CN108640884B - 2-morpholinone salt, preparation method thereof and preparation method of 2-morpholinone - Google Patents
2-morpholinone salt, preparation method thereof and preparation method of 2-morpholinone Download PDFInfo
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Abstract
The invention relates to a 2-morpholinone salt, a preparation method thereof and a preparation method of 2-morpholinone, belonging to the technical field of synthesis of drug intermediates. The preparation method of the 2-morpholone salt comprises the following steps: heating N- (2-hydroxyethyl) glycine with amino protecting group and catalyst in a reflux solvent for reflux reaction to prepare 2-morpholinone with amino protecting group; the catalyst is p-toluenesulfonic acid or concentrated sulfuric acid; acidifying the 2-morpholinone with the amino protecting group to remove the protecting group to obtain the 2-morpholinone salt. The 2-morpholone is obtained by reacting 2-morpholone salt with alkali in a solvent. In the preparation method of the 2-morpholone salt and the 2-morpholone, the used raw materials are cheap and easy to obtain, the synthetic route is short, and all reaction intermediates and final products do not need column chromatography purification. The method has low cost, high efficiency, and high purity of the obtained product.
Description
Technical Field
The invention relates to a 2-morpholinone salt, a preparation method thereof and a preparation method of 2-morpholinone, belonging to the technical field of synthesis of drug intermediates.
Background
2-morpholone is colorless oily liquid with molecular formula of C4H7NO2And the molecular weight is 101.05. The hydrochloride is crystalline white powder with molecular formula of C4H8ClNO2And the molecular weight is 137.02. In the prior art, 2-morpholone is used as an important medical intermediate and is mainly used for synthesizing quinazoline medicaments, and the medicaments are mainly used for treating cancers.
In the prior art, the synthesis process of 2-morpholone is generally complex, the cost of raw materials is high, the yield is low, and the large-scale production is not facilitated. Such as "Oxidant-Free Conversion of Cyclic Amines to spectra and H2Use Water As the Oxygen Atom Source (JACS, Julia R et al, 2014.2)A synthesis process of 2-morpholone is provided, and when the method is used for synthesizing the 2-morpholone, the reaction process is complex and the efficiency is low.
Disclosure of Invention
The invention aims to provide a preparation method of 2-morpholone salt with simple reaction process and the 2-morpholone salt prepared by the method.
The invention also aims to provide a preparation method of the 2-morpholone.
In order to realize the aim, the technical scheme of the preparation method of the 2-morpholone salt is as follows:
scheme 1: a preparation method of 2-morpholone salt comprises the following steps:
1) heating N- (2-hydroxyethyl) glycine with amino protecting group and catalyst in a reflux solvent for reflux reaction to prepare 2-morpholinone with amino protecting group; the catalyst is p-toluenesulfonic acid or concentrated sulfuric acid;
2) acidifying the 2-morpholinone with the amino protecting group to remove the protecting group to obtain the 2-morpholinone salt.
In the preparation method of the 2-morpholinone salt, N- (2-hydroxyethyl) glycine (namely hydroxyethyl glycine) with an amino protecting group is subjected to reflux reaction under the action of a catalyst to prepare the 2-morpholinone with the protecting group, and then the 2-morpholinone salt or the 2-morpholinone is prepared. The method has low cost, high efficiency, and high purity of the obtained product.
Scheme 2: on the basis of scheme 1, in the preparation method of the 2-morpholinone salt: the mol ratio of N- (2-hydroxyethyl) glycine with amino protecting group in the step 1) to the catalyst is 1: 0.01-0.1.
Scheme 3: based on scheme 1, the reaction time of the heating reflux reaction in the step 1) is 4-6 h. The temperature of heating reflux is 80-140 ℃. Stirring is carried out during the heating reflux process. The reflux solvent is one or more of benzene, toluene and xylene. The benzene, the toluene and the xylene are respectively anhydrous benzene, anhydrous toluene and anhydrous xylene.
Scheme 4: on the basis of scheme 1, the dosage of the reflux solvent is as follows: 5-10mL of refluxing solvent per 1g of N- (2-hydroxyethyl) glycine with an amino protecting group.
Scheme 5: on the basis of scheme 1, the entrained water is heated under reflux. And cooling to room temperature. After cooling, the organic phase is washed with saturated sodium bicarbonate solution. Directly evaporating the washed organic phase to dryness to obtain a crude product, and recrystallizing the crude product with n-hexane to obtain a pure product.
In scheme 1, the acidification removal of the protecting group of 2-morpholinone with an amino protecting group in step 2) can be performed by the following two schemes:
scheme 6: on the basis of scheme 1, the step 2) of removing the protecting group by acidification of the 2-morpholinone with an amino protecting group comprises the following steps: mixing the 2-morpholone with the amino protecting group with an acid solution to carry out catalytic hydrogenation reduction reaction.
The amino protecting groups in scheme 6 are typically Bn or Cbz protecting groups.
On the basis of scheme 6, preferably, the dosage ratio of the 2-morpholone with the amino protecting group and the acid solution in the step 2) is as follows: 3-20mL of acid solution per 1g of 2-morpholinone with an amino protecting group. The mass concentration of the acid solution is 5-10%.
On the basis of the scheme 6, the catalyst adopted in the catalytic hydrogenation reaction in the step 2) is preferably a Pd-C catalyst. Preferably, the catalyst accounts for 3-10% of the mass fraction of the 2-morpholone with the amino protecting group in the step 2).
On the basis of scheme 6, preferably, the acid solution in step 2) comprises an acidic substance and a solvent, wherein the acidic substance is hydrogen chloride (HCl), formic acid (HCOOH), acetic acid (CH)3COOH), trifluoroacetic acid (CF)3COOH); the solvent is any one or combination of several of methanol, ethanol, toluene and 1, 4-dioxane. Preferably, the mass fraction of the acidic substances in the acid solution in the step 2) is 5% -10%.
