl] 2 And dissolving the chiral phosphine-pyridine ligand in anhydrous dichloroethane, and stirring for 8 minutes at room temperature to prepare the first catalyst.
Step 1-2, taking the substrate of ethyl 4-chloroacetoacetate and dissolving the substrate in anhydrous dichloroethane according to the amount of the first catalyst substance theoretically prepared in the step 1-1 and the ratio of the amount of the first catalyst substance to the amount of the ethyl 4-chloroacetoacetate substance of 1: 7000. Wherein the volume ratio of the total volume of the anhydrous dichloroethane used in the step 1-1 and the anhydrous dichloroethane used in the step 1-2 to the substrate ethyl 4-chloroacetoacetate is 7: 1. Then, the above-mentioned anhydrous dichloroethane solution of ethyl 4-chloroacetoacetate was added to the first catalyst prepared in the step 1-1.
Step 1-3, according to the molar ratio of sodium carbonate to 4-ethyl chloroacetoacetate of 1:40 and the molar ratio of Ru-MACHO complex to 4-ethyl chloroacetoacetate of 1:600, placing the sodium carbonate and the Ru-MACHO complex in a high-pressure reaction kettle, replacing 3 times with hydrogen, then introducing hydrogen to 6MPa and keeping the pressure unchanged, reacting for 5.5 hours at 60 ℃, then slowly releasing the hydrogen, removing the solvent anhydrous dichloroethane, and separating by using a silica gel column to obtain the chiral 4-chloro-3-hydroxy-1-butanol.
Step 2, preparing chiral 3-hydroxytetrahydrofuran:
dissolving the chiral 4-chloro-3-hydroxy-1-butanol prepared in the step 1 into isopropanol according to the volume ratio of 8:1 of the isopropanol to the chiral 4-chloro-3-hydroxy-1-butanol, adding sulfuric acid as a catalyst according to the ratio of 7:1 of the sulfuric acid to the chiral 4-chloro-3-hydroxy-1-butanol theoretically prepared in the step 1, reacting for 4 hours at 40 ℃, performing short-range distillation on the reaction liquid, cooling the distillate, performing rotary evaporation to remove the isopropanol, and finally performing reduced pressure distillation to obtain(s) -3-hydroxytetrahydrofuran. The total yield of(s) -3-hydroxytetrahydrofuran was 82.5%. The chemical purity of the prepared(s) -3-hydroxytetrahydrofuran is 97.6 percent, and the optical purity is 99 percent.
< example five >
Step 1, preparation of(s) -4-chloro-3-hydroxy-1-butanol:
step 1-1, under the protection of nitrogen gas, [ Ir (COD) Cl] 2 And dissolving the chiral phosphine-pyridine ligand in anhydrous tetrahydrofuran, and stirring at room temperature for 12 minutes to prepare the first catalyst.
Step 1-2, according to the amount of the first catalyst substance theoretically prepared in the step 1-1, taking a substrate of 4-chloroacetoacetic acid ethyl ester to dissolve in anhydrous tetrahydrofuran according to the ratio of the amount of the first catalyst substance to the amount of the 4-chloroacetoacetic acid ethyl ester substance being 1: 10000. Wherein the volume ratio of the total volume of the anhydrous tetrahydrofuran used in the step 1-1 and the anhydrous tetrahydrofuran used in the step 1-2 to the substrate ethyl 4-chloroacetoacetate is 10: 1. Then, the above-mentioned anhydrous tetrahydrofuran solution of ethyl 4-chloroacetoacetate was added to the first catalyst prepared in the step 1-1.
Step 1-3, according to the molar ratio of sodium bicarbonate to ethyl 4-chloroacetoacetate of 1:5 and the molar ratio of Ru-MACHO complex to ethyl 4-chloroacetoacetate of 1:100, placing the sodium bicarbonate and the Ru-MACHO complex in a high-pressure reaction kettle, replacing 3 times with hydrogen, introducing hydrogen to 8MPa while keeping the pressure unchanged, reacting for 6 hours at 20 ℃, then slowly releasing the hydrogen, removing solvent anhydrous tetrahydrofuran, and separating by using a silica gel column to obtain the chiral 4-chloro-3-hydroxy-1-butanol.
