CN116082153A - Acrylic ester derivative 13 Process for the preparation of C - Google Patents

Acrylic ester derivative 13 Process for the preparation of C Download PDF

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CN116082153A
CN116082153A CN202211589372.3A CN202211589372A CN116082153A CN 116082153 A CN116082153 A CN 116082153A CN 202211589372 A CN202211589372 A CN 202211589372A CN 116082153 A CN116082153 A CN 116082153A
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crude product
ester derivative
acrylic acid
reaction
alanine
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陈晓晖
伍君
谭雅彬
李刚
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Changsha Beita Pharmatech Co ltd
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Changsha Beita Pharmatech Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • 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
    • 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
    • C07C227/14—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
    • C07C227/18—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 involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses an acrylic ester derivative- 13 The preparation method of C comprises the following steps: step one: 3-hydroxy propionitrile-1- 13 Preparing a crude product C; step two: 3-hydroxy propionitrile-1- 13 Placing the crude product of C in a closed tank to prepare and react into N, N-dimethyl-beta-alanine-1- 13 C, crude product; step three: with N, N-dimethyl-beta-alanine-1- 13 The crude product of C is taken as a backing material and synthesized into acrylic ester derivative 13 C. The invention adopts N, N-dimethyl-beta-alanine to replace acrylic acid for ester condensation reaction, avoids acrylic acid polymerization reaction in the process of synthesizing acrylic acid and ester condensation, thereby improving reaction yield and filling the blank of synthesizing the isotope labeled acrylic ester derivative in China.

Description

Acrylic ester derivative 13 Process for the preparation of C
Technical Field
The invention relates to the technical field of acrylic ester derivatives, in particular to an acrylic ester derivative- 13 C, preparation method.
Background
The acrylic ester derivative is an important high molecular monomer and a basic organic chemical raw material. The polymer has stable chemical property, can meet the requirements of different pharmaceutical dosage forms, and is widely applied to pharmaceutical preparations. Because the chemical property of the acrylic acid and the derivative thereof, namely the acrylic acid and the acrylic acid derivative, is active, and the acrylic acid derivative are easy to polymerize under the conditions of air and illumination, the synthesis yield of the carbon acrylate derivative marked by the synthetic isotope in the traditional ester condensation mode is lower.
DiemDuyLe (J.Labelled Cpd. Radio handle.43, 1107-1111 (2000)) et al reported that reaction of 14C-labeled carbon dioxide with vinylmagnesium bromide gave 14C-labeled acrylic acid, and synthesis thereof gave 14C-labeled methyl acrylate in lower yields. Gift corporation (WO 2021/118877) reports the use of vinylmagnesium bromide with 13 C-labeled carbon dioxide is synthesized by reaction 13 C-labeled acrylic acid also has a problem of low yield.
The existing method for labeling acrylic acid by using synthetic isotopes mainly comprises the following steps:
DiemDuyLe (J. Labelled Cpd. Radiopharm.43,1107-1111 (2000)) et al reported that reaction of 14C-labeled carbon dioxide with vinylmagnesium bromide gave 14C-labeled acrylic acid, and synthesis thereof gave 14C-labeled methyl acrylate, which was 24% in yield and lower in yield, calculated as its specific activity.
2. Gift corporation (WO 2021/118877) reports the use of vinylmagnesium bromide with 13 C-labeled carbon dioxide is synthesized by reaction 13 C-labeled acrylic acid, which has a yield of 24%, also has a problem of excessively low yield. Based on the above, the invention provides an acrylic ester derivative 13 C, preparation method.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide an acrylic ester derivative- 13 The preparation method of C solves the problems in the prior art.
The invention solves the technical problems by adopting the following technical scheme:
the invention provides an acrylic esterDerivatives of the generic class- 13 The preparation method of C comprises the following steps:
step one: 3-hydroxy propionitrile-1- 13 Preparing a crude product C;
step two: 3-hydroxy propionitrile-1- 13 Placing the crude product of C in a closed tank to prepare and react into N, N-dimethyl-beta-alanine-1- 13 C, crude product;
step three: with N, N-dimethyl-beta-alanine-1- 13 The crude product of C is taken as a backing material and synthesized into acrylic ester derivative 13 C。
Preferably, the 3-hydroxypropionitrile-1- 13 The specific reaction process in the preparation of the crude product C is as follows:
s1: under the protection of nitrogen, adding 2-bromoethanol and K into a 25mL single-neck flask 13 CN, deionized water and absolute ethyl alcohol, heating to 80 ℃ and stirring for 6 hours;
s2: the cyanide detection shows that the raw materials are completely reacted, the reaction solution is cooled to room temperature, the solvent is removed by concentration, 5mL of acetone is added, stirring is carried out at room temperature for 20 minutes, filtration is carried out, filtrate is collected, and the solvent is removed by concentration, thus obtaining the 3-hydroxy propionitrile-1- 13 C crude product.
