Preparation method of glyoxylic acid derivative-13C
By synthesizing 2-methylamine acetonitrile-1-13C with methylamine hydrochloride and labeled potassium cyanide and reacting with sodium hypobromate, the efficient labeling synthesis of glyoxylic acid derivatives was successfully achieved, solving the problems of complex synthesis routes and low yields in the prior art, and the reaction conditions were mild and the total yield was high.
Patent Information
- Application Number
- CN202411935991.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-26
- Publication Date
- 2025-03-25
AI Technical Summary
The existing glyoxylic acid synthesis methods have problems such as complex equipment, high cost, long time and low yield, and lack effective isotope labeling synthesis routes.
Using methylamine hydrochloride as raw material, 2-methylamine acetonitrile-1-13C was synthesized with labeled potassium cyanide and reacted with sodium hypobromate to obtain labeled glyoxylic acid, achieving a completely new synthesis route.
The efficient labeling and synthesis of glyoxylic acid derivatives is achieved, and the reaction device with high airtightness requirements is avoided. The reaction conditions are mild and the total yield is between 50% and 60%, which is relatively efficient.
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Figure CN119684111A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of chemical technology, and in particular to a glyoxylic acid 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] Glyoxylic acid derivatives are important polymer monomers and basic organic chemical raw materials. Glyoxylic acid is the simplest keto acid (aldehyde acid), which has the properties of both acid and aldehyde. It is used as a varnish raw material, and an intermediate for spices, medicines, dyes, plastics and industrial chemicals. Ethyl vanillin made from glyoxylic acid is widely used as a perfume and fixative for cosmetics, flavors for daily chemicals, and flavoring for food. Allantoin made from glyoxylic acid is used as a good healing agent for skin wounds, an additive for high-end cosmetics, and a plant growth regulator. In addition, glyoxylic acid is an important raw material for fine chemicals and is widely used in medicine, water quality stabilizers, spices (ethyl vanillin), pesticide intermediates, etc. There are currently several methods for synthesizing glyoxylic acid. Method one is the oxalic acid electrolysis method. The oxalic acid aqueous solution is electrolytically reduced to generate a dilute glyoxylic acid solution, which is then gradually concentrated by evaporation, concentration, freezing, and filtration, and finally the qualified product is packaged. This method is cumbersome, requires many devices, is costly, time-consuming, and has a low yield; Method 2 is a glyoxal oxidation method, in which glyoxal is oxidized by air or oxygen under the action of a catalyst to generate glyoxylic acid, which is then refined and purified to obtain a finished product; Method 3 is a dichloroacetic acid method, in which sodium methoxide and methanol are put into a reaction tank, heated to 40-50°C, and dichloroacetic acid is slowly added dropwise, and treated to obtain a sodium dimethoxyacetate methanol solution, which is then treated to obtain a finished product. The disadvantage is that the operating conditions are harsh and the production cost is high; Method 4 is a maleic anhydride ozonation reduction method, in which maleic anhydride is dissolved in formic acid, ozone is introduced for oxidation, and then reduced with zinc powder or the like to obtain glyoxylic acid. The disadvantage is that it is relatively complicated and costly. Summary of the invention
[0004] The purpose of the present invention is to provide a glyoxylic acid derivative- 13 The present invention adopts methylamine hydrochloride as raw material to synthesize glyoxylic acid, which belongs to a completely new synthesis route. The key is to start with the synthesis of 2-methylaminoacetonitrile-1- 13 C and 2-methylaminoacetic acid-1- 13 C reacts with sodium hypobromite to obtain the desired labeled glyoxylic acid, filling the gap in the synthesis of isotope-labeled glyoxylic acid derivatives in China.
[0005] The purpose of the embodiment of the present invention is achieved through the following technical solutions:
[0006] A glyoxylic acid derivative 13 The preparation method of C comprises the following steps:
[0007]
[0008] Methylamine hydrochloride, formaldehyde solution, K 13 CN and deionized water, nitrogen replacement, after the reaction is complete, add NaOH, heat, generate the intermediate substance 2-methylaminoacetic acid-1- 13 C;
[0009] After stirring NaOH and deionized water, add Br 2 , stirred at room temperature for 1 h to obtain a reaction solution, and 2-methylaminoacetic acid-1- 13 C was added dropwise to the obtained reaction solution, and stirred until no 2-methylaminoacetic acid-1- 13 C, adjust the pH to 2-3, extract, combine the organic phases, wash and chromatograph to obtain 2-glyoxylic acid-1- 13 C.