Step 2, preparing chiral 3-hydroxytetrahydrofuran:
dissolving the chiral 4-chloro-3-hydroxy-1-butanol prepared in the step 1 into tetrahydrofuran according to the volume ratio of 1:1 of tetrahydrofuran to the chiral 4-chloro-3-hydroxy-1-butanol, adding phosphoric acid as a catalyst according to the volume ratio of 10:1 of phosphoric acid to the chiral 4-chloro-3-hydroxy-1-butanol theoretically prepared in the step 1, reacting at 100 ℃ for 3 hours, performing short-path distillation on the reaction liquid, cooling the distillate, performing rotary evaporation to remove tetrahydrofuran, and finally performing reduced pressure distillation to obtain(s) -3-hydroxy tetrahydrofuran. The total yield of(s) -3-hydroxytetrahydrofuran was 36.8%. The chemical purity of the prepared(s) -3-hydroxytetrahydrofuran is 98.0%, and the optical purity is 99%.
< example six >
Step 1, preparation of(s) -4-chloro-3-hydroxy-1-butanol:
step 1-1, under the protection of nitrogen gas, [ Ir (COD) Cl] 2 And dissolving the chiral phosphine-pyridine ligand in anhydrous toluene, and stirring for 11 minutes at room temperature to prepare the first catalyst.
Step 1-2, taking the substrate ethyl 4-chloroacetoacetate and dissolving the substrate in anhydrous toluene according to the amount of the first catalyst substance theoretically prepared in the step 1-1 and the ratio of the amount of the first catalyst substance to the amount of the ethyl 4-chloroacetoacetate being 1: 1000. Wherein the volume ratio of the total volume of the anhydrous toluene used in the step 1-1 and the anhydrous toluene used in the step 1-2 to the substrate ethyl 4-chloroacetoacetate is 1: 1. Then, the above-mentioned anhydrous toluene solution of ethyl 4-chloroacetoacetate was added to the first catalyst prepared in the step 1-1.
Step 1-3, according to the molar ratio of potassium carbonate to ethyl 4-chloroacetoacetate of 1:100 and the molar ratio of Ru-MACHO complex to ethyl 4-chloroacetoacetate of 1:1000, placing the potassium carbonate and the Ru-MACHO complex in a high-pressure reaction kettle, replacing with hydrogen for 3 times, then introducing hydrogen to 1MPa and keeping the pressure unchanged, reacting for 6 hours at 150 ℃, then slowly releasing the hydrogen, removing the solvent anhydrous toluene, and separating with a silica gel column to obtain the chiral 4-chloro-3-hydroxy-1-butanol.
Step 2, preparing chiral 3-hydroxytetrahydrofuran:
dissolving the chiral 4-chloro-3-hydroxy-1-butanol prepared in the step 1 into dioxane according to the volume ratio of 10:1 of dioxane to chiral 4-chloro-3-hydroxy-1-butanol, adding p-toluenesulfonic acid as a catalyst according to the amount ratio of 1:1 of p-toluenesulfonic acid to the amount of the chiral 4-chloro-3-hydroxy-1-butanol theoretically prepared in the step 1, reacting at 0 ℃ for 3.5 hours, performing short-path distillation on the reaction liquid, cooling the distillate, performing rotary distillation to remove dioxane, and finally performing reduced pressure distillation to obtain(s) -3-hydroxytetrahydrofuran. The total yield of(s) -3-hydroxytetrahydrofuran was 35%. The chemical purity of the prepared(s) -3-hydroxytetrahydrofuran is 98.2%, and the optical purity is 99%.
The method for producing(s) -3-hydroxytetrahydrofuran according to the present invention is not limited to the scope of the specific examples. The above description is only a basic description of the present invention, and any equivalent changes made according to the technical solution of the present invention should fall within the protection scope of the present invention.
Claims (8)
1. A preparation method of(s) -3-hydroxytetrahydrofuran is characterized by comprising the following steps:
step 1, preparing(s) -4-chloro-3-hydroxy-1-butanol shown as formula II: dissolving 4-chloroacetoacetic acid ethyl ester shown in a formula I in a first solvent, adding alkali, and carrying out an asymmetric hydrogenation reaction with hydrogen under the catalytic action of a first catalyst and a second catalyst to generate(s) -4-chloro-3-hydroxy-1-butanol shown in a formula II, wherein the pressure of the hydrogen is 2-4 MPa, the reaction temperature is 80-120 ℃,
step 2, preparing chiral 3-hydroxytetrahydrofuran: dissolving the chiral 4-chloro-3-hydroxy-1-butanol prepared in the step 1 in a second solvent, adding acid as a catalyst, reacting to obtain(s) -3-hydroxytetrahydrofuran shown in a formula V at the reaction temperature of 50-80 ℃,
wherein the first catalyst is [ Ir (COD) Cl] 2 A complex generated by the reaction with a phosphine-pyridine ligand shown in a formula III,
the second catalyst is a Ru-MACHO complex represented by formula IV.