On the basis of scheme 6, the temperature of the catalytic hydrogenation reduction reaction in step 2) is preferably 20 to 80 ℃. The catalytic hydrogenation reduction reaction was carried out at 1 atmosphere. Cooling to room temperature after catalytic hydrogenation reduction reaction. After cooling, filtration was carried out. The purpose of the filtration is mainly to remove the Pd-C catalyst. Filtering, and concentrating the filtrate to dryness to obtain white solid, namely 2-morpholinone salt.
Scheme 7: on the basis of scheme 1, the step 2) of removing the protecting group by acidification of the 2-morpholinone with an amino protecting group comprises the following steps: reacting 2-morpholone with amino protecting group with hydrogen chloride or trifluoroacetic acid in solvent.
The amino protecting group in scheme 7 is typically a Boc protecting group.
On the basis of scheme 7, preferably, the solvent is dichloromethane, methanol, ethanol or tetrahydrofuran. Introducing hydrogen chloride until the reaction is complete. The judgment of the completion of the reaction can be controlled by TLC or GC detection.
On the basis of scheme 7, preferably, 2-morpholone reacts with hydrogen chloride or trifluoroacetic acid in a solvent completely, and then the solvent is evaporated under reduced pressure until the solvent is dried, so that the 2-morpholone salt is obtained.
Based on scheme 7, preferably, when 2-morpholone with amino protecting group reacts with hydrogen chloride or trifluoroacetic acid in solvent, the ratio of 2-morpholone with amino protecting group to solvent is: 3-20mL of solvent is used per 1g of 2-morpholinone with an amino protecting group.
Scheme 8: on the basis of scheme 1, the preparation method of N- (2-hydroxyethyl) glycine with amino protecting group in step 1) comprises the following steps: mixing N- (2-hydroxyethyl) glycine, an amino protective agent and alkali in a solvent for reaction to prepare the N- (2-hydroxyethyl) glycine with an amino protective group.
Scheme 9: in the above method for preparing N- (2-hydroxyethyl) glycine having an amino protecting group according to scheme 8, the amino protecting agent is tert-butyl dicarbonate, benzyl bromide, triphenylchloromethane, or benzyl chloroformate. Mixing N- (2-hydroxyethyl) glycine, an amino protective agent and alkali in a solvent for reaction for 4-8 h. The mol ratio of the N- (2-hydroxyethyl) glycine to the amino protective agent is 1: 0.8-2.
Scheme 10: on the basis of scheme 8, in the preparation method of the N- (2-hydroxyethyl) glycine with the amino protecting group, the base is one of sodium hydroxide, sodium carbonate, potassium carbonate or triethylamine. The solvent is at least one of water, dioxane and tetrahydrofuran. Preferably, the solvent is water and dioxane. The volume ratio of the water to the dioxane is 0.8-1.5: 2-15.
Scheme 11: in the method for producing N- (2-hydroxyethyl) glycine having an amino-protecting group according to scheme 8, N- (2-hydroxyethyl) glycine, an amino-protecting agent and a base are mixed in a solvent and stirred during the reaction.
Scheme 12: based on scheme 8, the molar ratio of N- (2-hydroxyethyl) glycine to base is 1: 0.5-1.5.
Scheme 13: in the above method for producing N- (2-hydroxyethyl) glycine having an amino-protecting group according to scheme 8, when N- (2-hydroxyethyl) glycine, an amino-protecting agent and a base are mixed in a solvent, the amount of the solvent used is 5 to 15mL per 1g of N- (2-hydroxyethyl) glycine.
Scheme 14: in the above method for producing N- (2-hydroxyethyl) glycine having an amino-protecting group according to scheme 8, the pH of the mixed solution is adjusted to 2 to 4 after the reaction.
Scheme 15: in the above-mentioned process for producing N- (2-hydroxyethyl) glycine having an amino-protecting group according to scheme 14, an acidic substance is used for adjusting pH. The acidic substance is inorganic acid or inorganic acidic salt. The inorganic acid is one of hydrochloric acid, sulfuric acid and phosphoric acid. The inorganic acid salt is one of sodium bisulfate and potassium bisulfate.
Scheme 16: based on scheme 14, in the preparation method of N- (2-hydroxyethyl) glycine with amino protecting group, pH is adjusted and then extraction is carried out by using an extracting agent. The extractant is ethyl acetate. The number of extractions was 3. After each extraction, the organic phases were separated, combined and washed with saturated brine. And (4) concentrating the organic phase to dryness after washing.
Scheme 17: on the basis of scheme 1, the preparation method of the N- (2-hydroxyethyl) glycine comprises the following steps: and (3) carrying out hydrogenation reduction reaction on the glyoxylic acid and the ethanolamine to obtain the product.
Scheme 18: on the basis of scheme 17, the hydrogenation reduction reaction is a catalytic hydrogenation reaction, and a palladium-carbon material is used as a catalyst. The reaction temperature of the hydrogenation reduction reaction is 25-50 ℃. The reaction time of the hydrogenation reduction reaction is 12-24 h.
Scheme 19: on the basis of scheme 17, the molar ratio of the glyoxylic acid to the ethanolamine is 1: (0.8-2.2).
Scheme 20: on the basis of the scheme 17, the step of carrying out hydrogenation reduction reaction on the glyoxylic acid and the ethanolamine is to uniformly mix the glyoxylic acid, the ethanolamine, a catalyst and a solvent and then carry out hydrogenation reduction reaction. The solvent is water. The amount of water is 8-15mL per 1g glyoxylic acid.