Preferably, the 2-bromoethanol, K 13 The amounts of CN, deionized water and absolute ethanol added were 524.8mg, 132mg, 1.6mL and 3.2mL, respectively.
Preferably, the 3-hydroxypropionitrile-1- 13 In the synthesis process of C, 2-bromoethanol can be used as a raw material, and 2-chloroethanol can be used as a starting material.
Preferably, the N, N-dimethyl-beta-alanine- 13 The preparation reaction process of the crude product C comprises the following steps:
s01: 3-hydroxy propionitrile-1- 13 Placing the crude product C in a closed tank, adding 4mL of concentrated hydrochloric acid, heating to 130 ℃ for reaction for 7 hours, adding 8mL of water, extracting with ethyl acetate, concentrating and removing the solvent to obtain 3-chloropropionic acid-1- 13 C, crude product;
s02: 3-Chloropropionic acid-1- 13 Placing the crude product C in a 25mL single-neck flask, adding dimethylamine hydrochloride, sodium iodide, potassium carbonate, acetone and stirring at room temperature for 20 minutes, then heating to 60 ℃ for reaction for 6 hours, and detecting the raw materials by TLCThe reaction is complete, and the solvent is removed by concentration;
s03: adding 10mL of water, regulating the pH of the system to 6-7 by adopting 1N hydrochloric acid aqueous solution, concentrating and removing water to obtain N, N-dimethyl-beta-alanine- 13 C crude product.
Preferably, the addition amounts of dimethylamine hydrochloride, sodium iodide, potassium carbonate and acetone are 489mg, 90mg, 1.1g and 5mL respectively.
Preferably, the acrylic acid ester derivative 13 C is 2- (triphenylmethoxy) ethyl acrylate-1- 13 C. 2- (benzyloxy) ethyl acrylate-1 13 C and 3- (tert-butoxy) -3-oxopropyl acrylate-1- 13 One of C.
Preferably, the 2- (triphenylmethoxy) ethyl acrylate-1- 13 The synthetic reaction method of C is as follows:
s11: n, N-dimethyl-beta-alanine-1- 13 Placing the crude product C in a 25mL single-neck flask, adding 2- (trityl) ethanol, 4-dimethylaminopyridine and methylene dichloride, stirring at room temperature for 20 minutes, then adding N, N' -dicyclohexylcarbodiimide, and stirring the reaction solution at room temperature for 16 hours;
s12: TLC showed N, N-dimethyl-beta-alanine-1- 13 The reaction C is completed, methylene dichloride (20 mL) is added, saturated ammonium chloride aqueous solution is used for washing, the organic phase anhydrous sodium sulfate is dried, and the 2- (triphenylmethoxy) ethyl 3- (dimethylamino) propionate-1- 13 C, crude product;
s13: 2- (triphenylmethoxy) ethyl 3- (dimethylamino) propionate-1- 13 Placing the C crude product into a 25mL single-neck flask, adding 6mL of N, N-dimethylformamide for dissolution, then adding 125mg of 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine, 74mg of triethylamine, reacting at room temperature for 30 minutes after the addition, TLC (thin layer chromatography) indicating that the raw material is completely reacted, adding 20mL of water, extracting with ethyl acetate, washing an organic phase with saturated saline, and performing column chromatography to obtain 2- (triphenylmethoxy) ethyl acrylate-1- 13 C。
Preferably, the 2- (tritoxy) ethanol, 4-dimethylaminopyridine, methylene chloride, N' -dicyclohexyl-carbodiimide are added in amounts of 731mg, 49mg, 8mL and 495mg, respectively.
