CN112300012A - Method for preparing 2-methoxy ethylamine hydrochloride - Google Patents
Method for preparing 2-methoxy ethylamine hydrochloride Download PDFInfo
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- CN112300012A CN112300012A CN201910687428.0A CN201910687428A CN112300012A CN 112300012 A CN112300012 A CN 112300012A CN 201910687428 A CN201910687428 A CN 201910687428A CN 112300012 A CN112300012 A CN 112300012A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
- C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
- C07D291/04—Five-membered rings
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Abstract
A method for preparing 2-methoxy ethylamine comprises the steps of taking N-Boc-ethanolamine as a raw material, carrying out a ring closing reaction to generate 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide, oxidizing, then preparing 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide, carrying out a ring opening reaction with methanol to obtain N-Boc-2-methoxy ethylamine, and removing a Boc protective group to obtain 2-methoxy ethylamine hydrochloride. The method avoids the use of a highly toxic methylating agent, simultaneously completely avoids the generation of N-methylated impurities, is convenient for the quality control of the raw material medicaments, is environment-friendly, has mild reaction conditions and simple and convenient operation, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of 2-methoxyethylamine hydrochloride.
Background
As an important organic chemical raw material, the organic aliphatic amine has wide application and huge market demand. The organic fatty amine can be used for synthesizing various organic or fine chemical products or intermediates such as pesticides, medicines, rubber auxiliaries, dyes and pigments, synthetic resins, photosensitive materials and the like, and is frequently used in the fields of daily chemicals, petrochemical industry and the like. 2-methoxy ethylamine is an important organic chemical raw material and is widely used for synthesizing medicine and pesticide intermediates. The document reports that 2-methoxyethylamine is used as a ligand to synthesize the platinum (II) complex for synthesizing the anti-tumor, cancer and other medicines. There are also literature reports on the synthesis of potassium ion modulators and polymerase inhibitors as potential small molecules for cancer treatment drugs.
The industrial production of 2-methoxy ethylamine is carried out by dehydrating ethylene glycol monomethyl ether and ammonia under nickel or alumina catalysis at high temperature. Also useful is the nickel-catalyzed hydrogenation of methoxyacetonitrile. However, the yield of the existing method is very low (17%); the reaction conditions are harsh, the reaction is usually carried out at high temperature (200-; the three wastes are more. Other synthetic methods reported in the literature are mainly prepared by using the Gabriel reaction in combination with the Mitsunobu reaction. However, the method has low atom economic efficiency, and the generated phthalic acid or the salt thereof causes a large amount of waste residues and great pressure on the environment. The literature reports that synthetic methods using ethanolamine as the starting material generally require the use of highly toxic methylating agents, such as: methyl iodide, dimethyl sulfate, etc., and thus is difficult to apply to industrial production. Therefore, the search and exploration of a synthetic method which is suitable for industrial production, avoids the use of high-toxicity, high-temperature and high-pressure reaction conditions, is simple to operate and has higher comprehensive efficiency are the technical problems to be solved in the field at present.
Disclosure of Invention
One object of the present invention is to provide a process for the preparation of 2-methoxyethylamine avoiding the use of common highly toxic methylating agents, such as: methyl iodide, dimethyl sulfate and the like, and is safe and environment-friendly in operation environment.
The invention also aims to provide a method for preparing 2-methoxyethylamine, which avoids the generation of N-methylated impurities, facilitates the quality control of raw material medicaments and improves the purity of the obtained product.
It is a further object of the present invention to provide a process for the preparation of 2-methoxyethylamine that increases the yield of the product and allows for the low-cost and high-efficiency manufacture of 2-methoxyethylamine.
The invention also aims to provide a method for preparing 2-methoxyethylamine, which is more suitable for synthesizing 2-methoxyethylamine by an industrial production process route.
A method for preparing 2-methoxy ethylamine comprises the steps of taking N-Boc-ethanolamine as a raw material, carrying out a ring closing reaction to generate 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide, oxidizing, then preparing 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide, carrying out a ring opening reaction with methanol to obtain N-Boc-2-methoxy ethylamine, and removing a Boc protective group to obtain 2-methoxy ethylamine hydrochloride.