Scheme 21: on the basis of the scheme 17, after hydrogenation reduction reaction, cooling to room temperature, filtering, and concentrating the filtrate to be dry to obtain the catalyst.
The technical scheme of the 2-morpholone salt is as follows:
a 2-morpholinone salt produced by any one of the above methods.
The technical scheme of the preparation method of the 2-morpholone is as follows:
scheme 1: a preparation method of 2-morpholone comprises the following steps:
1) heating N- (2-hydroxyethyl) glycine with amino protecting group and catalyst in a reflux solvent for reflux reaction to prepare 2-morpholinone with amino protecting group; the catalyst is p-toluenesulfonic acid or concentrated sulfuric acid;
2) acidifying the 2-morpholinone with the amino protecting group to remove the protecting group to obtain the 2-morpholinone salt.
3) Then reacting the 2-morpholinone salt with alkali in a solvent to obtain the compound.
Scheme 2: on the basis of scheme 1, in the preparation method of the 2-morpholinone salt: the mol ratio of N- (2-hydroxyethyl) glycine with amino protecting group in the step 1) to the catalyst is 1: 0.01-0.1.
Scheme 3: based on scheme 1, the reaction time of the heating reflux reaction in the step 1) is 4-6 h. The temperature of heating reflux is 80-140 ℃. Stirring is carried out during the heating reflux process. The reflux solvent is one or more of benzene, toluene and xylene. The benzene, the toluene and the xylene are respectively anhydrous benzene, anhydrous toluene and anhydrous xylene.
Scheme 4: on the basis of scheme 1, the dosage of the reflux solvent is as follows: 5-10mL of refluxing solvent per 1g of N- (2-hydroxyethyl) glycine with an amino protecting group.
Scheme 5: on the basis of scheme 1, the entrained water is heated under reflux. And cooling to room temperature. After cooling, the organic phase is washed with saturated sodium bicarbonate solution. Directly evaporating the washed organic phase to dryness to obtain a crude product, and recrystallizing the crude product with n-hexane to obtain a pure product.
In scheme 1, the acidification removal of the protecting group of 2-morpholinone with an amino protecting group in step 2) can be performed by the following two schemes:
scheme 6: on the basis of scheme 1, the acidification reaction of the 2-morpholinone with an amino-protecting group in step 2) comprises the following steps: mixing the 2-morpholone with the amino protecting group with an acid solution to carry out catalytic hydrogenation reduction reaction.
The amino protecting groups in scheme 6 are typically Bn or Cbz protecting groups.
On the basis of scheme 6, preferably, the dosage ratio of the 2-morpholone with the amino protecting group and the acid solution in the step 2) is as follows: 3-20mL of acid solution per 1g of 2-morpholinone with an amino protecting group. The mass concentration of the acid solution is 5-10%.
On the basis of the scheme 6, the catalyst adopted in the catalytic hydrogenation reaction in the step 2) is preferably a Pd-C catalyst. Preferably, the catalyst accounts for 3-10% of the mass fraction of the 2-morpholone with the amino protecting group in the step 2).
On the basis of scheme 6, preferably, the acid solution in step 2) comprises an acidic substance and a solvent, wherein the acidic substance is hydrogen chloride (HCl), formic acid (HCOOH), acetic acid (CH)3COOH), trifluoroacetic acid (CF)3COOH); the solvent is any one or combination of methanol, ethanol, toluene and 1, 4-dioxane. Preferably, the mass fraction of the acidic substances in the acid solution in the step 2) is 5% -15%.
On the basis of scheme 6, the temperature of the catalytic hydrogenation reduction reaction in step 2) is preferably 20 to 80 ℃. The catalytic hydrogenation reduction reaction was carried out at 1 atmosphere. Cooling to room temperature after catalytic hydrogenation reduction reaction. After cooling, filtration was carried out. The purpose of the filtration is mainly to remove the Pd-C catalyst. Filtering, and concentrating the filtrate to dryness to obtain white solid, namely 2-morpholinone salt.
Scheme 7: on the basis of scheme 1, the step 2) of removing the protecting group by acidification of the 2-morpholinone with an amino protecting group comprises the following steps: reacting 2-morpholone with amino protecting group with hydrogen chloride or trifluoroacetic acid in solvent.
The amino protecting group in scheme 7 is typically a Boc protecting group.
On the basis of scheme 7, preferably, the solvent is dichloromethane, methanol, ethanol or tetrahydrofuran. Introducing hydrogen chloride until the reaction is complete. The judgment of the completion of the reaction can be controlled by TLC or GC detection.
On the basis of scheme 7, preferably, 2-morpholone reacts with hydrogen chloride or trifluoroacetic acid in a solvent completely, and then the solvent is evaporated under reduced pressure until the solvent is dried, so that the 2-morpholone salt is obtained.
Based on scheme 7, preferably, when 2-morpholone with amino protecting group reacts with hydrogen chloride or trifluoroacetic acid in solvent, the ratio of 2-morpholone with amino protecting group to solvent is: 3-20mL of solvent is used per 1g of 2-morpholinone with an amino protecting group.
Scheme 8: on the basis of scheme 1, the preparation method of N- (2-hydroxyethyl) glycine with amino protecting group in step 1) comprises the following steps: mixing N- (2-hydroxyethyl) glycine (i.e. hydroxyethyl aminoacetic acid), an amino protective agent and alkali in a solvent for reaction to prepare the N- (2-hydroxyethyl) glycine with an amino protective group.