Preferably, the 2- (triphenylmethoxy) ethyl acrylate-1- 13 C. 2- (benzyloxy) ethyl acrylate-1- 13 C and 3- (tert-butoxy) -3-oxopropyl acrylate-1- 13 In the synthesis process of C, besides adopting 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine and triethylamine as elimination reagents, methyl iodide and sodium bicarbonate can also be adopted to carry out Huffman elimination reaction.
Compared with the prior art, the invention has the following beneficial effects:
1. according to the invention, N-dimethyl-beta-alanine is adopted to replace acrylic acid to carry out ester condensation reaction, so that acrylic acid polymerization reaction in the acrylic acid synthesis process and the ester condensation process is avoided, the reaction yield is improved, and the blank of the synthesis of the isotope labeled acrylic acid ester derivative in China is filled;
2. the carbon dioxide reaction device with high air tightness requirement is avoided, the marked potassium cyanide which is easily obtained in the market is directly used as the initial raw material, the reaction condition is mild, and the realization is easy;
3. the invention avoids the self-polymerization reaction of acrylic acid and improves the reaction yield.
Drawings
FIG. 1 is a schematic view of 2- (triphenylmethoxy) ethyl acrylate-1- 13 C, synthesizing a reaction diagram;
FIG. 2 is a schematic illustration of 2- (benzyloxy) ethyl acrylate-1- 13 C, synthesizing a reaction diagram;
FIG. 3 is a schematic illustration of 3- (tert-butoxy) -3-oxopropyl acrylate-1-) 13 C, synthesizing a reaction diagram.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Referring to FIGS. 1-3, an acrylic acid ester derivative according to the present embodiment 13 The preparation method of C comprises the following steps:
step one: 3-hydroxy propionitrile-1- 13 Preparing a crude product C;
step two: 3-hydroxy propionitrile-1- 13 Placing the crude product of C in a closed tank to prepare and react into N, N-dimethyl-beta-alanine-1- 13 C, crude product;
step three: with N, N-dimethyl-beta-alanine-1- 13 The crude product of C is taken as a backing material and synthesized into acrylic ester derivative 13 C。
The 3-hydroxypropionitrile-1- 13 The specific reaction process in the preparation of the crude product C is as follows:
s1: under the protection of nitrogen, adding 2-bromoethanol and K into a 25mL single-neck flask 13 CN, deionized water and absolute ethyl alcohol, heating to 80 ℃ and stirring for 6 hours;
s2: the cyanide detection shows that the raw materials are completely reacted, the reaction solution is cooled to room temperature, the solvent is removed by concentration, 5mL of acetone is added, stirring is carried out at room temperature for 20 minutes, filtration is carried out, filtrate is collected, and the solvent is removed by concentration, thus obtaining the 3-hydroxy propionitrile-1- 13 C crude product.
2-Bromoethanol, K of the example 13 The amounts of CN, deionized water and absolute ethanol added were 524.8mg, 132mg, 1.6mL and 3.2mL, respectively.
The 3-hydroxypropionitrile-1- 13 In the synthesis process of C, 2-bromoethanol can be used as a raw material, and 2-chloroethanol can be used as a starting material.
N, N-dimethyl-beta-alanine- 13 The preparation reaction process of the crude product C comprises the following steps:
s01: 3-hydroxy propionitrile-1- 13 Placing the crude product C in a closed tank, adding 4mL of concentrated hydrochloric acid, heating to 130 ℃ for reaction for 7 hours, adding 8mL of water, extracting with ethyl acetate, concentrating and removing the solvent to obtain 3-chloropropionic acid-1- 13 C, crude product;
s02: 3-Chloropropionic acid-1- 13 Placing the crude product C in a 25mL single-neck flask, adding dimethylamine hydrochloride, sodium iodide, potassium carbonate, acetone, stirring at room temperature for 20 minutes, and thenHeating to 60 ℃ for reaction for 6 hours, detecting that the raw materials are completely reacted by TLC, concentrating and removing the solvent;
s03: adding 10mL of water, regulating the pH of the system to 6-7 by adopting 1N hydrochloric acid aqueous solution, concentrating and removing water to obtain N, N-dimethyl-beta-alanine- 13 C crude product.
The amounts of dimethylamine hydrochloride, sodium iodide, potassium carbonate, and acetone added in this example were 489mg, 90mg, 1.1g, and 5mL, respectively.