[0010] Further, the following steps are included:
[0011]
[0012] In a 10 mL two-necked flask, add 264 mg, 3.9 mmol, 1.3 eq of methylamine hydrochloride, 316 mg, 3.9 mmol, 1.3 eq, 37% formaldehyde solution, and 198 mg, 3 mmol, 1 eq of K 13 CN, 2mL deionized water, nitrogen replacement, stirring at 80°C for 3 hours, adding 800mg, 20mmol NaOH, heating and stirring for 1 hour, LCMS monitoring has generated the desired intermediate 2-methylaminoacetic acid-1- 13 C;
[0013] Prepare another 25ml three-necked flask, add 480mg, 12mmol, 4eq of NaOH, 4.5mL of deionized water, stir for 10min, then add 2.4g, 15mmol, 5eq of Br 2 , stirred at room temperature for 1 h, and 2-methylaminoacetic acid-1- 13 The reaction system of C was added dropwise to the obtained reaction solution, and after stirring at room temperature for 1 hour, LCMS monitoring showed that no 2-methylaminoacetic acid-1- 13 C, adjust the pH to 2 or 3 with concentrated hydrochloric acid, extract with ethyl acetate, combine the organic phases and then wash with water and saturated brine, column chromatography to obtain 135 mg of 2-glyoxylic acid-1- 13 C.
[0014] Further, the following steps are included:
[0015]
[0016] In a 10 mL two-necked flask, add 439 mg, 6.5 mmol, 1.3 eq of methylamine hydrochloride, 527 mg, 6.5 mmol, 1.3 eq, 37% formaldehyde solution, and 331 mg, 5 mmol, 1 eq of K 13 CN, 4 mL of deionized water, nitrogen replacement, stirring at 80 ° C for 3 hours, adding 1.6 g, 40 mmol of NaOH, heating and stirring for 1 hour, LCMS monitoring has generated the desired intermediate 2-methylaminoacetic acid-1- 13 C.
[0017] Prepare another 25ml three-necked flask, add 800mg, 20mmol, 4eq of NaOH, 7.5mL of deionized water, stir for 10min, then add 4.0g, 25mmol, 5eq of Br 2 , stirred at room temperature for 1 h, and 2-methylaminoacetic acid-1- 13 The reaction system of C was added dropwise to the obtained reaction solution, and after stirring at room temperature for 1 hour, LCMS monitoring showed that no 2-methylaminoacetic acid-1- 13 C, adjust the pH to 2 or 3 with concentrated hydrochloric acid, extract with ethyl acetate, combine the organic phases and then wash with water and saturated brine, column chromatography to obtain 244 mg of 2-glyoxylic acid-1- 13 C.
[0018] Further, the following steps are included:
[0019]
[0020] In a 10 mL two-necked flask, add 88 mg, 1.3 mmol, 1.3 eq of methylamine hydrochloride, 105 mg, 1.3 mmol, 1.3 eq of 37% formaldehyde solution, and 66 mg, 1 mmol, 1 eq of K 13 CN, 1 mL of deionized water, nitrogen replacement, stirring at 80 ° C for 3 hours, adding 400 mg, 10 mmol of NaOH, heating and stirring for 1 hour, LCMS monitoring has generated the desired intermediate 2-methylaminoacetic acid-1- 13 C;
[0021] Prepare another 25ml three-necked flask, add 240mg, 6mmol, 2eq of NaOH, 2.5mL of deionized water, stir for 10min, then add 800mg, 5mmol, 5eq of Br 2 , stirred at room temperature for 1 h, and 2-methylaminoacetic acid-1-13 The reaction system of C was added dropwise to the obtained reaction solution, and after stirring at room temperature for 1 hour, LCMS monitoring showed that no 2-methylaminoacetic acid-1- 13 C, adjust the pH to 2 or 3 with concentrated hydrochloric acid, extract with ethyl acetate, combine the organic phases and then wash with water and saturated brine, column chromatography to obtain 40 mg of 2-glyoxylic acid-1- 13 C.
[0022] The embodiments of the present invention have the following beneficial effects:
[0023] The present invention uses methylamine hydrochloride as a raw material to synthesize glyoxylic acid, which belongs to a completely new synthesis route. The key is to start with the synthesis of 2-methylaminoacetonitrile-1- 13 C and 2-methylaminoacetic acid-1- 13 C reacts with sodium hypobromite to obtain the desired labeled glyoxylic acid, filling the gap in the synthesis of isotope-labeled glyoxylic acid derivatives in China. DETAILED DESCRIPTION
[0024] The present application is further described below in conjunction with embodiments.
[0025] 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.