Scheme 9: in the above method for preparing N- (2-hydroxyethyl) glycine having an amino protecting group according to scheme 8, the amino protecting agent is tert-butyl dicarbonate, benzyl bromide, triphenylchloromethane, or benzyl chloroformate. Mixing N- (2-hydroxyethyl) glycine, an amino protective agent and alkali in a solvent for reaction for 4-8 h. The mol ratio of the N- (2-hydroxyethyl) glycine to the amino protective agent is 1: 0.8-2.
Scheme 10: on the basis of scheme 8, in the preparation method of the N- (2-hydroxyethyl) glycine with the amino protecting group, the base is one of sodium hydroxide, sodium carbonate, potassium carbonate or triethylamine. The solvent is at least one of water, dioxane and tetrahydrofuran. Preferably, the solvent is water and dioxane. The volume ratio of the water to the dioxane is 0.8-1.5: 2-15.
Scheme 11: in the method for producing N- (2-hydroxyethyl) glycine having an amino-protecting group according to scheme 8, N- (2-hydroxyethyl) glycine, an amino-protecting agent and a base are mixed in a solvent and stirred during the reaction.
Scheme 12: based on scheme 8, the molar ratio of N- (2-hydroxyethyl) glycine to base is 1: 0.5-1.5.
Scheme 13: in the above method for producing N- (2-hydroxyethyl) glycine having an amino-protecting group according to scheme 8, when N- (2-hydroxyethyl) glycine, an amino-protecting agent and a base are mixed in a solvent, the amount of the solvent used is 5 to 15mL per 1g of N- (2-hydroxyethyl) glycine.
Scheme 14: in the above method for producing N- (2-hydroxyethyl) glycine having an amino-protecting group according to scheme 8, the pH of the mixed solution is adjusted to 2 to 4 after the reaction.
Scheme 15: in the above-mentioned process for producing N- (2-hydroxyethyl) glycine having an amino-protecting group according to scheme 14, an acidic substance is used for adjusting pH. The acidic substance is inorganic acid or inorganic acidic salt. The inorganic acid is one of hydrochloric acid, sulfuric acid and phosphoric acid. The inorganic acid salt is one of sodium bisulfate and potassium bisulfate.
Scheme 16: based on scheme 14, in the preparation method of N- (2-hydroxyethyl) glycine with amino protecting group, pH is adjusted and then extraction is carried out by using an extracting agent. The extractant is ethyl acetate. The number of extractions was 3. After each extraction, the organic phases were separated, combined and washed with saturated brine. And (4) concentrating the organic phase to dryness after washing.
Scheme 17: on the basis of scheme 1, the preparation method of the N- (2-hydroxyethyl) glycine comprises the following steps: and (3) carrying out hydrogenation reduction reaction on the glyoxylic acid and the ethanolamine to obtain the product.
Scheme 18: on the basis of scheme 17, the hydrogenation reduction reaction is a catalytic hydrogenation reaction, and a palladium-carbon material is used as a catalyst. The reaction temperature of the hydrogenation reduction reaction is 25-50 ℃. The reaction time of the hydrogenation reduction reaction is 12-24 h.
Scheme 19: on the basis of scheme 17, the molar ratio of glyoxylic acid to ethanolamine is 1: (0.8-2.2).
Scheme 20: on the basis of the scheme 17, the step of carrying out hydrogenation reduction reaction on the glyoxylic acid and the ethanolamine is to uniformly mix the glyoxylic acid, the ethanolamine, a catalyst and a solvent and then carry out hydrogenation reduction reaction. The solvent is water. The amount of water is 8-15mL per 1g glyoxylic acid.
Scheme 21: on the basis of the scheme 17, after hydrogenation reduction reaction, cooling to room temperature, filtering, and concentrating the filtrate to be dry to obtain the N- (2-hydroxyethyl) glycine.
Scheme 22: on the basis of scheme 1, the molar ratio of 2-morpholinone salt to base in step 3) is from 1:2 to 5.
Scheme 23: on the basis of the scheme 1, the solvent used in the reaction of the 2-morpholinone salt and the base in the solvent in the step 3) is one of dichloromethane, ethanol, tetrahydrofuran and water.
Scheme 24: on the basis of scheme 1, the amount of solvent used in step 3) is 5-15mL per 1g of 2-morpholinone salt.
Scheme 25: on the basis of scheme 1, the step 3) of reacting the 2-morpholinone salt with the base in the solvent is to mix the 2-morpholinone salt with the solvent uniformly and then add the organic base or the inorganic base solution.
Adding organic alkali or alkali solution as dropping. The organic base is one or two of triethylamine and diisopropylethylamine. The inorganic alkali solution comprises inorganic alkali and water, and the inorganic alkali is any one or two of potassium carbonate and sodium carbonate.
Scheme 26: on the basis of scheme 1, the reaction time of the 2-morpholinone salt in step 3) with the base in the solvent is 1-2 h.
Scheme 27: on the basis of scheme 1, 2-morpholone salt reacts with alkali in a solvent in the step 3), and the reacted material is concentrated to 1/5-1/10 of the volume of the original material or concentrated to be dry.
Scheme 28: on the basis of scheme 27, the concentration in step 3) is followed by extraction. The extractant used for extraction is methyl tert-butyl ether. The amount of extractant used is 10-30mL per 1g of concentrated residue.
Scheme 29: on the basis of scheme 28, the organic phase after extraction in step 3) is concentrated to dryness to obtain 2-morpholinone.
The invention has the beneficial effects that:
the preparation method of the 2-morpholone has the advantages of cheap and easily obtained raw materials, short synthetic route, no need of column chromatography purification of all reaction intermediates and final products, easy synthesis of a large amount of target compounds by utilizing the cheap and easily obtained raw material glyoxylic acid, and reduction of heavy metal residues compared with a metal catalytic oxidation method. The problem that the isomers are difficult to separate is avoided, and the yield is greatly improved. Each reaction step is common operation, and the industrial production is easy to realize. Is beneficial to reducing the cost and has great economic benefit.