Acrylic acid ester derivative of this example 13 C is 2- (triphenylmethoxy) ethyl acrylate-1- 13 C. 2- (benzyloxy) ethyl acrylate-1 13 C and 3- (tert-butoxy) -3-oxopropyl acrylate-1- 13 One of C.
2- (triphenylmethoxy) ethacrylate-1- 13 The synthetic reaction method of C is as follows:
s11: n, N-dimethyl-beta-alanine-1- 13 Placing the crude product C in a 25mL single-neck flask, adding 2- (trityl) ethanol, 4-dimethylaminopyridine and methylene dichloride, stirring at room temperature for 20 minutes, then adding N, N' -dicyclohexylcarbodiimide, and stirring the reaction solution at room temperature for 16 hours;
s12: TLC showed N, N-dimethyl-beta-alanine-1- 13 The reaction C is completed, methylene dichloride (20 mL) is added, saturated ammonium chloride aqueous solution is used for washing, the organic phase anhydrous sodium sulfate is dried, and the 2- (triphenylmethoxy) ethyl 3- (dimethylamino) propionate-1- 13 C, crude product;
s13: 2- (triphenylmethoxy) ethyl 3- (dimethylamino) propionate-1- 13 Placing the C crude product into a 25mL single-neck flask, adding 6mL of N, N-dimethylformamide for dissolution, then adding 125mg of 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine, 74mg of triethylamine, reacting at room temperature for 30 minutes after the addition, TLC (thin layer chromatography) indicating that the raw material is completely reacted, adding 20mL of water, extracting with ethyl acetate, washing an organic phase with saturated saline, and performing column chromatography to obtain 2- (triphenylmethoxy) ethyl acrylate-1- 13 C。
The amounts of 2- (trityloxy) ethanol, 4-dimethylaminopyridine, methylene chloride and N, N' -dicyclohexylcarbodiimide added in this example were 731mg, 49mg, 8mL and 495mg, respectively.
2- (triphenylmethoxy) ethacrylate-1- 13 C. 2- (benzyloxy) ethyl acrylate-1- 13 C and 3- (tert-butoxy) -3-oxopropyl acrylate-1- 13 In the synthesis process of C, besides adopting 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine and triethylamine as elimination reagents, methyl iodide and sodium bicarbonate can also be adopted to carry out Huffman elimination reaction.
Example 1:
in step two, N-dimethyl-beta-alanine-1- 13 Based on the preparation of the crude product of C, N-dimethyl-beta-alanine-1- 13 The crude C was placed in a 25mL single-neck flask, 2- (trityloxy) ethanol (731 mg), 4-dimethylaminopyridine (49 mg) and methylene chloride (8 mL) were added, stirred at room temperature for 20 minutes, then N, N' -dicyclohexylcarbodiimide (495 mg) was added, and the reaction mixture was stirred at room temperature for 16 hours, and TLC showed N, N-dimethyl- β -alanine-1- 13 The reaction C is completed, methylene dichloride (20 mL) is added, saturated ammonium chloride aqueous solution is used for washing, the organic phase anhydrous sodium sulfate is dried, and the 2- (triphenylmethoxy) ethyl 3- (dimethylamino) propionate-1- 13 C crude product. 2- (triphenylmethoxy) ethyl 3- (dimethylamino) propionate-1- 13 Placing the C crude product into a 25mL single-neck flask, adding N, N-dimethylformamide (6 mL) for dissolution, then adding 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (125 mg), triethylamine (74 mg), after the addition, reacting for 30 minutes at room temperature, TLC (thin layer chromatography) shows that the raw material is completely reacted, adding water (20 mL), extracting with ethyl acetate, washing an organic phase with saturated saline solution, and performing column chromatography to obtain 2- (triphenylmethoxy) ethyl acrylate-1- 13 C(335mg,yield 48％)。
Example 2:
