A process for the preparation of a lactamide 13 of formula (I)

Abstract

This invention belongs to the field of chemical synthesis technology and discloses a lactamide- 13 The preparation method of C includes the following steps: under nitrogen protection, acetaldehyde is added, and K is added. 13 CN, add 1 ml H2O, purge with nitrogen, add 30% sulfuric acid aqueous solution, react to complete, add sodium chloride solid until supersaturated, extract, and evaporate to dryness to obtain a yellow oily liquid; add 2-hydroxypropionitrile-1- 13 C. Add acetic acid, add hexamethylenetetramine, purge with nitrogen, allow the reaction to complete, add palladium nitrate, react for 30 minutes, concentrate, and column chromatography to obtain 2-hydroxypropionamide-1- 13 C. This invention avoids the use of reaction equipment with high airtightness requirements and low-temperature reaction conditions down to -78°C. It directly uses commercially available labeled potassium cyanide as the starting material, and the reaction conditions are mild and easy to implement. Moreover, the two-step reaction yield of this invention is higher than that of the prior art.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a lactamide- 13 Preparation method of C. Background Technology

[0002] The description of the background art in this invention pertains to related technologies and is used merely for illustration and to facilitate understanding of the invention. It should not be construed as the applicant explicitly believing or presuming that the invention was prior art on the filing date of the first application.

[0003] Lactic acid is an important chemical raw material widely used in pharmaceuticals, pesticides, cosmetics, and other fields. In cosmetics and skincare products, it primarily functions as a skin conditioning agent, with a relatively low risk factor and high safety, giving it a significant advantage in the cosmetics and skincare industry. With the continuous improvement of people's living standards, the demand for cosmetics and skincare products is also constantly increasing, and lactamide, due to its wide application, has a very promising future. There are many methods for synthesizing lactamide, with the main production methods currently being synthesis and natural drug extraction. Hoshino, Jun-ichi; Yamamoto, Yukio; Hasegawa, Takeshi; Takahashi, Sho; Sawada, Seiji [Bioscience, Biotechnology and Biochemistry, 1994, vol. 58, #11, pp. 1939-1941] et al. reported the use of acetaldehyde and... 13 The reaction of C-labeled sodium cyanide yields 13 C-labeled lactonitrile, but no subsequent synthesis was performed. 13 C-labeled lactamide. Kanda, Tomoya ; Naraoka, Asuka ; Naka, Hiroshi [Journal of the American Chemical Society, 2019, vol. 141, #2, pp. 825-830] reports the reaction of lactonitrile with hexamethylenetetramine and acetic acid to obtain lactamide. The industrial method involves cooling ethyl lactate to below -78°C, adding liquid ammonia, and allowing the mixture to rise to room temperature in an autoclave. After 24 hours, excess ammonia is discharged. Unreacted ethyl lactate and ethanol produced in the reaction mixture are dissolved in anhydrous diethyl ether. The mixture is filtered, the filter cake is washed with diethyl ether, and dried to obtain lactamide. This method suffers from slightly low yields and stringent reaction conditions. Summary of the Invention

[0004] The purpose of this invention is to provide a lactamide- 13The method for preparing C avoids the use of reaction equipment with high airtightness requirements and low-temperature reaction conditions of -78°C. It directly uses commercially available labeled potassium cyanide as the starting material, and the reaction conditions are mild and easy to implement. Moreover, the two-step reaction yield of the present invention is higher than that of the prior art.

[0005] A type of lactamide- 13 The preparation method of C includes the following steps:

[0006] Under nitrogen protection, acetaldehyde and K were added. 13 CN, add 1 ml H2O, replace with nitrogen, add 30% sulfuric acid aqueous solution, react until complete, add sodium chloride solid until supersaturated, extract, and evaporate to dryness to obtain a yellow oily liquid;

[0007] Add 2-hydroxypropionitrile-1- 13 C. Add acetic acid, add hexamethylenetetramine, purge with nitrogen, allow the reaction to complete, add palladium nitrate, react for 30 minutes, concentrate, and column chromatography to obtain 2-hydroxypropionamide-1- 13 C.

[0008] Furthermore, after adding a 30% sulfuric acid aqueous solution, a sample was taken, and cyanide detection showed that the raw materials had reacted completely.

[0009] Further, the extraction was performed three times by adding excess diethyl ether.

[0010] Furthermore, after adding palladium nitrate, TLC was used for spot monitoring. Since there was no raw material left, the sample was concentrated, mixed directly with silica gel, and then subjected to column chromatography.