Furthermore, the invention adopts p-toluenesulfonic acid as a catalyst, and the p-toluenesulfonic acid is dehydrated in toluene to generate lactonization ring closing reaction to obtain a target compound skeleton, and the reaction is simple and high in efficiency.
Drawings
FIG. 1 is a NMR spectrum of N-Boc-2-morpholinone prepared in example 2;
FIG. 2 is a nuclear magnetic resonance spectrum of 2-morpholinone hydrochloride prepared in example 2.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples.
The synthetic route of the preparation method of the 2-morpholone of the invention is as follows:
example 1
The preparation method of the 2-morpholinone salt of the embodiment includes the following steps:
1) adding 2000mL of water, 149g (2mol) of glyoxylic acid, 122g (2mol) of ethanolamine and 8g of palladium-carbon composite material into a single-mouth bottle with a stirrer, wherein the mass fraction of palladium in the palladium-carbon composite material is 10%; stirring and mixing uniformly, heating to 40 ℃, carrying out normal-pressure hydrogenation reduction reaction for 24 hours, and cooling to room temperature after the reaction is finished; filtering, wherein filter residues are palladium-carbon composite materials, concentrating the filtrate to be dry, and then recrystallizing with ethanol to obtain N- (2-hydroxyethyl) glycine (230 g); the yield thereof was found to be 97%.
2) Adding 1000mL of dioxane, 500mL of water, 80g (2mol) of sodium hydroxide and 238g (2mol) of N- (2-hydroxyethyl) glycine prepared in the step 1) into a three-necked bottle with a mechanical stirrer at room temperature, stirring for 0.5h, slowly adding 340g (2mol) of benzyl chloroformate dropwise, reacting for 8h at room temperature, adjusting the pH of the system to 2 by using concentrated hydrochloric acid after the reaction is finished, extracting and separating by using ethyl acetate for 3 times, combining organic phases, washing by using saturated saline solution, and concentrating the organic phase to dryness to obtain N-Cbz-N- (2-hydroxyethyl) glycine (470g) with the yield of 94%.
3) 2000mL of anhydrous toluene, 8.6g (0.05mol) of p-toluenesulfonic acid and 253g (1mol) of N-Cbz-N- (2-hydroxyethyl) glycine prepared in the step 2) are added into a three-necked bottle with a stirrer, after the addition is finished, the temperature is raised to 110 ℃, reflux reaction with water is carried out for 4 hours, after the reaction is finished, an organic phase is cooled to room temperature, the organic phase is washed by saturated sodium bicarbonate solution, saturated saline solution and purified water in sequence, and the organic phase is concentrated to dryness to obtain N-Cbz-2-morpholinone (200g), wherein the yield is 85%.
4) Dissolving 191g (0.81mol) of N-Cbz-2-morpholinone in 1000mL of methanol solution containing HCl, wherein the mass fraction of HCl in the methanol solution is 5%, then adding 10g of palladium-carbon composite material (the mass fraction of palladium in the palladium-carbon composite material is 10%), carrying out catalytic hydrogenation reaction under the conditions of 1 atmosphere and 40 ℃, cooling to room temperature, filtering, taking filter residue as the palladium-carbon composite material, concentrating the filtrate (evaporating the solvent under reduced pressure) to dryness, and obtaining a white solid, namely 2-morpholinone hydrochloride; the yield is 90%; the total yield based on glyoxylic acid was 69%.
The 2-morpholinone salt prepared by the above method is an example of the 2-morpholinone salt of this example.
The preparation method of 2-morpholone of the embodiment comprises the following steps:
adding 68g (0.5mol) of the 2-morpholinone hydrochloride into 400mL of solvent dichloromethane, slowly dropwise adding 103mL (1.5mol) of triethylamine at room temperature, stirring for 1h, concentrating to dryness after the reaction is finished, extracting the residue with methyl tert-butyl ether, wherein the dosage of the methyl tert-butyl ether is 800 mL; concentrating to dryness to obtain 47g of 2-morpholone, wherein the yield is 94%, the product is light yellow oily matter, and the total yield is 65% based on glyoxylic acid.
Example 2
The preparation method of the 2-morpholinone salt of the embodiment includes the following steps:
1) adding 2000mL of water, 149g (2mol) of glyoxylic acid, 122g (2mol) of ethanolamine and 8g of palladium-carbon composite material into a single-mouth bottle with a stirrer, wherein the mass fraction of palladium in the palladium-carbon composite material is 10%; stirring and mixing uniformly, heating to 40 ℃, carrying out normal-pressure hydrogenation reduction reaction for 24 hours, and cooling to room temperature after the reaction is finished; filtering, wherein filter residue is a palladium-carbon composite material, concentrating the filtrate to dryness, and then recrystallizing with ethanol to obtain N- (2-hydroxyethyl) glycine (230 g); the yield thereof was found to be 97%.
2) Adding 1000mL of dioxane, 500mL of purified water, 80g (2mol) of sodium hydroxide and 238g (2mol) of N- (2-hydroxyethyl) glycine prepared in the step 1) into a three-necked bottle with a mechanical stirrer, stirring for 0.5h, slowly adding 536g (2mol) of di-tert-butyl dicarbonate under stirring, stirring at room temperature for reacting for 6h, adjusting the pH of the system to 2 by using a saturated potassium hydrogen sulfate solution after the reaction is finished, extracting and separating by using ethyl acetate for 3 times, combining organic phases, washing by using saturated saline water and purified water in sequence, and concentrating the organic phase to dryness to obtain N-Boc-N- (2-hydroxyethyl) glycine (430g), wherein the yield is 92%.
