Preparation method of ethyl glycolate derivative-13C

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of an ethyl glycolate derivative 13C. Comprising the following steps: step 1, enabling paraformaldehyde to react with labeled potassium cyanide until cyanogen is completely reacted to obtain glycolonitrile; 2, adding a hydrochloric acid ethanol solution or an alcohol solution, introducing hydrochloric acid gas, reacting until glycolonitrile is completely reacted, and adding hydrochloric acid and sodium chloride solid saturated reaction liquid; performing extraction, drying, filtration and column chromatography purification to obtain the 2-ethyl glycolate-1-13C; the # imgabs0 is mild in reaction condition, simple and convenient to operate, easy to implement and high in yield.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a glycolic acid ethyl ester derivative - 13 Preparation method of C. Background Art

[0002] The description of the background technology in the present invention belongs to the related technology related to the present invention, which is only used to illustrate and facilitate the understanding of the invention content of the present invention, and should not be understood as the applicant explicitly believes or inferred that the applicant believes that it is the prior art of the present invention on the filing date of the first application.

[0003] Ethyl glycolate is a chemical substance with many functions and uses. In organic synthesis, ethyl glycolate is one of the important solvents for organic synthesis. It is widely used in organic synthesis processes such as esterification, amination, etherification, and transesterification. It has good solubility and volatility and is suitable for synthesis reactions at room temperature, high temperature, and high pressure. In industry, ethyl glycolate is widely used as an organic solvent for the production and analysis of resins, paints, inks, and coatings. It can dissolve most organic substances and has good solubility for many inorganic substances. It is soluble in chloroform and methanol (a small amount). It has high water solubility and can be well dissolved in water, alcohols, acetone, and acetate. It is slightly soluble in ether and almost insoluble in hydrocarbon solvents. In the food and beverage industry, ethyl glycolate is used as a solvent, extractant, and flavoring agent.

[0004] At present, there are several production methods in the world. According to reports, there are methods for indirectly preparing ethyl glycolate, such as the pressure method, the cyanohydrin method, and the ester exchange method. For example: ① Using dioxane, formaldehyde, and HCN as raw materials, CH2(OH)CN and ethanol and hydrochloric acid are refluxed and decomposed to form ethyl glycolate, with a yield of 50%. ② Using ethanol and polyformaldehyde, NiI2-SiO2 is heated at 200kg / cm2 and 200℃ for 3 hours in the presence of a mixed gas containing 94% CO and 6% N2, which can be converted into 24-50% ethyl glycolate. ③ In a boiling bed, ethyl diazoacetate is decomposed into ethyl glycolate and N2 through a polystyrene sulfonic acid catalyst. The current methods have the disadvantages of high cost, low yield, and complicated process routes. Summary of the invention

[0005] The purpose of the present invention is to provide a glycolic acid ethyl ester derivative- 13 The preparation method of C. The present invention directly uses paraformaldehyde and labeled potassium cyanide as starting materials, has mild reaction conditions, is simple to operate, is easy to implement, and has a significantly higher yield than other reported synthesis methods.

[0006] The purpose of the embodiment of the present invention is achieved through the following technical solutions:

[0007] A method for preparing ethyl glycolate derivative-13C, characterized in that it comprises the following steps:

[0008] Step 1: paraformaldehyde reacts with labeled potassium cyanide until the cyanide reaction is complete to obtain hydroxyacetonitrile;

[0009] Step 2: Add hydrochloric acid ethanol solution or alcohol solution and pass hydrochloric acid gas to react until the hydroxyacetonitrile reacts completely, add hydrochloric acid and sodium chloride solid to saturate the reaction solution; extract, dry, filter and purify by column chromatography to obtain ethyl 2-hydroxyacetate-1- 13 C;

[0010]

[0011] Further, the following steps are included:

[0012] Synthesis of ethyl 2-hydroxyacetate-1- 13 C:

[0013]

[0014] In a 50mL two-necked flask, add K 13 CN (198 mg, 3 mmol, 1 eq), EtOH (3 ml), nitrogen replacement, ice bath cooling to 0-5 ° C, add paraformaldehyde (135 mg, 4.5 mmol, 1.5 eq), maintain 0-5 ° C stirring for 3 h, cyanide monitoring reaction is complete, add 6 ml hydrochloric acid ethanol solution (mass fraction 30%), stir at room temperature for 1 h, TLC spot plate monitoring intermediate hydroxyacetonitrile reaction is complete, 35 ° C concentration, add 2N hydrochloric acid aqueous solution (3 mL), stir at room temperature for 20 minutes, add sodium chloride solid saturated reaction solution, DCM extraction three times, add anhydrous sodium sulfate and anhydrous magnesium sulfate to dry, filter, 20 ° C spin dry, column chromatography purification to obtain ethyl 2-hydroxyacetate-1- 13 C (283 mg, yield 89.8%).