A process for the preparation of 2-methoxyethylamine, comprising the steps of:
mixing N-Boc-ethanolamine with thionyl chloride, a first organic base and a first solvent, and carrying out a ring closure reaction to obtain 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide;
then, mixing the prepared 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide, sodium periodate, ruthenium trichloride trihydrate and a second solvent, and carrying out oxidation reaction to obtain 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide;
then, the prepared 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide is mixed with absolute methanol and a second organic base, and ring-opening reaction is carried out at the temperature of 0-60 ℃ for 10-30 hours to obtain N-Boc-2-methoxyethylamine. Anhydrous methanol as both ring-opening reagent and reaction solvent, the volume usage (ml) of the anhydrous methanol is compared with the weight (g) of 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide, such as: but not limited to (5-20) to 1; preferably (8-12) to 1.
And finally, carrying out deprotection reaction on the prepared N-Boc-2-methoxyethylamine to obtain 2-methoxyethylamine hydrochloride.
In the method, in the ring closing reaction, the first organic base and thionyl chloride react at the temperature of-10 ℃ to 30 ℃ for 1 hour to 3 hours. The temperature of the N-Boc-ethanolamine solution is minus 30 ℃ to 10 ℃ and the time is 1 hour to 3 hours. After the dropwise addition is finished, the reaction solution is continuously stirred and reacts for 2 to 8 hours, more preferably for 3 hours at the temperature of minus 30 to 10 ℃; the reaction is stirred at 10 ℃ to 15 ℃ for 1 hour to 5 hours, more preferably 2 hours. Adding water to quench the ring closing reaction, after quenching is finished, washing an organic phase obtained by liquid separation with a citric acid aqueous solution and water, and directly using the organic solution obtained by liquid separation for the next oxidation reaction.
First organic bases such as: but are not limited to, imidazole, N-methylimidazole, pyridine, triethylamine, diisopropylethylamine, etc., which are used alone or in combination in the present invention.
The first solvent is as follows: but are not limited to, dichloromethane, 1, 2-dichloroethane, chloroform, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and the like, alone or in combination, with dichloromethane being preferred for use in the present invention.
According to the method, the molar ratio of the N-Boc-ethanolamine to the thionyl chloride to the first organic base is 1: 1.0-5.0: 1.0-10.0, and 1: 1.0-3.0: 2.0-8.0 is preferably selected, especially 1: 1.0-2.0: 3.0-5.0. The mass ratio of the N-Boc-ethanolamine to the first solvent is 1: 10-70, preferably 1: 10-30, and particularly 1: 15-20.
In the oxidation reaction, the method of the invention preferably performs the stirring reaction at 0-50 ℃ for 10-30 hours, preferably 10-30 ℃ for 10-20 hours, and especially 16-18 hours at 15-25 ℃. The molar ratio of the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide to the sodium periodate and ruthenium trichloride trihydrate is preferably 1: 1.0-5.0: 0.002-0.02, preferably 1: 1.0-3.0: 0.004-0.01, particularly 1: 1.5-2.0: 0.005-0.008.
After the oxidation reaction is finished, standing and layering the reaction solution, washing an organic phase obtained by liquid separation with a citric acid aqueous solution and water, mixing the organic solution obtained by liquid separation with activated carbon, and stirring for 1-8 hours, particularly 2-3 hours. Filtering, concentrating, pulping and purifying by using a mixed solvent of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is preferably (3-10) to 1, particularly (4-6) to 1, and the high-purity (more than 95.0%) dioxide is obtained.
The second solvent is as follows: but are not limited to, dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran and 2-methyltetrahydrofuran, alone or in combination, with dichloromethane being preferred for use in the present invention.
In the ring-opening reaction, the reaction is carried out for 10 to 30 hours under stirring at 0 to 60 ℃, more preferably for 10 to 20 hours under stirring at 20 to 40 ℃, particularly for 16 to 18 hours under stirring at 30 to 35 ℃, and the molar ratio of the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide to the second organic base is preferably 1: 0.5 to 3.0, preferably 1: 0.8 to 2.0, particularly 1: 1.0 to 1.4. Second organic bases such as: but are not limited to, 2, 6-lutidine, 1, 8-diazacyclo [5, 4, 0] undecene-7 (DBU), and the like, which are used in the present invention either singly or in combination.