3) 2000mL of anhydrous toluene, 8.6g (0.05mol) of p-toluenesulfonic acid and 233g (1mol) of N-Boc-N- (2-hydroxyethyl) glycine prepared in the step 2) are added into a three-necked flask with a stirrer, after the addition is finished, the temperature is raised to 110 ℃, reflux reaction with water is carried out for 4 hours, after the reaction is finished, an organic phase is cooled to room temperature, the organic phase is sequentially washed by saturated sodium bicarbonate solution, saturated saline solution and purified water, the organic phase is concentrated to dryness to obtain a crude product of N-Boc-2-morpholinone (180g), and after N-hexane is recrystallized, 140g of the target compound N-Boc-2-morpholinone is obtained, wherein the yield is 70%.
4) Dissolving 100g (0.5mol) of the N-Boc-2-morpholinone in 600mL of dichloromethane, introducing hydrogen chloride until the N-Boc-2-morpholinone completely reacts to generate a large amount of white solid, concentrating the reaction liquid to 1/3 of the original volume, adding methyl tert-butyl ether to completely separate out the solid, and filtering the solid to obtain 2-morpholinone hydrochloride (64 g); the yield is 94%; the total yield based on glyoxylic acid was 59%.
The 2-morpholinone salt prepared by the above method is an example of the 2-morpholinone salt of this example.
The preparation method of 2-morpholone of the embodiment comprises the following steps:
68g (0.5mol) of the 2-morpholinone hydrochloride are added to 400mL of dichloromethane as a solvent, then 103mL (1.5mol) of triethylamine is slowly added dropwise with stirring at room temperature, the mixture is stirred for 1h, after the reaction is finished, the mixture is concentrated to dryness, and the residue is extracted with 800mL of methyl tert-butyl ether. Concentrating to dryness to obtain 2-morpholone (44g) as light yellow oil with yield of 89%; the total yield based on glyoxylic acid was 52%.
The N-Boc-2-morpholinone and 2-morpholinone hydrochloride prepared in example 2 were subjected to nuclear magnetic resonance testing, and the results are shown in FIGS. 1 and 2.
Example 3
The preparation method of the 2-morpholinone salt of the embodiment includes the following steps:
1) adding 2000mL of water, 149g (2mol) of glyoxylic acid, 147g (2.4mol) of ethanolamine and 8g of palladium-carbon composite material into a single-mouth bottle with a stirrer, wherein the mass fraction of palladium in the palladium-carbon composite material is 10%; stirring and mixing uniformly, heating to 40 ℃, carrying out normal-pressure hydrogenation reduction reaction for 12 hours, and cooling to room temperature after the reaction is finished; filtering, wherein filter residue is a palladium-carbon composite material, concentrating the filtrate to dryness, and then recrystallizing with ethanol to obtain N- (2-hydroxyethyl) glycine (227 g); the yield thereof was found to be 96%.
2) 1000mL of dioxane, 500mL of purified water, 80g (2mol) of sodium hydroxide and 238g (2mol) of N- (2-hydroxyethyl) glycine prepared in the step 1) are added into a three-necked flask with a mechanical stirrer, the mixture is stirred for 0.5h, 643g (2.4mol) of di-tert-butyl dicarbonate is slowly added into the mixture under stirring, the mixture is stirred and reacted for 4h at room temperature, the pH of the system is adjusted to 3 by saturated potassium hydrogen sulfate solution after the reaction is finished, the mixture is extracted and separated by ethyl acetate for 3 times, organic phases are combined, the mixture is sequentially washed by saturated saline and purified water, and the organic phase is concentrated to dryness to obtain N-Boc-N- (2-hydroxyethyl) glycine (435g) with the yield of 93%.
3) 2000mL of benzene, 17.5g (0.1mol) of p-toluenesulfonic acid and 233g (1mol) of N-Boc-N- (2-hydroxyethyl) glycine prepared in the step 2) are added into a three-necked bottle with a stirrer, after the addition is finished, the temperature is raised to 80 ℃, reflux reaction with water is carried out for 6 hours, after the reaction is finished, an organic phase is cooled to room temperature, the organic phase is sequentially washed with a saturated sodium bicarbonate solution, a saturated saline solution and purified water, the organic phase is concentrated to dryness to obtain a crude product of N-Boc-2-morpholinone (180g), and after N-hexane is recrystallized, 150g of N-Boc-2-morpholinone is obtained, wherein the yield is 75%.
4) Dissolving 100g (0.5mol) of the N-Boc-2-morpholinone in 600mL of dichloromethane, introducing hydrogen chloride until the N-Boc-2-morpholinone completely reacts to generate a large amount of white solid, concentrating the reaction liquid to 1/3 of the original volume, adding methyl tert-butyl ether to completely separate out the solid, and filtering the solid to obtain 2-morpholinone hydrochloride (64 g); the yield is 94%; the total yield based on glyoxylic acid was 62%.
The 2-morpholinone salt prepared by the above method is an example of the 2-morpholinone salt of this example.
The preparation method of 2-morpholone of the embodiment comprises the following steps:
68g (0.5mol) of the 2-morpholinone hydrochloride are added to 400mL of dichloromethane as a solvent, then 103mL (1.5mol) of triethylamine is slowly added dropwise with stirring at room temperature, the mixture is stirred for 1h, after the reaction is finished, the mixture is concentrated to dryness, and the residue is extracted with 800mL of methyl tert-butyl ether. Concentrating to dryness to obtain 2-morpholone (44g) as light yellow oil with yield of 89%; the total yield based on glyoxylic acid was 55%.
