CN110698356A - Preparation and purification method of N-benzyl glycine ethyl ester - Google Patents
Preparation and purification method of N-benzyl glycine ethyl ester Download PDFInfo
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- CN110698356A CN110698356A CN201911080829.6A CN201911080829A CN110698356A CN 110698356 A CN110698356 A CN 110698356A CN 201911080829 A CN201911080829 A CN 201911080829A CN 110698356 A CN110698356 A CN 110698356A
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- C07—ORGANIC CHEMISTRY
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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Abstract
The invention provides a preparation and purification method of N-benzyl glycine ethyl ester, which comprises the following steps: preparation of ethyl N-benzylglycine hydrochloride: and (2) taking benzylamine and halogenated ethyl acetate in an organic solvent, stirring at room temperature for reaction, after the reaction is completely detected by HPLC, adding water, extracting, dropwise adding an organic mixed solution of hydrochloric acid into an organic layer, adjusting the pH value to 1-2, separating out a solid, filtering and drying. Adding water into the N-benzyl glycine ethyl ester hydrochloride, stirring and dissolving, adjusting the pH value to 7-8 by using alkali, adding an organic solvent for extraction, drying an organic layer by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure until the organic layer is dried to obtain the product N-benzyl glycine ethyl ester hydrochloride.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation and purification method of N-benzyl glycine ethyl ester.
Background
The N-benzyl glycine ethyl ester is an important intermediate of a novel hypnotic gaboxadol, and has a structural formula as follows:
the current synthesis method (ZL031320163) is: benzyl chloride and glycine ethyl ester react in the presence of a catalyst and an organic solvent, anhydrous sodium sulfate is added into a reaction system, the reaction temperature is 110-140 ℃, and the reaction lasts for 6-12 hours, so that the N-benzyl glycine ethyl ester is generated.
The disadvantages of this synthetic method are: the catalyst is needed in the reaction process, the high-purity product can be obtained only by a high-temperature rectification step after the product is generated, the distillation temperature is high, the requirement on equipment is high, and the cost is high.
Disclosure of Invention
The purpose of the invention is as follows: the invention provides a preparation and purification method of N-benzyl glycine ethyl ester.
The technical scheme is as follows:
a preparation and purification method of N-benzyl glycine ethyl ester comprises the following steps:
1. a preparation and purification method of N-benzyl glycine ethyl ester comprises the following steps:
(1) preparation of ethyl N-benzylglycine hydrochloride: benzylamine and halogenated ethyl acetate are taken to be in an organic solvent, stirring reaction is carried out at room temperature, after HPLC detection reaction is completed, water is added, extraction is carried out, organic mixed liquor of hydrochloric acid is dripped into an organic layer, the pH value is adjusted to be 1-2, solid is separated out, filtering and drying are carried out, N-benzyl glycine ethyl ester hydrochloride is obtained,
the reaction equation is:
(2) preparation of ethyl N-benzylglycine: adding water into the N-benzylglycine ethyl ester hydrochloride obtained in the step (1), stirring and dissolving, adjusting the pH value to 7-8 by using alkali, adding an organic solvent for extraction, drying an organic layer by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain the product N-benzylglycine ethyl ester hydrochloride.
A preparation and purification method of N-benzyl glycine ethyl ester comprises the step (1), wherein the molar ratio of benzylamine to halogenated ethyl butyrate is 1: 1-1.5.
A preparation and purification method of N-benzyl glycine ethyl ester, in step (1), the said organic solvent is selected from one of N, N-dimethylformamide, tetrahydrofuran, acetone; the organic mixed solution of hydrochloric acid is one selected from 30% hydrochloric acid ethanol, 30% hydrochloric acid methanol, 30% hydrochloric acid isopropanol and 30% hydrochloric acid acetone.
A preparation and purification method of N-benzyl glycine ethyl ester, in step (2), the said alkali is selected from one in sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; the organic solvent is selected from one of ethyl acetate and dichloromethane.
A preparation and purification method of N-benzyl glycine ethyl ester comprises the step (1), wherein the molar ratio of benzylamine to halogenated ethyl butyrate is 1: 1.
A preparation and purification method of N-benzyl glycine ethyl ester comprises the steps of (1), wherein an organic solvent is tetrahydrofuran; the organic mixed solution of hydrochloric acid is a 30% hydrochloric acid ethanol solution.
A preparation and purification method of N-benzyl glycine ethyl ester, in step (2), the alkali is sodium hydroxide; the organic solvent is ethyl acetate.
Has the advantages that: the method for preparing the N-benzyl glycine ethyl ester by condensing benzylamine serving as an initial raw material with halogenated ethyl acetate has the advantages of short route synthesis step, simple process operation, avoidance of a high-temperature rectification step, low requirement on equipment, low cost of used raw materials, high product yield and high purity, and is easy for industrial production.
Detailed Description
The foregoing aspects of the present invention are described in further detail below by way of examples, but it should not be construed that the scope of the subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above aspects of the present invention are within the scope of the present invention.