[0011] Furthermore, 2-hydroxypropionitrile-1- 13 C can be replaced with methyl lactate or ethyl lactate.

[0012] Further steps include the following:

[0013] Under nitrogen protection, 503 mg of acetaldehyde and 65 mg of potassium were added to a 10 ml three-necked flask. 13 CN, add 1 ml H2O, purge with nitrogen, add 30% sulfuric acid aqueous solution, incubate overnight at room temperature, take a sample, cyanide detection shows that the reactants have reacted completely, add sodium chloride solid to the system until supersaturated, add a large amount of diethyl ether for extraction three times, aspirate the upper diethyl ether solution, evaporate to dryness to obtain a yellow oily liquid for the next step; add 2-hydroxypropionitrile-1- in a 50 ml single-necked flask 13 C. Add 2 ml of acetic acid, add 461 mg of hexamethylenetetramine, purge with nitrogen, react at 50 °C for half an hour, add 4 mg of palladium nitrate, and continue the reaction for 30 minutes; monitor by TLC, no raw material remains, slightly concentrate, add silica gel directly to the sample, and column chromatography to obtain 2-hydroxypropionamide-1- 13 C.

[0014] Further steps include the following:

[0015] Under nitrogen protection, 880 mg of acetaldehyde and 325 mg of potassium were added to a 10 ml three-necked flask. 13 CN, add 1 ml H2O, purge with nitrogen, add 30% sulfuric acid aqueous solution, incubate overnight at room temperature, take a sample, cyanide detection shows that the starting material has reacted completely, add sodium chloride solid to the system until supersaturated, extract three times with a large amount of diethyl ether, remove the upper diethyl ether solution, evaporate to dryness to obtain a yellow oily liquid for the next step. Add 2-hydroxypropionitrile-1- to a 50 ml single-necked flask. 13 C. Add 10 ml of acetic acid, add 2303 mg of hexamethylenetetramine, purge with nitrogen, react at 50 °C for half an hour, add 20 mg of palladium nitrate, and continue the reaction for 30 minutes. Monitor by TLC; no starting material remains. Slightly concentrate, add silica gel directly, and column chromatography to obtain 2-hydroxypropionamide-1- 13 C.

[0016] Further steps include the following:

[0017] Under nitrogen protection, 1.16g of propionaldehyde and 325mg of potassium were added to a 10ml three-necked flask. 13 CN, add 1 ml H2O, purge with nitrogen, add 30% sulfuric acid aqueous solution, incubate overnight at room temperature, take a sample, cyanide detection shows that the starting material has reacted completely, add sodium chloride solid to the system until supersaturated, extract three times with a large amount of diethyl ether, aspirate the upper diethyl ether solution, evaporate to dryness to obtain a yellow oily liquid for the next step. Add 2-hydroxybutyronitrile-1-13C to a 50 ml single-necked flask, add 10 ml acetic acid, add 2303 mg hexamethylenetetramine, purge with nitrogen, react at 50 °C for half an hour, add 20 mg palladium nitrate, and continue the reaction for 30 minutes. TLC monitoring shows that there is no starting material left, slightly concentrate, add silica gel directly and mix, column chromatography to obtain 2-hydroxybutyronitrile-1-13C.

[0018] The embodiments of the present invention have the following beneficial effects:

[0019] This invention uses acetaldehyde and 13 The reaction of C-labeled potassium cyanide yields 13 C-labeled lactonitrile, then reacted with hexamethylenetetramine, acetic acid, and palladium nitrate to give 13 C-labeled lactamide fills the gap in the domestic synthesis of isotope-labeled lactamide.

[0020] This invention avoids the use of reaction equipment with high airtightness requirements and low-temperature reaction conditions of -78°C. It directly uses commercially available labeled potassium cyanide as the starting material, and the reaction conditions are mild and easy to implement. Moreover, the two-step reaction yield of this invention is higher than that of the prior art. Detailed Implementation

[0021] The present application will be further described below with reference to the embodiments.

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, in the following description, different "an embodiment" or "an embodiment" do not necessarily refer to the same embodiment. Different embodiments can be substituted or combined, and for those skilled in the art, other implementation methods can be obtained based on these embodiments without creative effort.