Example 4
The preparation method of the 2-morpholinone salt of the embodiment includes the following steps:
1) adding 2000mL of water, 149g (2mol) of glyoxylic acid, 122g (2mol) of ethanolamine and 8g of palladium-carbon composite material into a single-mouth bottle with a stirrer, wherein the mass fraction of palladium in the palladium-carbon composite material is 10%; stirring and mixing uniformly, heating to 50 ℃, carrying out normal pressure hydrogenation reduction reaction for 20h, and cooling to room temperature after the reaction is finished; filtering, wherein filter residue is a palladium-carbon composite material, concentrating the filtrate to dryness, and then recrystallizing with ethanol to obtain N- (2-hydroxyethyl) glycine (230 g); the yield thereof was found to be 97%.
2) 1000mL of dioxane, 500mL of purified water, 212g (2mol) of sodium carbonate and 238g (2mol) of N- (2-hydroxyethyl) glycine prepared in the step 1) are added into a three-necked flask with a mechanical stirrer, the mixture is stirred for 0.5h, 536g (2mol) of di-tert-butyl dicarbonate is slowly added into the mixture under stirring, then the mixture is stirred and reacted for 4h at room temperature, the pH of the system is adjusted to 3 by saturated potassium hydrogen sulfate solution after the reaction is finished, then the mixture is extracted and separated by ethyl acetate for 3 times, organic phases are combined, the organic phases are sequentially washed by saturated saline and purified water, and the organic phase is concentrated to dryness to obtain N-Boc-N- (2-hydroxyethyl) glycine (430g), and the yield is 92%.
3) Adding 2000mL of anhydrous toluene, 8.6g (0.05mol) of p-toluenesulfonic acid and 233g (1mol) of N-Boc-N- (2-hydroxyethyl) glycine prepared in the step 2) into a three-necked bottle with a stirrer, heating to 120 ℃ after the addition is finished, carrying out reflux water-carrying reaction for 4 hours, cooling an organic phase to room temperature after the reaction is finished, washing with a saturated sodium bicarbonate solution, a saturated saline solution and purified water in sequence, concentrating the organic phase to dryness to obtain a crude product of N-Boc-2-morpholinone (196g), and recrystallizing N-hexane to obtain 152g of N-Boc-2-morpholinone with the yield of 76%;
4) dissolving 100g (0.5mol) of the N-Boc-2-morpholinone in 600mL of dichloromethane, introducing hydrogen chloride until the N-Boc-2-morpholinone completely reacts to generate a large amount of white solid, concentrating the reaction liquid to 1/3 of the original volume, adding methyl tert-butyl ether to completely separate out the solid, and filtering the solid to obtain 2-morpholinone hydrochloride (64 g); the yield is 94%; the total yield based on glyoxylic acid was 64 percent.
The 2-morpholinone salt prepared by the above method is an example of the 2-morpholinone salt of this example.
The preparation method of 2-morpholone of the embodiment comprises the following steps:
68g (0.5mol) of the 2-morpholinone hydrochloride is added into 400mL of solvent dichloromethane, then 160mL of sodium carbonate solution (the concentration of sodium carbonate is 1.6mol/L or saturated sodium carbonate solution) is slowly added dropwise at room temperature under stirring, the stirring is carried out for 1h, after the reaction is finished, the concentration is carried out till the reaction is dry, the residue is extracted by methyl tert-butyl ether, and the dosage of the methyl tert-butyl ether is 800 mL. Concentrating to dryness to obtain 2-morpholone (41g) as light yellow oil with yield of 82%; the total yield based on glyoxylic acid was 52%.
Example 5
The preparation method of the 2-morpholinone salt of the embodiment includes the following steps:
1) adding 2000mL of ethanol, 149g (2mol) of glyoxylic acid, 122g (2mol) of ethanolamine and 8g of palladium-carbon composite material into a single-mouth bottle with a stirrer, wherein the mass fraction of palladium in the palladium-carbon composite material is 10%; stirring and mixing uniformly, heating to 30 ℃, carrying out normal pressure hydrogenation reduction reaction for 12h, and cooling to room temperature after the reaction is finished; filtering, wherein filter residues are palladium-carbon composite materials, and filtering to obtain N- (2-hydroxyethyl) glycine (210g) when filtrate is concentrated to 300 mL; the yield thereof was found to be 88%.
2) 1500mL of tetrahydrofuran, 205g (2mol) of triethylamine and 238g (2mol) of N- (2-hydroxyethyl) glycine prepared in the step 1) are added into a three-necked flask with a mechanical stirrer at room temperature, the mixture is stirred for 0.5h, 340g (2mol) of benzyl chloroformate is slowly added dropwise, the mixture is reacted for 6h at room temperature, the pH of the system is adjusted to 3 by concentrated hydrochloric acid after the reaction is finished, the mixture is concentrated to 1/3 of the original volume, extracted and separated by ethyl acetate for 3 times, organic phases are combined and washed by saturated saline, the organic phase is concentrated to dryness, and N-Cbz-N- (2-hydroxyethyl) glycine (415g) is obtained, wherein the yield is 83%.