After the ring-opening reaction is finished, concentrating the obtained product system, and adding water and methyl tert-butyl ether into the residue obtained by concentration for extraction. After extraction, the organic phase is washed with citric acid and saturated brine, and the separated organic phase is concentrated under reduced pressure to obtain a crude product.
In the deprotection reaction, the reaction temperature is as follows: 10-60 ℃ for 1-10 hours. And mixing the N-Boc-2-methoxyethylamine with an organic solution containing hydrogen chloride gas and a third solvent, and removing the Boc group. After the deprotection reaction is finished, the reaction solution is decompressed and concentrated or the solid is directly filtered to obtain the 2-methoxy ethylamine hydrochloride.
The organic solution containing hydrogen chloride gas is prepared by dissolving hydrogen chloride gas in organic solvent such as: but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and the like, alone or in combination, are useful in the present invention.
The third solvent is as follows: but are not limited to, methylene chloride, 1, 2-dichloroethane, methyl t-butyl ether, ethyl acetate, isopropyl acetate, and the like, which are used alone or in combination in the present invention.
The method provided by the invention has few reaction steps, avoids the generation of N-methylated impurities, does not need additional purification steps, has the product purity of more than 99.0 percent and the total yield of 40.0 to 70.0 percent, and is convenient for the quality control of the raw material medicines.
The method provided by the invention avoids the use of a highly toxic methylating agent, is environment-friendly, mild in reaction condition and simple and convenient to operate, and is suitable for industrial production.
Detailed Description
The technical solution of the present invention is described in detail below. Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention as defined in the appended claims.
In order to obtain better test effects, for example: the product purity is more than 99.0 percent, the total yield is 40.0 to 70.0 percent, the quality control of raw materials and the like is convenient, the following implementation modes of the invention all follow the following method to prepare the 2-methoxy ethylamine, and the steps comprise:
mixing N-Boc-ethanolamine with thionyl chloride, a first organic base and a first solvent, and carrying out a ring closure reaction to obtain 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide; the molar ratio of the N-Boc-ethanolamine to the thionyl chloride to the first organic base is 1: 1.0-5.0: 1.0-10.0, preferably 1: 1.0-3.0: 2.0-8.0, and especially 1: 1.0-2.0: 3.0-5.0. The mass ratio of the N-Boc-ethanolamine to the first solvent is 1: 10-70, preferably 1: 10-30, and particularly 1: 15-20.
In the ring closing reaction, the first organic alkali and thionyl chloride react at the temperature of-10 ℃ to 30 ℃ for 1 hour to 3 hours. The temperature of the N-Boc-ethanolamine solution is minus 30 ℃ to 10 ℃ and the time is 1 hour to 3 hours. After the dropwise addition is finished, the reaction solution is continuously stirred and reacts for 2 to 8 hours, more preferably for 3 hours at the temperature of minus 30 to 10 ℃; the reaction is stirred at 10 ℃ to 15 ℃ for 1 hour to 5 hours, more preferably 2 hours.
Then mixing the prepared 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide with sodium periodate, ruthenium trichloride trihydrate and a second solvent, wherein the molar ratio of the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide to the sodium periodate to the ruthenium trichloride trihydrate is preferably 1: 1.0-5.0: 0.002-0.02, preferably 1: 1.0-3.0: 0.004-0.01, especially 1: 1.5-2.0: 0: 0.005-0.008, stirring and reacting at 0-50 ℃ for 10-30 hours, preferably 10-30 ℃ for 10-20 hours, especially at 15-25 ℃ for 16-18 hours, and carrying out oxidation reaction to obtain 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide.
After the oxidation reaction is finished, standing and layering the reaction solution, washing an organic phase obtained by liquid separation with a citric acid aqueous solution and water, mixing the organic solution obtained by liquid separation with activated carbon, and stirring for 1-8 hours, particularly 2-3 hours. Filtering, concentrating, pulping and purifying by using a mixed solvent of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is preferably (3-10) to 1, particularly (4-6) to 1, and the high-purity (more than 95.0%) dioxide is obtained.