[0023] Example 1

[0024] Synthesis of 2-hydroxypropionamide-1- 13 C:

[0025]

[0026] Under nitrogen protection, acetaldehyde (503 mg, 4 mmol, 4 eq) was added to a 10 ml three-necked flask, followed by K. 13 CN (65 mg, 1 mmol, 1 eq) was added to 1 ml of H₂O, purged with nitrogen, and then incubated overnight at room temperature. A sample was taken; cyanide detection showed the reactants had reacted completely. Sodium chloride solid was added to the system until supersaturated, and the mixture was extracted three times with a large amount of diethyl ether. The upper ether layer was removed, and the solution was evaporated to dryness to obtain a yellow oily liquid for the next step. 2-Hydroxypropionitrile-1- was added to a 50 ml single-necked flask. 13 C. Add 2 ml of acetic acid, then add hexamethylenetetramine (461 mg, 4 mmol, 4 eq), purge with nitrogen, and react at 50 °C for half an hour. Add palladium nitrate (4 mg, 0.02, 0.02 eq) and continue the reaction for 30 minutes. Monitor by TLC; no more starting material is available. Slightly concentrate the sample, add silica gel directly, and column chromatography to obtain 2-hydroxypropionamide-1- 13 C (57mg, yield 63%).

[0027] Example 2.

[0028] Synthesis of 2-hydroxypropionamide-1- 13 C

[0029]

[0030] Under nitrogen protection, acetaldehyde (880 mg, 20 mmol, 4 eq) was added to a 10 ml three-necked flask, followed by K. 13CN (325 mg, 5 mmol, 1 eq) was added to 1 ml of H₂O, purged with nitrogen, and then incubated overnight at room temperature. A sample was taken; cyanide detection showed the reactants had reacted completely. Sodium chloride solid was added to the system until supersaturated, and the mixture was extracted three times with a large amount of diethyl ether. The upper ether layer was removed, and the solution was evaporated to dryness to obtain a yellow oily liquid for the next step. 2-Hydroxypropionitrile-1- was added to a 50 ml single-necked flask. 13 C. Add 10 ml of acetic acid, then add hexamethylenetetramine (2303 mg, 20 mmol, 4 eq), purge with nitrogen, and react at 50 °C for half an hour. Add palladium nitrate (20 mg, 0.1 mmol, 0.02 eq) and continue the reaction for 30 minutes. Monitor by TLC; no more starting material is available. Slightly concentrate the sample, add silica gel directly, and column chromatography to obtain 2-hydroxypropionamide-1- 13 C (315mg, yield 70%).

[0031] Example 3.

[0032] Synthesis of 2-hydroxybutyramide-1-13C

[0033] Under nitrogen protection, propionaldehyde (1.16 g, 20 mmol, 4 eq) was added to a 10 ml three-necked flask, followed by K. 13 CN (325 mg, 5 mmol, 1 eq) was added to 1 ml of H2O, purged with nitrogen, and then 30% sulfuric acid aqueous solution was added. The mixture was incubated overnight at room temperature. A sample was taken, and cyanide detection showed complete reaction of the starting material. Sodium chloride solid was added to the system until supersaturated. A large amount of diethyl ether was added for extraction three times. The upper ether solution was aspirated and evaporated to dryness to obtain a yellow oily liquid for the next step. 2-hydroxybutyrone-1-13C was added to a 50 ml single-necked flask, followed by 10 ml of acetic acid and hexamethylenetetramine (2303 mg, 20 mmol, 4 eq). The mixture was purged with nitrogen and reacted at 50 °C for half an hour. Palladium nitrate (20 mg, 0.1 mmol, 0.02 eq) was added, and the reaction continued for 30 minutes. TLC monitoring showed no more starting material. The mixture was slightly concentrated, and silica gel was added directly for mixing. Column chromatography yielded 2-hydroxybutyrone-1-13C (338 mg, yield 65%). In some embodiments, 2-hydroxypropionamide-1- 13 In the synthesis of C, besides using 2-hydroxypropionitrile-1- 13 C can be used as a raw material, and methyl lactate or ethyl lactate can also be used as starting materials.

[0034] In other embodiments, the present invention is also applicable to the isotope-labeled synthesis of lactamides. 14 Synthesis of C.

[0035] This invention uses acetaldehyde and 13 The reaction of C-labeled potassium cyanide yields 13 C-labeled lactonitrile, then reacted with hexamethylenetetramine, acetic acid, and palladium nitrate to give13 C-labeled lactamide fills the gap in the domestic synthesis of isotope-labeled lactamide.

[0036] This invention avoids the use of reaction equipment with high airtightness requirements and low-temperature reaction conditions of -78°C. It directly uses commercially available labeled potassium cyanide as the starting material, and the reaction conditions are mild and easy to implement. Moreover, the two-step reaction yield of this invention is higher than that of the prior art.