[0015] Further, the following steps are included:

[0016] Synthesis of ethyl 2-hydroxyacetate-1- 13 C:

[0017]

[0018] In a 50mL two-necked flask, add K 13CN (66 mg, 1 mmol, 1 eq), EtOH (2 ml), nitrogen replacement, ice bath cooling to 0-5 ° C, add paraformaldehyde (45 mg, 1.5 mmol, 1.5 eq), maintain 0-5 ° C stirring for 3 h, cyanide monitoring reaction is complete, add 2 ml hydrochloric acid ethanol solution (mass fraction 30%), stir at room temperature for 1 h, TLC spot plate monitoring intermediate hydroxyacetonitrile reaction is complete, 35 ° C concentration, add 2N hydrochloric acid aqueous solution (1 mL), stir at room temperature for 20 minutes, add sodium chloride solid saturated reaction solution, DCM extraction three times, add anhydrous sodium sulfate and anhydrous magnesium sulfate to dry, filter, 20 ° C spin dry, column chromatography purification to obtain ethyl 2-hydroxyacetate-1- 13 C (85 mg, yield 84.7%).

[0019] Further, the following steps are included:

[0020] Synthesis of ethyl 2-hydroxyacetate-1- 13 C:

[0021]

[0022] In a 50mL two-necked flask, add K 13 CN (330mg, 5mmol, 1eq), EtOH (6ml), nitrogen replacement, ice bath cooling to 0-5℃, add paraformaldehyde (225mg, 7.5mmol, 1.5eq), maintain 0-5℃ stirring for 3h, monitor the reaction with cyanide, add 10ml hydrochloric acid ethanol solution (mass fraction 30%), stir at room temperature for 1h, monitor the reaction of intermediate hydroxyacetonitrile with TLC spot plate, concentrate at 35℃, add 2N hydrochloric acid aqueous solution (5mL), stir at room temperature for 20 minutes, add sodium chloride solid to saturate the reaction solution, extract with DCM three times, add anhydrous sodium sulfate and anhydrous magnesium sulfate to dry, filter, spin dry at 20℃, and purify by column chromatography to obtain 2-hydroxyethyl 1-acetate. 13 C (436 mg, yield 83%).

[0023] The embodiments of the present invention have the following beneficial effects:

[0024] The invention adopts paraformaldehyde and labeled potassium cyanide as raw materials to synthesize ethyl glycolate. The raw materials are easily available, the production cost and equipment requirements are low, the operation is simple, and the yield is high. The invention fills the blank of the synthesis of isotope labeled ethyl glycolate at home and abroad, and is also suitable for the optimization of the synthesis process of non-labeled ethyl glycolate.

[0025] The present invention directly uses paraformaldehyde and labeled potassium cyanide as starting materials, has mild reaction conditions, is simple to operate, is easy to implement, and has a significantly higher yield than other reported synthesis methods. DETAILED DESCRIPTION

[0026] The present application is introduced in some embodiments of the present invention in conjunction with embodiments below.

[0027] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, in the following description, different "one embodiment" or "embodiment" does not necessarily refer to the same embodiment. Different embodiments can be replaced or combined, and for ordinary technicians in this field, other implementation methods can be obtained based on these embodiments without creative work.

[0028] A method for preparing ethyl glycolate derivative-13C, characterized in that it comprises the following steps:

[0029] Step 1: paraformaldehyde reacts with labeled potassium cyanide until the cyanide reaction is complete to obtain hydroxyacetonitrile;

[0030] Step 2: Add hydrochloric acid ethanol solution or alcohol solution and pass hydrochloric acid gas to react until the hydroxyacetonitrile reacts completely, add hydrochloric acid and sodium chloride solid to saturate the reaction solution; extract, dry, filter and purify by column chromatography to obtain ethyl 2-hydroxyacetate-1- 13 C.