Then, the prepared 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide is mixed with absolute methanol and a second organic base, and ring-opening reaction is carried out at the temperature of 0-60 ℃ for 10-30 hours to obtain N-Boc-2-methoxyethylamine. Anhydrous methanol as both ring-opening reagent and reaction solvent, the volume usage (ml) of the anhydrous methanol is compared with the weight (g) of 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide, such as: but not limited to (5-20) to 1; preferentially selecting (8-12) to 1; the molar ratio of the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide to the second organic base is preferably 1: 0.5-3.0, preferably 1: 0.8-2.0, especially 1: 1.0-1.4.
In the ring-opening reaction, the stirring reaction is preferably carried out for 10 to 20 hours at a temperature of between 20 and 40 ℃, and particularly for 16 to 18 hours at a temperature of between 30 and 35 ℃.
And finally, carrying out deprotection reaction on the prepared N-Boc-2-methoxyethylamine to obtain 2-methoxyethylamine hydrochloride.
Example 1
250mL of methylene chloride and 12.7g of imidazole were added to the reaction flask under nitrogen. Cooling to 0 ℃ under stirring, dripping 3.7g of thionyl chloride, stirring and reacting for 1 hour at 0 ℃ after dripping, and then heating to 10-15 ℃ for reacting for 1 hour. Cooling the reaction liquid to-15 to-10 ℃, dropwise adding a solution of 5.0g of N-Boc-ethanolamine dissolved in 10mL of dichloromethane, stirring at 0 ℃ for reaction for 3 hours after dropwise adding, and then heating to 10-15 ℃ for reaction for 2 hours. 50mL of water was added dropwise to the reaction mixture, and the mixture was stirred for 30 min. After allowing to stand and separating the phases, the organic phase was washed once with 20mL of 5% wt aqueous citric acid solution and once with 30mL of water to give a dichloromethane solution containing 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide.
The resulting dichloromethane solution containing 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide was transferred to a reaction flask, and water and sodium periodate were added. Controlling the temperature of the reaction solution at 15-25 ℃, and adding the ruthenium trichloride trihydrate, 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide, sodium periodate and ruthenium trichloride trihydrate in a molar ratio of 1: 1.5-2.0: 0.005-0.008. Stirring and reacting for 16-18 hours at the temperature of 15-25 ℃. Sampling, and after TLC shows that the reaction is complete, filtering the reaction solution by using a Buchner funnel, standing the filtrate, and separating the liquid. The organic phase was washed once with 50mL of 5% wt aqueous citric acid and once with 30mL of water. Standing and separating the liquid. 1.0g of activated carbon was added to the organic phase and stirred for 2 to 3 hours. Filtering with a Buchner funnel, filling a layer of diatomite, and concentrating the filtered mother liquor under reduced pressure to dryness. The solid was completely precipitated by distillation with 10ml of petroleum ether. Adding ethyl acetate and petroleum ether into the concentrated residue, wherein the volume ratio of the petroleum ether to the ethyl acetate is 5: 1, and stirring and pulping for 1-2 hours. Filtering the mixture by using a Buchner funnel, and drying the filter cake for 18 hours under vacuum to obtain the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide which is white solid with the yield of 70.5 to 77.3 percent.
GC-MS calcd for C7H13NO5S(M+H)+224.0，found 224.0。
1H NMR(500MHz，CDCl3-d)δ4.61(t，J＝6.4Hz，2H)，4.05(t，J＝6.5Hz，2H)，1.56(s， 9H)。
Example 2
Dichloromethane and pyridine were added to the reaction flask under nitrogen. Cooling to 0 ℃ under stirring, dripping thionyl chloride, stirring and reacting for 1 hour at 0 ℃, and then heating to 10-15 ℃ for reacting for 1 hour. Cooling the reaction liquid to-15 to-10 ℃, dropwise adding a solution of N-Boc-ethanolamine dissolved in dichloromethane, wherein the molar ratio of the N-Boc-ethanolamine to thionyl chloride to the first organic base is 1: 1.0 to 5.0: 1.0 to 10.0, stirring and reacting for 3 hours at 0 ℃, and then heating to 10 to 15 ℃ for reacting for 2 hours. 50mL of water was added dropwise to the reaction mixture, and the mixture was stirred for 30 min. After the mixture was allowed to stand and separated, the organic phase was washed once with 20mL of a 5% wt aqueous citric acid solution and once with 30mL of water to obtain a dichloromethane solution containing 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide.