3) Adding 2000mL of anhydrous toluene, 10g (0.1mol) of concentrated sulfuric acid and 253g (1mol) of N-Cbz-N- (2-hydroxyethyl) glycine prepared in the step 2) into a three-neck flask with a stirrer, heating to 80 ℃ after the addition is finished, reacting for 6 hours, cooling an organic phase to room temperature after the reaction is finished, washing the organic phase with saturated sodium bicarbonate solution, saturated saline solution and purified water in sequence, and concentrating the organic phase to dryness to obtain N-Cbz-2-morpholinone (175g), wherein the yield is 75%;
4) 191g (0.81mol) of N-Cbz-2-morpholinone were dissolved in 1000mL of CH-containing solution3Ethanol solution of COOH, CH in ethanol solution3The mass fraction of COOH is 10%, then 10g of palladium-carbon (the mass fraction of palladium in the palladium-carbon composite material is 10%) composite material is added into the COOH, the catalytic hydrogenation reaction is completed under the conditions of 1 atmosphere and 40 ℃, then the mixture is cooled to room temperature and filtered, the filter residue is the palladium-carbon composite material, and the filtrate is concentrated (the solvent is evaporated under reduced pressure) to be dry, so that 117g of white solid 2-morpholone acetate is obtained; the yield is 90%; the total yield based on the glyoxylic acid is 54 percent;
the 2-morpholinone salt prepared by the above method is an example of the 2-morpholinone salt of this example.
The preparation method of 2-morpholone of the embodiment comprises the following steps:
adding 64g (0.4mol) of the 2-morpholinone salt into 400mL of solvent dichloromethane, slowly dropwise adding 76mL (0.44mol) of diisopropylethylamine at room temperature, stirring for 1h, concentrating to dryness after the reaction is finished, extracting the residue with methyl tert-butyl ether, wherein the dosage of the methyl tert-butyl ether is 800 mL; concentration to dryness gave 37g of 2-morpholinone as a pale yellow oil in 92% yield.
Claims (10)
1. A preparation method of 2-morpholone salt is characterized by comprising the following steps:
1) heating N- (2-hydroxyethyl) glycine with amino protecting group and catalyst in a reflux solvent for reflux reaction to prepare 2-morpholinone with amino protecting group; the catalyst is p-toluenesulfonic acid or concentrated sulfuric acid; the reflux solvent is one or more of benzene, toluene and xylene; the temperature of heating reflux is 80-140 ℃; the mol ratio of the N- (2-hydroxyethyl) glycine with the amino protecting group to the catalyst is 1: 0.01-0.1;
2) acidifying the 2-morpholinone with the amino protecting group to remove the protecting group to obtain the 2-morpholinone salt.
2. The method of claim 1, wherein the step of removing the protecting group by acidification of the 2-morpholinone having an amino-protecting group in step 2) comprises the steps of: mixing the 2-morpholone with the amino protecting group with an acid solution to carry out catalytic hydrogenation reduction reaction.
3. The method according to claim 2, wherein the acid solution comprises an acidic substance and a solvent, and the acidic substance is HCl or CF3COOH、HCOOH、CH3One of COOH; the solvent is any one or combination of several of dichloromethane, methanol, ethanol and 1, 4-dioxane.
4. The method of claim 1, wherein the step of removing the protecting group by acidification of the 2-morpholinone having an amino-protecting group in step 2) comprises the steps of: reacting 2-morpholone with amino protecting group with hydrogen chloride or trifluoroacetic acid in solvent.
5. The method for preparing 2-morpholinone salt according to any one of claims 1 to 4, wherein the method for preparing N- (2-hydroxyethyl) glycine having an amino-protecting group comprises the steps of: mixing N- (2-hydroxyethyl) glycine, an amino protective agent and alkali in a solvent for reaction to prepare the N- (2-hydroxyethyl) glycine with an amino protective group.
6. The method according to claim 5, wherein the amino protecting agent is tert-butyl dicarbonate, benzyl bromide, triphenylchloromethane, or benzyl chloroformate.
7. The preparation method of 2-morpholone is characterized by comprising the following steps:
1) heating N- (2-hydroxyethyl) glycine with amino protecting group and catalyst in a reflux solvent for reflux reaction to prepare 2-morpholinone with amino protecting group; the catalyst is p-toluenesulfonic acid or concentrated sulfuric acid; the reflux solvent is one or more of benzene, toluene and xylene; the temperature of heating reflux is 80-140 ℃; the mol ratio of the N- (2-hydroxyethyl) glycine with the amino protecting group to the catalyst is 1: 0.01-0.1;
2) acidifying the 2-morpholinone with the amino protecting group to remove the protecting group to obtain 2-morpholinone salt;
3) then reacting the 2-morpholinone salt with alkali in a solvent to obtain the compound.
8. The method according to claim 7, wherein the step of reacting the 2-morpholinone salt with the base in the solvent in the step 3) comprises mixing the 2-morpholinone salt with the solvent, and adding the base.
9. The method for producing 2-morpholinone according to claim 8, wherein the base is an organic base or an inorganic base solution; the organic base is one or two of triethylamine and diisopropylethylamine; the inorganic alkali solution comprises inorganic alkali and water, and the inorganic alkali is any one or two of potassium carbonate and sodium carbonate.
10. The method according to claim 7, wherein the molar ratio of the 2-morpholinone salt to the base is from 1:2 to 5.
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| US5206157A (en) * | 1988-09-28 | 1993-04-27 | Texaco Inc. | Preparation of N-substituted-2-morpholone |
| CN102260224A (en) * | 2011-06-14 | 2011-11-30 | 南京信息工程大学 | Method for synthesizing 2-morpholone derivatives |
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| US5206157A (en) * | 1988-09-28 | 1993-04-27 | Texaco Inc. | Preparation of N-substituted-2-morpholone |
| CN102260224A (en) * | 2011-06-14 | 2011-11-30 | 南京信息工程大学 | Method for synthesizing 2-morpholone derivatives |
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| Crystallization-induced dynamic resolution (CIDR) and its application to the synthesis of unnatural N-substituted amino acids derived from aroylacrylic acids;Andrej Kolarovic等;《Tetrahedron Letters》;20011231;第2580页图3，第2581页左栏 * |
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