[0026] Example 1
[0027] A glyoxylic acid derivative 13 The preparation method of C comprises the following steps:
[0028]
[0029] In a 10 mL two-necked flask, methylamine hydrochloride (264 mg, 3.9 mmol, 1.3 eq), 37% formaldehyde solution (316 mg, 3.9 mmol, 1.3 eq), K 13 CN (198 mg, 3 mmol, 1 eq), deionized water (2 mL), nitrogen replacement, stirring at 80 ° C for 3 hours, adding NaOH (800 mg, 20 mmol), heating and stirring for 1 hour, LCMS monitoring has generated the desired intermediate 2-methylaminoacetic acid-1- 13 C.
[0030] Prepare another 25 ml three-necked flask, add NaOH (480 mg, 12 mmol, 4 eq) and deionized water (4.5 mL), stir for 10 min, then add Br 2 (2.4 g, 15 mmol, 5 eq), stirred at room temperature for 1 h, and 2-methylaminoacetic acid-1- 13 The reaction system of C was added dropwise to the obtained reaction solution, and after stirring at room temperature for 1 hour, LCMS monitoring showed that no 2-methylaminoacetic acid-1- 13 C, adjust the pH to 2 or 3 with concentrated hydrochloric acid, extract with ethyl acetate, combine the organic phases and then wash with water and saturated brine, and column chromatography to obtain 2-glyoxylic acid-1- 13 C (135 mg).
[0031] Example 2
[0032] A glyoxylic acid derivative 13 The preparation method of C comprises the following steps:
[0033]
[0034] In a 10 mL two-necked flask, methylamine hydrochloride (439 mg, 6.5 mmol, 1.3 eq), 37% formaldehyde solution (527 mg, 6.5 mmol, 1.3 eq), K 13 CN (331 mg, 5 mmol, 1 eq), deionized water (4 mL), nitrogen replacement, stirring at 80 ° C for 3 hours, adding NaOH (1.6 g, 40 mmol), heating and stirring for 1 hour, LCMS monitoring has generated the desired intermediate 2-methylaminoacetic acid-1- 13 C.
[0035] Prepare another 25 ml three-necked flask, add NaOH (800 mg, 20 mmol, 4 eq) and deionized water (7.5 mL), stir for 10 min, then add Br 2 (4.0 g, 25 mmol, 5 eq), stirred at room temperature for 1 h, and 2-methylaminoacetic acid-1- 13 The reaction system of C was added dropwise to the obtained reaction solution, and after stirring at room temperature for 1 hour, LCMS monitoring showed that no 2-methylaminoacetic acid-1- 13 C, adjust the pH to 2 or 3 with concentrated hydrochloric acid, extract with ethyl acetate, combine the organic phases and then wash with water and saturated brine, and column chromatography to obtain 2-glyoxylic acid-1- 13 C (244 mg).
[0036] Example 3
[0037] A glyoxylic acid derivative 13 The preparation method of C comprises the following steps:
[0038]
[0039] In a 10 mL two-necked flask, methylamine hydrochloride (88 mg, 1.3 mmol, 1.3 eq), 37% formaldehyde solution (105 mg, 1.3 mmol, 1.3 eq), K 13 CN (66 mg, 1 mmol, 1 eq), deionized water (1 mL), nitrogen replacement, stirring at 80 ° C for 3 hours, adding NaOH (400 mg, 10 mmol), heating and stirring for 1 hour, LCMS monitoring has generated the desired intermediate 2-methylaminoacetic acid-1- 13 C.
[0040] Prepare another 25 ml three-necked flask, add NaOH (240 mg, 6 mmol, 2 eq) and deionized water (2.5 mL), stir for 10 min, then add Br 2 (800 mg, 5 mmol, 5 eq), stirred at room temperature for 1 h, and 2-methylaminoacetic acid-1- 13 The reaction system of C was added dropwise to the obtained reaction solution, and after stirring at room temperature for 1 hour, LCMS monitoring showed that no 2-methylaminoacetic acid-1- 13 C, adjust the pH to 2 or 3 with concentrated hydrochloric acid, extract with ethyl acetate, combine the organic phases and then wash with water and saturated brine, and column chromatography to obtain 2-glyoxylic acid-1- 13 C (40 mg).
[0041] The present invention avoids the use of a reaction device with high airtightness requirements, directly uses other raw materials that are easily available on the market and labeled potassium cyanide as starting materials, and the reaction conditions are mild and easy to implement;
[0042] The present invention is a completely new synthetic route, which can realize the labeling of glyoxylic acid derivatives;
[0043] The total yield of the three steps of the present invention is basically maintained between 50% and 60%, and the yield is relatively high;
[0044] It should be noted that the present invention is also applicable to the isotope-labeled synthesis of glyoxylic acid derivatives. 14 Synthesis of C.