The resulting dichloromethane solution containing 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide was transferred to a reaction flask, and water and sodium periodate were added. Controlling the temperature of the reaction solution at 15-25 ℃, and adding the ruthenium trichloride trihydrate, 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide, sodium periodate and ruthenium trichloride trihydrate in a molar ratio of 1: 1.5-2.0: 0.005-0.008. Stirring and reacting for 16-18 hours at the temperature of 15-25 ℃. Sampling, and after TLC shows that the reaction is complete, filtering the reaction solution by using a Buchner funnel, standing the filtrate, and separating the liquid. The organic phase was washed once with 50mL of 5% wt aqueous citric acid and once with 30mL of water. Standing and separating the liquid. Adding 1.0g of activated carbon into the organic phase, and stirring for 2-3 hours. Filtering with a Buchner funnel, filling a layer of diatomite, and concentrating the filtered mother liquor under reduced pressure to dryness. The solid was completely precipitated by distillation with 10ml of petroleum ether. Adding ethyl acetate and petroleum ether into the concentrated residue, wherein the volume ratio of the petroleum ether to the ethyl acetate is (4-6) to 1, and stirring and pulping for 1-2 hours. Filtering the mixture by using a Buchner funnel, and drying a filter cake for 18 hours under vacuum to obtain 3.81g of 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide which is white solid, wherein the yield is 53.6 to 60.8 percent.
Example 3
To a 10L reaction flask were added 4.5L of methylene chloride and 422g of imidazole. After nitrogen replacement three times, the temperature was reduced to 0 ℃ and 222g of SOCl was added dropwise2Stirring for 1 hour, heating to 10-15 ℃, and continuing stirring for 1 hour. Cooling the system to-15-10 ℃, and dropwise adding N-Boc ethanolamine 250g of 500ml dichloromethane solution. After stirring and reacting for 3 hours, heating to 10-15 ℃, and continuing stirring and reacting for 2 hours. 2.5L of water was added dropwise to the reaction system, and the aqueous phase was separated after stirring for 30 minutes. The organic phase was washed once with 500ml of a 5% wt aqueous citric acid solution and once with 1.25L of water to give a dichloromethane solution containing 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide.
530g of sodium periodate was added to 2.5L of water, and a prepared methylene chloride solution containing tert-butyl 1, 2, 3-oxathiazolidine-3-carboxylate-2-oxide was added. The temperature of the system is controlled between 15 ℃ and 25 ℃, 3.0g of ruthenium trichloride trihydrate is added, and the system is stirred for 16 hours to 18 hours at the temperature of between 15 ℃ and 25 ℃. Sampling and TLC showing that insoluble matters are removed by filtration after the reaction is finished. The aqueous phase was separated off by settling. The organic phase is washed once with 2.5L of 5% wt aqueous citric acid and once with 1.25L brine. 50g of activated carbon was added to the organic phase and stirred for 2 to 3 hours. Filtering to remove active carbon, filtering mother liquor, and concentrating under reduced pressure to dry. The solid was brought to complete precipitation by 500ml of petroleum ether. Adding ethyl acetate and petroleum ether into the residue, wherein the volume ratio of the petroleum ether to the ethyl acetate is (3-10): 1, and stirring and pulping for 1-2 hours. And (3) performing vacuum drying on the filter cake for 18 hours by using a Buchner funnel to obtain the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide which is a white solid, wherein the product yield is 72-75%.
Example 4
Anhydrous methanol and 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide are added into a reaction bottle, and the volume usage (ml) of the anhydrous methanol and the weight (g) of the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide are (5-20) to 1. Adding 2, 6-lutidine, 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide and a second organic base in a molar ratio of 1: 0.5-3.0 under stirring. Heating the reaction liquid to 30-35 ℃, and stirring for 16-18 hours. Sampling, and after the reaction is completely detected by GC, carrying out reduced pressure concentration on the reaction solution at the temperature of 35-45 ℃ to remove methanol. To the concentrate was added 10mL of water and 20mL of methyl t-butyl ether. Stirring to dissolve, standing, and separating. The organic phase is separated off and the aqueous phase is extracted once more with 20mL of methyl tert-butyl ether. The organic phases were combined and 100mg of citric acid and 10mL of saturated brine were added. Stirring to dissolve, standing, and separating. The organic phase was washed once more with 10mL of saturated brine. The organic phase is decompressed and concentrated to be dry, the obtained N-Boc-2-methoxy ethylamine is colorless oily matter, the product yield is 80.4-85.7 percent and 82.9 percent, and the product has gas phase purity of more than 99.0 percent.