[0031] Example 1

[0032] Synthesis of ethyl 2-hydroxyacetate-1- 13 C:

[0033]

[0034] In a 50mL two-necked flask, add K 13 CN (198 mg, 3 mmol, 1 eq), EtOH (3 ml), nitrogen replacement, ice bath cooling to 0-5 ° C, add paraformaldehyde (135 mg, 4.5 mmol, 1.5 eq), maintain 0-5 ° C stirring for 3 h, cyanide monitoring reaction is complete, add 6 ml hydrochloric acid ethanol solution (mass fraction 30%), stir at room temperature for 1 h, TLC spot plate monitoring intermediate hydroxyacetonitrile reaction is complete, 35 ° C concentration, add 2N hydrochloric acid aqueous solution (3 ml), stir at room temperature for 20 minutes, add sodium chloride solid saturated reaction solution, DCM extraction three times, add anhydrous sodium sulfate and anhydrous magnesium sulfate to dry, filter, 20 ° C spin dry, column chromatography purification to obtain ethyl 2-hydroxyacetate-1- 13 C (283 mg, yield 89.8%).

[0035] Example 2

[0036] Synthesis of ethyl 2-hydroxyacetate-1- 13 C:

[0037]

[0038] In a 50mL two-necked flask, add K 13 CN (66 mg, 1 mmol, 1 eq), EtOH (2 ml), nitrogen replacement, ice bath cooling to 0-5 ° C, add paraformaldehyde (45 mg, 1.5 mmol, 1.5 eq), maintain 0-5 ° C stirring for 3 h, cyanide monitoring reaction is complete, add 2 ml hydrochloric acid ethanol solution (mass fraction 30%), stir at room temperature for 1 h, TLC spot plate monitoring intermediate hydroxyacetonitrile reaction is complete, 35 ° C concentration, add 2N hydrochloric acid aqueous solution (1 ml), stir at room temperature for 20 minutes, add sodium chloride solid saturated reaction solution, DCM extraction three times, add anhydrous sodium sulfate and anhydrous magnesium sulfate drying, filter, 20 ° C spin dry, column chromatography purification to obtain 2-hydroxyethyl 1- 13 C (85 mg, yield 84.7%).

[0039] Example 3

[0040] Synthesis of ethyl 2-hydroxyacetate-1- 13 C:

[0041]

[0042] In a 50mL two-necked flask, add K 13 CN (330mg, 5mmol, 1eq), EtOH (6ml), nitrogen replacement, ice bath cooling to 0-5℃, add paraformaldehyde (225mg, 7.5mmol, 1.5eq), maintain 0-5℃ stirring for 3h, monitor the reaction with cyanide, add 10ml hydrochloric acid ethanol solution (mass fraction 30%), stir at room temperature for 1h, monitor the reaction of intermediate hydroxyacetonitrile with TLC spot plate, concentrate at 35℃, add 2N hydrochloric acid aqueous solution (5ml), stir at room temperature for 20 minutes, add sodium chloride solid saturated reaction solution, extract three times with DCM, add anhydrous sodium sulfate and anhydrous magnesium sulfate to dry, filter, spin dry at 20℃, and purify by column chromatography to obtain 2-hydroxyethyl 1- 13 C (436 mg, yield 83%).

[0043] The invention adopts paraformaldehyde and labeled potassium cyanide as raw materials to synthesize ethyl glycolate. The raw materials are easily available, the production cost and equipment requirements are low, the operation is simple, and the yield is high. The invention fills the blank of the synthesis of isotope labeled ethyl glycolate at home and abroad, and is also suitable for the optimization of the synthesis process of non-labeled ethyl glycolate.

[0044] The present invention directly uses paraformaldehyde and labeled potassium cyanide as starting materials, has mild reaction conditions, is simple to operate, is easy to implement, and has a significantly higher yield than other reported synthesis methods.

[0045] It should be noted that the present invention is also applicable to the synthesis of isotope-labeled ethyl glycolate-14C and the synthesis of unlabeled ethyl glycolate.