[0045] 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 glyoxylic acid derivative - 13 The preparation method of C is characterized in that The steps include: Methylamine hydrochloride, formaldehyde solution, K 13 CN and deionized water, nitrogen replacement, after the reaction is complete, add NaOH, heat, generate the intermediate substance 2-methylaminoacetic acid-1- 13 C; After stirring NaOH and deionized water, Br2 was added and stirred at room temperature for 1 h to obtain a reaction solution. 13 C was added dropwise to the obtained reaction solution, and stirred until no 2-methylaminoacetic acid-1- 13 C, adjust the pH to 2-3, extract, combine the organic phases, wash and chromatograph to obtain 2-glyoxylic acid-1- 13 C.
2. The glyoxylic acid derivative according to claim 1 13 The preparation method of C is characterized in that The steps include: In a 10 mL two-necked flask, add 264 mg, 3.9 mmol, 1.3 eq of methylamine hydrochloride, 316 mg, 3.9 mmol, 1.3 eq, 37% formaldehyde solution, and 198 mg, 3 mmol, 1 eq of K 13 CN, 2mL deionized water, nitrogen replacement, stirring at 80°C for 3 hours, adding 800mg, 20mmol NaOH, heating and stirring for 1 hour, LCMS monitoring has generated the desired intermediate 2-methylaminoacetic acid-1- 13 C; Prepare another 25ml three-necked flask, add 480mg, 12mmol, 4eq of NaOH, 4.5mL of deionized water, stir for 10min, then add 2.4g, 15mmol, 5eq of Br2, stir at room temperature for 1h, and 2-methylaminoacetic acid-1- 13 The reaction system of C was added dropwise to the obtained reaction solution, and after stirring at room temperature for 1 hour, LCMS monitoring showed that no 2-methylaminoacetic acid-1- 13 C, adjust the pH to 2 or 3 with concentrated hydrochloric acid, extract with ethyl acetate, combine the organic phases and then wash with water and saturated brine, column chromatography to obtain 135 mg of 2-glyoxylic acid-1- 13 C.
3. The glyoxylic acid derivative according to claim 1 13 The preparation method of C is characterized in that The steps include: In a 10 mL two-necked flask, add 439 mg, 6.5 mmol, 1.3 eq of methylamine hydrochloride, 527 mg, 6.5 mmol, 1.3 eq, 37% formaldehyde solution, and 331 mg, 5 mmol, 1 eq of K 13 CN, 4 mL of deionized water, nitrogen replacement, stirring at 80 ° C for 3 hours, adding 1.6 g, 40 mmol of NaOH, heating and stirring for 1 hour, LCMS monitoring has generated the desired intermediate 2-methylaminoacetic acid-1- 13 C. Prepare another 25ml three-necked flask, add 800mg, 20mmol, 4eq of NaOH, 7.5mL of deionized water, stir for 10min, then add 4.0g, 25mmol, 5eq of Br2, stir at room temperature for 1h, and 2-methylaminoacetic acid-1- 13 The reaction system of C was added dropwise to the obtained reaction solution, and after stirring at room temperature for 1 hour, LCMS monitoring showed that no 2-methylaminoacetic acid-1- 13 C, adjust the pH to 2 or 3 with concentrated hydrochloric acid, extract with ethyl acetate, combine the organic phases and then wash with water and saturated brine, column chromatography to obtain 244 mg of 2-glyoxylic acid-1- 13 C.
4. The glyoxylic acid derivative according to claim 1 13 The preparation method of C is characterized in that The steps include: In a 10 mL two-necked flask, add 88 mg, 1.3 mmol, 1.3 eq of methylamine hydrochloride, 105 mg, 1.3 mmol, 1.3 eq of 37% formaldehyde solution, and 66 mg, 1 mmol, 1 eq of K 13 CN, 1 mL of deionized water, nitrogen replacement, stirring at 80 ° C for 3 hours, adding 400 mg, 10 mmol of NaOH, heating and stirring for 1 hour, LCMS monitoring has generated the desired intermediate 2-methylaminoacetic acid-1- 13 C; Prepare another 25ml three-necked flask, add 240mg, 6mmol, 2eq of NaOH and 2.5mL of deionized water, stir for 10min, then add 800mg, 5mmol, 5eq of Br2, stir at room temperature for 1h, and 2-methylaminoacetic acid-1- 13 The reaction system of C was added dropwise to the obtained reaction solution, and after stirring at room temperature for 1 hour, LCMS monitoring showed that no 2-methylaminoacetic acid-1- 13 C, adjust the pH to 2 or 3 with concentrated hydrochloric acid, extract with ethyl acetate, combine the organic phases and then wash with water and saturated brine, column chromatography to obtain 40 mg of 2-glyoxylic acid-1- 13 C.