Example 1: preparation of N-benzylglycine ethyl ester
The method comprises the following steps:
(1) preparation of ethyl N-benzylglycinate hydrochloride
Adding 107g (1mol) of benzylamine into a 1L four-mouth reaction bottle, adding 122g (1mol) of ethyl chloroacetate, adding 200ml of tetrahydrofuran, reacting at room temperature for 4hr, adding water after HPLC (high performance liquid chromatography) detection to basically complete the reaction, extracting, dropwise adding an ethanol hydrochloric acid solution into an organic layer, adjusting the pH to 1-2, precipitating a solid, filtering and drying to obtain 207.1g of N-benzyl glycine ethyl ester hydrochloride, wherein the yield is 90.2%.
(2) Preparation of N-benzylglycine ethyl ester
Adding the ethyl N-benzylglycine hydrochloride prepared in the previous step into a 1L four-mouth reaction bottle, adding 200ml of water, stirring to dissolve, adjusting the pH value to 7-8 by using a 20% sodium hydroxide aqueous solution, adding 200ml of ethyl acetate to extract, and washing a water layer for 2 times by using 100ml of ethyl acetate multiplied by 2. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 50 ℃ to give 165.5g of ethyl N-benzylglycinate as a product, with a yield of 95.0% and a content of 99.6% by assay.
Example 2: preparation of N-benzylglycine ethyl ester
The method comprises the following steps:
(1) preparation of ethyl N-benzylglycinate hydrochloride
107g (1mol) of benzylamine is added into a 1L four-mouth reaction bottle, 184g (1.5mol) of ethyl chloroacetate is added, 200ml of N, N-dimethylformamide is added, the reaction is carried out at room temperature for 3 hours, after the basic reaction is detected by HPLC, water is added, extraction is carried out, an isopropanol hydrochloride solution is dropwise added into an organic layer, the pH value is adjusted to be 1-2, a solid is separated out, and the solid is filtered and dried to obtain 207.5g of N-benzyl glycine ethyl ester hydrochloride, wherein the yield is 90.3%.
(2) Preparation of N-benzylglycine ethyl ester
Adding the ethyl N-benzylglycine hydrochloride prepared in the previous step into a 1L four-mouth reaction bottle, adding 200ml of water, stirring and dissolving, adjusting the pH value to 7-8 by using 20% potassium hydroxide aqueous solution, adding 200ml of dichloromethane for extraction, and washing an aqueous layer for 2 times by using 100ml of dichloromethane multiplied by 2. The dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness at 40 ℃ under reduced pressure to give 166.1g of ethyl N-benzylglycinate as a product with a yield of 95.1% and a content of 99.4% by assay.
Example 3: preparation of N-benzylglycine ethyl ester
The method comprises the following steps:
(1) preparation of ethyl N-benzylglycinate hydrochloride
Adding 107g (1mol) of benzylamine into a 1L four-mouth reaction bottle, adding 200g (1.2mol) of ethyl bromoacetate, adding 200ml of acetone, reacting at room temperature for 4hr, detecting by HPLC (high performance liquid chromatography) to detect that the reaction is almost complete, adding water, extracting, dropwise adding an acetone hydrochloride solution into an organic layer, adjusting the pH to 1-2, precipitating a solid, filtering and drying to obtain 208g of N-benzyl glycine ethyl ester hydrochloride, wherein the yield is 90.6%.
(2) Preparation of N-benzylglycine ethyl ester
Adding the N-benzylglycine ethyl ester hydrochloride prepared in the previous step into a 1L four-mouth reaction bottle, adding 200ml of water, stirring to dissolve, adjusting the pH value to 7-8 by using a 20% sodium carbonate aqueous solution, adding 200ml of ethyl acetate, extracting, and washing a water layer for 2 times by using 100ml of ethyl acetate multiplied by 2. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 50 ℃ to give 167.3g of ethyl N-benzylglycinate as a product, with a yield of 95.6% and a content of 99.5% by assay.
Comparative example 1: according to the synthesis method of embodiment 1 in ZL031320163, benzyl chloride and ethyl glycinate react in the presence of a catalyst and an organic solvent, anhydrous sodium sulfate is added into a reaction system, the reaction temperature is 110-140 ℃, the reaction is carried out for 6-12 hours, N-benzyl ethyl glycinate is generated, after the reaction is completed, the reaction system is filtered, filtrate is subjected to distillation treatment at 110-125 ℃, then rectification is carried out, fractions at 142-143 ℃ and 10mmHg are collected, and a product with the content of more than 97% is obtained.
Example 4: content determination of N-benzyl glycine ethyl ester
Taking the ethyl N-benzylglycinate prepared in the examples 1-4 and the comparative example 1 respectively, and testing by high performance liquid chromatography (the general rule 0512 in 2015 of Chinese pharmacopoeia), using octadecyl bonded silica gel as a filler (Waters symmetry C18 is applicable, 250mm multiplied by 4.6mm, 5 μm); the mobile phase A is 0.1 percent trifluoroacetic acid, the mobile phase B is acetonitrile, and gradient elution is carried out according to the following table; the column temperature is 30 ℃; the flow rate is 1.0 ml/min; the detection wavelength was 230 nm.