[0046] In step 2 of the present invention, in addition to using a hydrochloric acid ethanol solution (mass fraction 30%), hydrochloric acid gas may also be introduced into an alcohol solution to carry out the reaction.

[0047] The present invention is also applicable to the synthesis of labeled glycolate derivatives, including but not limited to the synthesis of methyl glycolate, tert-butyl glycolate, etc.

[0048] It should be noted that the above embodiments can be freely combined as needed. The above description is only the preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention can have various changes and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing 13C ethyl glycolate derivatives, characterized in that: The steps include: Step 1: paraformaldehyde reacts with labeled potassium cyanide until the cyanide reaction is complete to obtain hydroxyacetonitrile; Step 2: Add hydrochloric acid ethanol solution or alcohol solution and pass hydrochloric acid gas to react until the hydroxyacetonitrile reacts completely, and then add hydrochloric acid and sodium chloride solid to saturate the reaction solution; After extraction, drying, filtration and column chromatography purification, 2-hydroxyethyl 1- 13 C; 2. The method for preparing ethyl glycolate derivative-13C according to claim 1, characterized in that: The steps include: Synthesis of ethyl 2-hydroxyacetate-1- 13 C: In a 50mL two-necked flask, add 198mg, 3mmol, 1eq of K 13 CN, 3ml of EtOH, nitrogen replacement, ice bath cooling to 0-5℃, add 135mg, 4.5mmol, 1.5eq of paraformaldehyde, maintain 0-5℃ and stir for 3h, monitor the reaction with cyanide, add 6ml of 30% hydrochloric acid ethanol solution, stir at room temperature for 1h, monitor the reaction of intermediate hydroxyacetonitrile with TLC spot plate, concentrate at 35℃, add 3mL of 2N hydrochloric acid aqueous solution, stir at room temperature for 20 minutes, add sodium chloride solid saturated reaction solution, extract three times with DCM, add anhydrous sodium sulfate and anhydrous magnesium sulfate to dry, filter, spin dry at 20℃, and purify by column chromatography to obtain 2-hydroxyethyl 1- 13 C283mg, yield 89.8%.

3. The method for preparing ethyl glycolate derivative-13C according to claim 1, characterized in that: The steps include: Synthesis of ethyl 2-hydroxyacetate-1- 13 C: In a 50mL two-necked flask, add 66mg, 1mmol, 1eq of K 13 CN, 2ml of EtOH, nitrogen replacement, ice bath cooling to 0-5℃, add 45mg, 1.5mmol, 1.5eq of paraformaldehyde, maintain 0-5℃ and stir for 3h, monitor the reaction with cyanide, add 2ml of 30% hydrochloric acid ethanol solution, stir at room temperature for 1h, monitor the reaction of intermediate hydroxyacetonitrile with TLC spot plate, concentrate at 35℃, add 1mL of 2N hydrochloric acid aqueous solution, stir at room temperature for 20 minutes, add sodium chloride solid to saturate the reaction solution, extract with DCM three times, add anhydrous sodium sulfate and anhydrous magnesium sulfate to dry, filter, spin dry at 20℃, and purify by column chromatography to obtain 2-hydroxyethyl 1- 13 C85mg, yield 84.7%.

4. The method for preparing ethyl glycolate derivative-13C according to claim 1, characterized in that: The steps include: Synthesis of ethyl 2-hydroxyacetate-1- 13 C: In a 50mL two-necked flask, add 330mg, 5mmol, 1eq of K 13 CN, 6ml of EtOH, nitrogen replacement, ice bath cooling to 0-5℃, add 225mg, 7.5mmol, 1.5eq of paraformaldehyde, maintain 0-5℃ and stir for 3h, monitor the reaction with cyanide, add 10ml of 30% hydrochloric acid ethanol solution, stir at room temperature for 1h, monitor the reaction of intermediate hydroxyacetonitrile with TLC spot plate, concentrate at 35℃, add 5mL of 2N hydrochloric acid aqueous solution, stir at room temperature for 20 minutes, add sodium chloride solid to saturate the reaction solution, extract with DCM three times, add anhydrous sodium sulfate and anhydrous magnesium sulfate to dry, filter, spin dry at 20℃, and purify by column chromatography to obtain 2-hydroxyethyl 1- 13 C436mg, yield 83%.

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