GC-MS calcd for C8H17NO3(M+H)+176.0，found 176.0。
1H NMR(500MHz，Chloroform-d)δ4.88(s，1H)，3.44(t，J＝5.1Hz，2H)，3.35(s，3H)，3.31 (q，J＝5.5Hz，2H)，1.45(s，9H)。
Example 5
To a reaction flask were added 100mL of anhydrous methanol and 10g of 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide. 5.76g of 2, 6-lutidine was added under stirring. Heating the reaction solution to 30-35 ℃, and stirring for 18 hours. Sampling, and after the reaction is completely detected by GC, carrying out reduced pressure concentration on the reaction solution at the temperature of 35-45 ℃ to remove methanol. To the concentrate were added 50mL of water and 70mL of methyl tert-butyl ether. Stirring to dissolve, standing, and separating. The organic phase is separated off and the aqueous phase is extracted once more with 40mL of methyl tert-butyl ether. The organic phases were combined and 2g of citric acid and 50mL of saturated brine were added. Stirring to dissolve, standing, and separating. The organic phase was washed once more with 50mL of saturated brine. The organic phase was concentrated to dryness under reduced pressure to give 6.62g of N-Boc-2-methoxyethylamine as a colorless oil, 84.3% product yield, and 99.2% product purity in the gas phase.
Example 6
Anhydrous methanol and 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide are added into a 5.0L reaction bottle, and the volume ratio (ml) of the anhydrous methanol to the weight (g) of the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide is (8-12) to 1. Adding 2, 6-lutidine, 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide and a second organic base in a molar ratio of 1: 1.0-1.4 under stirring. Heating the reaction solution to 30-35 ℃, and stirring for reacting for 16 hours. Sampling, and after the reaction is completely detected by GC, carrying out reduced pressure concentration on the reaction solution at the temperature of 35-45 ℃ to remove methanol. To the concentrate was added 1.25L of water and 1.75L of methyl tert-butyl ether. Stirring to dissolve, standing, and separating. The organic phase was separated off and the aqueous phase was extracted once more with 1.0L of methyl tert-butyl ether. The organic phases were combined and 50g of citric acid and 1.25L of saturated brine were added. Stirring to dissolve, standing, and separating. The organic phase was washed once more with 1.0L of saturated brine. And concentrating the organic phase under reduced pressure until the organic phase is dried to obtain the N-Boc-2-methoxyethylamine as colorless oily matter, wherein the product yield is 86.0-91.0%, and the product has the gas phase purity of more than 99.0%.
Example 7
To a reaction flask were added 240mL of dichloromethane and 24g of N-Boc-2-methoxyethylamine under nitrogen. Controlling the temperature of the reaction solution to be 30-40 ℃, and dropwise adding 42.8g of 35% wt HCl ethanol solution. After the addition, the reaction was stirred for 3 hours. Sampling, detecting the reaction completion by GC, and concentrating the reaction solution at 35-40 ℃ under reduced pressure. 30mL of methyl tert-butyl ether was added and the mixture was distilled twice. 30mL of methyl t-butyl ether was added, and the mixture was stirred and slurried for 1.0 hour. The mixture is filtered under the protection of nitrogen, and a filter cake is dried to obtain 15g of 2-methoxyethylamine hydrochloride as a white solid with the yield of 93 percent.