[0037] It should be noted that the above embodiments can be freely combined as needed. The above description is only a 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 modifications and variations. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A lactamide- 13 The method for preparing C is characterized by, Includes the following steps: Under nitrogen protection, acetaldehyde and K were added. 13 CN, add 1 ml H2O, replace with nitrogen, add 30% sulfuric acid aqueous solution, react until complete, add sodium chloride solid until supersaturated, extract, and evaporate to dryness to obtain a yellow oily liquid; Add 2-hydroxypropionitrile-1- 13 C. Add acetic acid, add hexamethylenetetramine, purge with nitrogen, allow the reaction to complete, add palladium nitrate, react for 30 min, concentrate, and column chromatography to obtain 2-hydroxypropionamide-1- 13 C.

2. The lactamide- according to claim 1 13 The method for preparing C is characterized by, After adding a 30% sulfuric acid aqueous solution, a sample was taken, and cyanide detection showed that the raw materials had reacted completely.

3. The lactamide- according to claim 1 13 The method for preparing C is characterized by, Extraction was performed three times with the addition of excess ether.

4. The lactamide according to claim 1 13 The method for preparing C is characterized by, After adding palladium nitrate, TLC was used for spot monitoring. When no raw material was available, the sample was concentrated, mixed directly with silica gel, and then subjected to column chromatography.

5. The lactamide according to claim 1 13 The method for preparing C is characterized by, Includes the following steps: Under nitrogen protection, 503 mg of acetaldehyde and 65 mg of potassium were added to a 10 ml three-necked flask. 13 CN, add 1 ml H2O, purge with nitrogen, add 30% sulfuric acid aqueous solution, incubate overnight at room temperature, take a sample, cyanide detection shows that the starting material has reacted completely, add sodium chloride solid to the system until supersaturated, add a large amount of diethyl ether for extraction three times, aspirate the upper diethyl ether solution, evaporate to dryness to obtain a yellow oily liquid for the next step; add 2-hydroxypropionitrile-1- in a 50 ml single-necked flask 13 C. Add 2 ml of acetic acid, add 461 mg of hexamethylenetetramine, purge with nitrogen, react at 50 °C for half an hour, add 4 mg of palladium nitrate, and continue the reaction for 30 minutes; monitor by TLC, no raw material remains, slightly concentrate, add silica gel directly to the sample, and column chromatography to obtain 2-hydroxypropionamide-1- 13 C.

6. The lactamide according to claim 1 13 The method for preparing C is characterized by, Includes the following steps: Under nitrogen protection, 880 mg of acetaldehyde and 325 mg of potassium were added to a 10 ml three-necked flask. 13 CN, add 1 ml H2O, purge with nitrogen, add 30% sulfuric acid aqueous solution, incubate overnight at room temperature, take a sample, cyanide detection shows that the starting material has reacted completely, add sodium chloride solid to the system until supersaturated, add a large amount of diethyl ether for extraction three times, aspirate the upper diethyl ether solution, evaporate to dryness to obtain a yellow oily liquid for the next step; add 2-hydroxypropionitrile-1- in a 50 ml single-necked flask 13 C. Add 10 ml of acetic acid, add 2303 mg of hexamethylenetetramine, purge with nitrogen, react at 50 °C for half an hour, add 20 mg of palladium nitrate, and continue the reaction for 30 minutes; monitor by TLC, no raw material remains, slightly concentrate, add silica gel directly to mix, and column chromatography to obtain 2-hydroxypropionamide-1- 13 C.

7. The lactamide- according to claim 1 13 The method for preparing C is characterized by, Includes the following steps: Under nitrogen protection, 1.16g of propionaldehyde and 325mg of potassium were added to a 10ml three-necked flask. 13 CN, add 1 ml H2O, purge with nitrogen, add 30% sulfuric acid aqueous solution, incubate overnight at room temperature, take a sample, cyanide detection shows that the starting material has reacted completely, add sodium chloride solid to the system until supersaturated, add a large amount of diethyl ether for extraction three times, aspirate the upper diethyl ether solution, evaporate to dryness to obtain a yellow oily liquid for the next step; add 2-hydroxybutyronitrile-1- in a 50 ml single-necked flask 13 C. Add 10 ml of acetic acid, add 2303 mg of hexamethylenetetramine, purge with nitrogen, react at 50 °C for half an hour, add 20 mg of palladium nitrate, and continue the reaction for 30 minutes; monitor by TLC, no raw material remains, slightly concentrate, add silica gel directly to the sample, and column chromatography to obtain 2-hydroxybutyramide-1- 13 C.

Images