in step two, N-dimethyl-beta-alanine-1- 13 Based on the preparation of the crude product of C, N-dimethyl-beta-alanine-1- 13 The crude C was placed in a 25mL single-neck flask, 2- (benzyloxy) ethanol (547 mg), 4-dimethylaminopyridine (74 mg) and methylene chloride (12 mL) were added, stirred at room temperature for 20 minutes, then N, N' -dicyclohexylcarbodiimide (743 mg) was added, the reaction solution was stirred at room temperature for 16 hours, and TLC showed N, N-dimethyl- β -propylAmino acid-1- 13 The reaction C is completed, methylene dichloride (20 mL) is added, saturated ammonium chloride aqueous solution is used for washing, the organic phase anhydrous sodium sulfate is dried, and the 2- (benzyloxy) ethyl 3- (dimethylamino) propionate-1- 13 C crude product. 2- (benzyloxy) ethyl 3- (dimethylamino) propionate-1- 13 Placing the C crude product into a 25mL single-neck flask, adding N, N-dimethylformamide (9 mL) for dissolution, then adding 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (188 mg), triethylamine (111 mg), after the addition, reacting for 30 minutes at room temperature, TLC (thin layer chromatography) shows that the raw material is completely reacted, adding water (30 mL), extracting with ethyl acetate, washing an organic phase with saturated saline solution, and performing column chromatography to obtain 2- (benzyloxy) ethyl acrylate-1- 13 C(279mg,yield 45％)。
Example 3:
in step two, N-dimethyl-beta-alanine-1- 13 Based on the preparation of the crude product of C, N-dimethyl-beta-alanine-1- 13 The crude C was placed in a 25mL single-neck flask, tert-butyl 3-hydroxypropionate (525 mg), 4-dimethylaminopyridine (74 mg) and methylene chloride (12 mL) were added, stirred at room temperature for 20 minutes, then N, N' -dicyclohexylcarbodiimide (743 mg) was added, and the reaction mixture was stirred at room temperature for 16 hours, and TLC showed N, N-dimethyl- β -alanine-1- 13 The reaction C was completed, methylene chloride (20 mL) was added thereto, the mixture was washed with saturated ammonium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, and the 3- (t-butoxy) -3-oxopropyl 3- (dimethylamino) propionate-1-one was purified by column chromatography 13 C crude product. 3- (tert-butoxy) -3-oxopropyl 3- (dimethylamino) propionate-1- 13 The crude product of C is placed in a 25mL single-neck flask, N-dimethylformamide (9 mL) is added for dissolution, then 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (188 mg) and triethylamine (111 mg) are added, reaction is carried out for 30 minutes at room temperature after the addition, TLC shows that the raw material is completely reacted, water (30 mL) is added, ethyl acetate is used for extraction, an organic phase is washed by saturated saline solution, and column chromatography is carried out to obtain 3- (tert-butoxy) -3-oxo propyl acrylate-1- 13 C(242mg,yield 40％)。
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.

Claims (10)

1. Acrylic ester derivative 13 The preparation method of C is characterized by comprising the following steps:
step one: 3-hydroxy propionitrile-1- 13 Preparing a crude product C;
step two: 3-hydroxy propionitrile-1- 13 Placing the crude product of C in a closed tank to prepare and react into N, N-dimethyl-beta-alanine-1- 13 C, crude product;
step three: with N, N-dimethyl-beta-alanine-1- 13 The crude product of C is taken as a backing material and synthesized into acrylic ester derivative 13 C。
2. An acrylic acid ester derivative according to claim 1 13 A process for producing C, characterized in that the 3-hydroxypropionitrile-1- 13 The specific reaction process in the preparation of the crude product C is as follows:
s1: under the protection of nitrogen, adding 2-bromoethanol and K into a 25mL single-neck flask 13 CN, deionized water and absolute ethyl alcohol, heating to 80 ℃ and stirring for 6 hours;
s2: the cyanide detection shows that the raw materials are completely reacted, the reaction solution is cooled to room temperature, the solvent is removed by concentration, 5mL of acetone is added, stirring is carried out at room temperature for 20 minutes, filtration is carried out, filtrate is collected, and the solvent is removed by concentration, thus obtaining the 3-hydroxy propionitrile-1- 13 C crude product.
3. An acrylic acid ester derivative according to claim 1 13 C, characterized in that the preparation method of the 2-bromoethanol and the K 13 The amounts of CN, deionized water and absolute ethanol added were 524.8mg, 132mg, 1.6mL and 3.2mL, respectively.
4. An acrylic acid ester derivative according to claim 2 13 A process for producing C, characterized in that the 3-hydroxypropionitrile-1- 13 In the synthesis process of C, 2-bromoethanol can be used as a raw material, and 2-chloroethanol can be used as a starting material.