GC-MS calcd for C3H9NO(M+H)+76.0，found 76.0。
1H NMR(500MHz，Chloroform-d)δ3.27-3.76(m，J＝5.0Hz，2H)，3.43(s，3H)，3.75 (t，J＝5.0Hz，2H)，8.11(s，3H)。
Example 8
Under nitrogen protection, 80mL of ethyl acetate and 24g of N-Boc-2-methoxyethylamine were added to the reaction flask. Controlling the temperature of the reaction solution to be 30-40 ℃, and dropwise adding 140mL of ethyl acetate solution of 4N hydrogen chloride gas. After the dropwise addition, the reaction was stirred for 3 hours, and a solid precipitated. Sampling, after GC detection reaction is completed, carrying out suction filtration under the protection of nitrogen, filtering and drying the cake to obtain 15g of 2-methoxyethylamine hydrochloride as a white solid, wherein the yield is 90%.
Claims (14)
1. A method for preparing 2-methoxyethylamine is characterized in that N-Boc-ethanolamine is used as a raw material, a cyclization reaction is carried out to generate 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide, the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide is obtained after oxidation and reproduction, the oxide is subjected to a ring-opening reaction with anhydrous methanol to obtain N-Boc-2-methoxyethylamine, a Boc protecting group is removed to obtain 2-methoxyethylamine hydrochloride, and the weight ratio of the volume usage of the anhydrous methanol to the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide is (5-20) to 1.
2. The method according to claim 1, wherein the N-Boc-ethanolamine is mixed with thionyl chloride, a first organic base and a first solvent to perform a ring closure reaction to obtain 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide, the first organic base and the thionyl chloride react at a temperature of-10 ℃ to 30 ℃ for 1 hour to 3 hours, the N-Boc-ethanolamine solution is dropwise added at a temperature of-30 ℃ to 10 ℃ for 1 hour to 3 hours, and after the dropwise addition is completed, the reaction solution is continuously stirred at a temperature of-30 ℃ to 10 ℃ for 2 hours to 8 hours.
3. The method according to claim 2, wherein the reaction solution is stirred at 10 ℃ to 15 ℃ for 1 hour to 5 hours after completion of the dropwise addition.
4. The method according to claim 1, wherein the N-Boc-ethanolamine is mixed with thionyl chloride, a first organic base and a first solvent to perform a ring-closing reaction, the molar ratio of the N-Boc-ethanolamine to the thionyl chloride to the first organic base is 1: 1.0-5.0: 1.0-10.0, and the mass ratio of the N-Boc-ethanolamine to the first solvent is 1: 10-70.
5. The method according to claim 1, wherein the oxidation reaction is carried out at 0 ℃ to 50 ℃ for 10 to 30 hours with stirring.
6. The method according to claim 1, wherein the oxidation reaction is carried out at 15 to 25 ℃ for 16 to 18 hours with stirring.
7. The method according to claim 1, wherein said 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide is mixed with sodium periodate, ruthenium trichloride trihydrate and a second solvent, and subjected to an oxidation reaction to obtain said 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide; the molar ratio of the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide to the sodium periodate and ruthenium trichloride trihydrate is 1: 1.0-5.0: 0.20-2.0%.
8. The method according to claim 1, wherein said 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide is mixed with sodium periodate, ruthenium trichloride trihydrate and a second solvent, and subjected to an oxidation reaction to obtain said 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide; the molar ratio of the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide to the sodium periodate and ruthenium trichloride trihydrate is 1: 1.5-2.0: 0.50-0.8%.
9. The method according to claim 7 or 8, wherein the second solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran and 2-methyltetrahydrofuran.
10. The method according to claim 1, wherein the ring-opening reaction is carried out at 0 ℃ to 60 ℃ for 10 to 30 hours with stirring.
11. The method according to claim 1, wherein the ring-opening reaction is carried out at 30 to 35 ℃ for 16 to 18 hours with stirring.
12. The method according to claim 1, wherein the ring-opening reaction of the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide, methanol and a second organic base is carried out to obtain N-Boc-2-methoxyethylamine, and the molar ratio of the 1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-dioxide to the second organic base is 1: 0.5-3.0.
13. The method according to claim 1, wherein the second organic base is selected from one or more of 2, 6-lutidine and DBU.
14. The method of claim 1, wherein the 2-methoxyethylamine hydrochloride is prepared without the formation of N-methylated impurities, without additional purification steps, with a product purity of > 99.0%, which facilitates quality control of the drug substance.
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