2. The process for the preparation of(s) -3-hydroxytetrahydrofuran according to claim 1, characterized in that:
and 2, dissolving(s) -4-chloro-3-hydroxy-1-butanol in a second solvent, adding acid serving as a catalyst, reacting for 3-4 hours, performing short-path distillation, cooling the distillate, performing rotary distillation to remove the second solvent, and performing reduced pressure distillation to obtain(s) -3-hydroxytetrahydrofuran.
3. The process for the preparation of(s) -3-hydroxytetrahydrofuran according to claim 1, characterized in that:
in step 1, before introducing hydrogen, replacing with hydrogen for 3-5 times,
after the reaction is completed, hydrogen is slowly released, the first solvent is removed, and then the(s) -4-chloro-3-hydroxy-1-butanol is obtained by silica gel column separation.
4. The process for the preparation of(s) -3-hydroxytetrahydrofuran according to claim 3, characterized in that:
the specific method for preparing the first catalyst comprises the following steps: under the protection of nitrogen gas, [ Ir (COD) Cl] 2 And dissolving the phosphine-pyridine ligand in a first solvent, and stirring for 8-12 min at room temperature.
5. The process for the preparation of(s) -3-hydroxytetrahydrofuran according to claim 1, characterized in that:
the volume ratio of the first solvent to the 4-chloroacetoacetic acid ethyl ester in the step 1 is 10: 1-1: 1, wherein the volume of the first solvent comprises the sum of the volumes of the first solvent added into the 4-chloroacetoacetic acid ethyl ester and the first solvent added in the preparation of the first catalyst, the molar ratio of the alkali to the 4-chloroacetoacetic acid ethyl ester is 1: 100-1: 5, the molar ratio of the first catalyst to the 4-chloroacetoacetic acid ethyl ester is 1: 10000-1: 1000 theoretically, and the molar ratio of the second catalyst to the 4-chloroacetoacetic acid ethyl ester is 1: 1000-1: 100;
the volume ratio of the second solvent to the(s) -4-chloro-3-hydroxy-1-butanol prepared in the step (2) is 10: 1-1: 1, and the ratio of the amount of the acid substance to the amount of the(s) -4-chloro-3-hydroxy-1-butanol theoretically prepared in the step (1) is 10: 1-1: 1.
6. The process for producing(s) -3-hydroxytetrahydrofuran according to claim 5, characterized in that:
the volume ratio of the first solvent to the 4-chloroacetoacetic acid ethyl ester in the step 1 is 5: 1-2: 1, wherein the volume of the first solvent comprises the sum of the volumes of the first solvent added into the 4-chloroacetoacetic acid ethyl ester and the first solvent added in the preparation of the first catalyst, the molar ratio of the alkali to the 4-chloroacetoacetic acid ethyl ester is 1: 20-1: 10, the molar ratio of the first catalyst to the 4-chloroacetoacetic acid ethyl ester is 1: 5000-1: 2000 theoretically, and the molar ratio of the second catalyst to the 4-chloroacetoacetic acid ethyl ester is 1: 500-1: 200;
the volume ratio of the second solvent to the(s) -4-chloro-3-hydroxy-1-butanol prepared in the step (2) is 5: 1-2: 1, and the ratio of the amount of the acid substance to the amount of the(s) -4-chloro-3-hydroxy-1-butanol theoretically prepared in the step (1) is 5: 1-2: 1.
7. The method for producing(s) -3-hydroxytetrahydrofuran according to claim 1, characterized in that:
the first solvent is any one of anhydrous dichloromethane, anhydrous dichloroethane, methanol, ethanol, anhydrous tetrahydrofuran and anhydrous toluene;
the second solvent is any one of deionized water, methanol, ethanol, isopropanol, tetrahydrofuran and dioxane;
the alkali is any one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, sodium bicarbonate and potassium carbonate;
the acid is any one of hydrochloric acid, sulfuric acid, phosphoric acid and p-toluenesulfonic acid.