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 95 | 5 |
| 10 | 65 | 35 |
| 20 | 65 | 35 |
| 21 | 95 | 5 |
| 30 | 95 | 5 |
Taking a proper amount of the product, precisely weighing, adding water to dissolve and dilute to prepare a solution containing 0.1mg of the product in 1ml, and shaking up to obtain a test solution. And accurately weighing a proper amount of N-benzyl glycine ethyl ester reference substance, adding water to dissolve and dilute the N-benzyl glycine ethyl ester reference substance to prepare a solution containing about 0.1mg of N-benzyl glycine ethyl ester in each 1ml of N-benzyl glycine ethyl ester, and shaking up to obtain the reference substance solution. Precisely measuring 10 μ l of each solution, injecting into a liquid chromatograph, and recording chromatogram. The test result is obtained by calculation according to an external standard method and is shown in the following table.
From the above results, according to the methods of the embodiments 1 to 3, the content of the product obtained by adjusting the acid content of N-benzylglycine ethyl ester to form a hydrochloride and then adjusting the alkali content is higher than that of N-benzylglycine ethyl ester prepared in the comparative embodiment 1, most of impurities are removed by crystallization filtration to form a hydrochloride and extraction with an organic solvent after adjusting the alkali content, the yield is high, the distillation temperature is low, the requirement on production equipment is low, and the method is suitable for industrial production.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And such obvious changes and modifications which fall within the spirit of the invention are deemed to be covered by the present invention.
Claims (7)
1. A preparation and purification method of N-benzyl glycine ethyl ester is characterized by comprising the following steps:
(1) preparation of ethyl N-benzylglycine hydrochloride: benzylamine and halogenated ethyl acetate are taken to be in an organic solvent, stirring reaction is carried out at room temperature, after HPLC detection reaction is completed, water is added, extraction is carried out, organic mixed liquor of hydrochloric acid is dripped into an organic layer, the pH value is adjusted to be 1-2, solid is separated out, filtering and drying are carried out, N-benzyl glycine ethyl ester hydrochloride is obtained,
the reaction equation is:
(2) preparation of ethyl N-benzylglycine: adding water into the N-benzylglycine ethyl ester hydrochloride obtained in the step (1), stirring and dissolving, adjusting the pH value to 7-8 by using alkali, adding an organic solvent for extraction, drying an organic layer by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain the product N-benzylglycine ethyl ester hydrochloride.
2. A process for the preparation and purification of ethyl N-benzylglycine according to claim 1, characterized in that: in the step (1), the molar ratio of benzylamine to halogenated ethyl butyrate is 1: 1-1.5.
3. A process for the preparation and purification of ethyl N-benzylglycine according to claim 1, characterized in that: in the step (1), the organic solvent is selected from one of N, N-dimethylformamide, tetrahydrofuran and acetone; the organic mixed solution of hydrochloric acid is one selected from 30% hydrochloric acid ethanol, 30% hydrochloric acid methanol, 30% hydrochloric acid isopropanol and 30% hydrochloric acid acetone.
4. A process for the preparation and purification of ethyl N-benzylglycine according to claim 1, characterized in that: in the step (2), the alkali is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; the organic solvent is selected from one of ethyl acetate and dichloromethane.
5. A process for the preparation and purification of ethyl N-benzylglycine according to claim 2, characterized in that: in the step (1), the molar ratio of benzylamine to halogenated ethyl butyrate is 1: 1.
6. A process for the preparation and purification of ethyl N-benzylglycine according to claim 3, characterized in that: in the step (1), the organic solvent is tetrahydrofuran; the organic mixed solution of hydrochloric acid is a 30% hydrochloric acid ethanol solution.
7. A process for the preparation and purification of ethyl N-benzylglycine according to claim 1, characterized in that: in the step (2), the alkali is sodium hydroxide; the organic solvent is ethyl acetate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040242890A1 (en) * | 2001-03-08 | 2004-12-02 | Coe Diane Mary | Agonists of beta-adrenoceptors |
| CN105622444A (en) * | 2015-12-31 | 2016-06-01 | 重庆威鹏药业有限公司 | Preparation method for 1-benzyl-3-piperidone hydrochloride |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040242890A1 (en) * | 2001-03-08 | 2004-12-02 | Coe Diane Mary | Agonists of beta-adrenoceptors |
| CN105622444A (en) * | 2015-12-31 | 2016-06-01 | 重庆威鹏药业有限公司 | Preparation method for 1-benzyl-3-piperidone hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| VALENTINA ZULIANI等: "5-Benzylidene-hydantoins: Synthesis and antiproliferative activity on A549 lung cancer cell line", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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