5. An acrylic acid ester derivative according to claim 1 13 C, characterized in that the above-mentioned N, N-dimethyl-beta-alanine- 13 The preparation reaction process of the crude product C comprises the following steps:
s01: 3-hydroxy propionitrile-1- 13 Placing the crude product C in a closed tank, adding 4mL of concentrated hydrochloric acid, heating to 130 ℃ for reaction for 7 hours, adding 8mL of water, extracting with ethyl acetate, concentrating and removing the solvent to obtain 3-chloropropionic acid-1- 13 C, crude product;
s02: 3-Chloropropionic acid-1- 13 Placing the crude product C in a 25mL single-neck flask, adding dimethylamine hydrochloride, sodium iodide, potassium carbonate, acetone and stirring at room temperature for 20 minutes, then heating to 60 ℃ for reaction for 6 hours, detecting that the raw materials are completely reacted by TLC, and concentrating to remove the solvent;
s03: adding 10mL of water, regulating the pH of the system to 6-7 by adopting 1N hydrochloric acid aqueous solution, concentrating and removing water to obtain N, N-dimethyl-beta-alanine- 13 C crude product.
6. An acrylic acid ester derivative according to claim 5 13 The preparation method of C is characterized in that the addition amounts of dimethylamine hydrochloride, sodium iodide, potassium carbonate and acetone are 489mg, 90mg, 1.1g and 5mL respectively.
7. According to claim1, an acrylic acid ester derivative- 13 The process for producing C, characterized in that the acrylic acid ester derivative 13 C is 2- (triphenylmethoxy) ethyl acrylate-1- 13 C. 2- (benzyloxy) ethyl acrylate-1 13 C and 3- (tert-butoxy) -3-oxopropyl acrylate-1- 13 One of C.
8. An acrylic acid ester derivative according to claim 5 13 C, characterized in that the 2- (triphenylmethoxy) ethyl acrylate-1- 13 The synthetic reaction method of C is as follows:
s11: n, N-dimethyl-beta-alanine-1- 13 Placing the crude product C in a 25mL single-neck flask, adding 2- (trityl) ethanol, 4-dimethylaminopyridine and methylene dichloride, stirring at room temperature for 20 minutes, then adding N, N' -dicyclohexylcarbodiimide, and stirring the reaction solution at room temperature for 16 hours;
s12: TLC showed N, N-dimethyl-beta-alanine-1- 13 The reaction C is completed, methylene dichloride (20 mL) is added, saturated ammonium chloride aqueous solution is used for washing, the organic phase anhydrous sodium sulfate is dried, and the 2- (triphenylmethoxy) ethyl 3- (dimethylamino) propionate-1- 13 C, crude product;
s13: 2- (triphenylmethoxy) ethyl 3- (dimethylamino) propionate-1- 13 Placing the C crude product into a 25mL single-neck flask, adding 6mL of N, N-dimethylformamide for dissolution, then adding 125mg of 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine, 74mg of triethylamine, reacting at room temperature for 30 minutes after the addition, TLC (thin layer chromatography) indicating that the raw material is completely reacted, adding 20mL of water, extracting with ethyl acetate, washing an organic phase with saturated saline, and performing column chromatography to obtain 2- (triphenylmethoxy) ethyl acrylate-1- 13 C。
9. An acrylic acid ester derivative according to claim 8 13 The preparation method of C is characterized in that the addition amounts of the 2- (trityl) ethanol, 4-dimethylaminopyridine, methylene dichloride and N, N' -dicyclohexyl carbodiimide are 731mg, 49mg, 8mL and 495mg respectively.
10. An acrylic acid ester derivative according to claim 8 13 C, characterized in that the 2- (triphenylmethoxy) ethyl acrylate-1- 13 C. 2- (benzyloxy) ethyl acrylate-1- 13 C and 3- (tert-butoxy) -3-oxopropyl acrylate-1- 13 In the synthesis process of C, besides adopting 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine and triethylamine as elimination reagents, methyl iodide and sodium bicarbonate are adopted to carry out Huffman elimination reaction.
CN202211589372.3A 2022-12-09 2022-12-09 Acrylic ester derivative 13 Process for the preparation of C Pending CN116082153A (en)

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