8. The process for the preparation of(s) -3-hydroxytetrahydrofuran according to claim 7, characterized in that:
the first solvent is methanol or ethanol;
the second solvent is deionized water or methanol;
the alkali is sodium methoxide or potassium tert-butoxide;
the acid is hydrochloric acid or sulfuric acid.
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Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2456937A1 (en) * | 1973-12-03 | 1975-06-26 | Monsanto Co | ASYMMETRIC CATALYSIS |
| CA1070711A (en) * | 1975-05-03 | 1980-01-29 | Hoechst Aktiengesellschaft | Process for preparing butanediol-(1.4) |
| CN101163656A (en) * | 2004-07-01 | 2008-04-16 | 英尼奥斯美国有限责任公司 | Catalysts for maleic acid hydrogenation to 1,4-butanediol |
| CN102040625A (en) * | 2010-11-19 | 2011-05-04 | 南开大学 | Chiral spiro pyridylamidophosphine ligand compounds and synthesis method and application thereof |
| CN102177170A (en) * | 2009-10-23 | 2011-09-07 | 高砂香料工业株式会社 | Novel ruthenium carbonyl complex having a tridentate ligand and manufacturing method and usage therefor |
| CN103347844A (en) * | 2011-02-03 | 2013-10-09 | 中央硝子株式会社 | Method for producing ss-fluoroalcohol |
| CN105153229A (en) * | 2015-06-18 | 2015-12-16 | 武汉凯特立斯科技有限公司 | Chiral tridentate PNN ligand and application of same in asymmetric hydrogenation |
| CN106853378A (en) * | 2015-12-08 | 2017-06-16 | 中国科学院大连化学物理研究所 | The ternary catalyst systems of the part of structural framework containing PNN and its application |
| CN107098872A (en) * | 2017-03-23 | 2017-08-29 | 苏州华道生物药业股份有限公司 | A kind of production technology of the hydroxyl tetrahydrofuran of high-optical-purity 3 |
| CN108101785A (en) * | 2016-11-24 | 2018-06-01 | 中国科学院大连化学物理研究所 | A kind of method that iridium catalysis asymmetric hydrogenation prepares chiral beta-hydroxy ester |
| CN110003005A (en) * | 2019-04-22 | 2019-07-12 | 上海欣海国际贸易有限公司 | The method for preparing chiral beta-hydroxy carboxylate compound |
-
2019
- 2019-09-02 CN CN201910821576.7A patent/CN110396072B/en active Active
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2456937A1 (en) * | 1973-12-03 | 1975-06-26 | Monsanto Co | ASYMMETRIC CATALYSIS |
| CA1070711A (en) * | 1975-05-03 | 1980-01-29 | Hoechst Aktiengesellschaft | Process for preparing butanediol-(1.4) |
| CN101163656A (en) * | 2004-07-01 | 2008-04-16 | 英尼奥斯美国有限责任公司 | Catalysts for maleic acid hydrogenation to 1,4-butanediol |
| CN102177170A (en) * | 2009-10-23 | 2011-09-07 | 高砂香料工业株式会社 | Novel ruthenium carbonyl complex having a tridentate ligand and manufacturing method and usage therefor |
| CN102040625A (en) * | 2010-11-19 | 2011-05-04 | 南开大学 | Chiral spiro pyridylamidophosphine ligand compounds and synthesis method and application thereof |
| CN103347844A (en) * | 2011-02-03 | 2013-10-09 | 中央硝子株式会社 | Method for producing ss-fluoroalcohol |
| CN105153229A (en) * | 2015-06-18 | 2015-12-16 | 武汉凯特立斯科技有限公司 | Chiral tridentate PNN ligand and application of same in asymmetric hydrogenation |
| CN106853378A (en) * | 2015-12-08 | 2017-06-16 | 中国科学院大连化学物理研究所 | The ternary catalyst systems of the part of structural framework containing PNN and its application |
| CN108101785A (en) * | 2016-11-24 | 2018-06-01 | 中国科学院大连化学物理研究所 | A kind of method that iridium catalysis asymmetric hydrogenation prepares chiral beta-hydroxy ester |
| CN107098872A (en) * | 2017-03-23 | 2017-08-29 | 苏州华道生物药业股份有限公司 | A kind of production technology of the hydroxyl tetrahydrofuran of high-optical-purity 3 |
| CN110003005A (en) * | 2019-04-22 | 2019-07-12 | 上海欣海国际贸易有限公司 | The method for preparing chiral beta-hydroxy carboxylate compound |
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