CN115806511A - Synthesis method of 5-p-toluenesulfonyl pentyl-2-methyl diethyl malonate - Google Patents
Synthesis method of 5-p-toluenesulfonyl pentyl-2-methyl diethyl malonate Download PDFInfo
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- CN115806511A CN115806511A CN202211553667.5A CN202211553667A CN115806511A CN 115806511 A CN115806511 A CN 115806511A CN 202211553667 A CN202211553667 A CN 202211553667A CN 115806511 A CN115806511 A CN 115806511A
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- methylmalonate
- toluenesulfonylpentyl
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Abstract
The application relates to a method for synthesizing 5-p-toluenesulfonyl amyl-2-methyl diethyl malonate, which comprises the following steps: under the protection of inert gas, diethyl methyl malonate and sodium hydride react in an organic solvent, and then 1, 5-pentanediol di (p-toluenesulfonic acid) ester is added for reaction to generate the 5-p-toluenesulfonylpentyl-2-diethyl methyl malonate.
Description
Technical Field
The application belongs to the technical field of radiopharmaceutical chemistry, and particularly relates to an apoptosis imaging agent 18 F-2- (5-fluoro-pentyl) -2-methylmalonic acid ( 18 F-ML-10), namely diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate.
Background
Apoptosis (Apoptosis), also known as Programmed Cell Death (PCD), is a genetically regulated active Death process of cells that is distinct from necrosis and accidental Death. As an important component of the cell life cycle, apoptosis is accompanied by a series of changes in biomolecules and cell morphology.
The tumor cell apoptosis imaging is one of the methods for early evaluation of tumor treatment, and can screen the most effective treatment scheme for patients, and reduce adverse reactions and unnecessary cost caused by ineffective treatment. 18 F-2- (5-fluoro-pentyl) -2-methylmalonic acid (F: (5-fluoro-pentyl)) ( 18 F-ML-10) is the first small molecule positron drug to enter apoptosis imaging of clinical studies, which can enter cells at the early stage of apoptotic cell and accumulate in cytoplasm, and can find depolarization of cell membrane and acidification of apoptotic cells. 18 F-ML-10 has a number of labeled precursors, of which the deprotection conditions for diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate are relatively mild and the most used.
In the prior art, two methods for synthesizing 5-p-toluenesulfonylpentyl-2-methylmalonic acid diethyl ester are provided, yuan Gui et al in patent CN201310547429.8 disclose that 5-bromo-1-pentanol is used as a starting material and is synthesized into a target product through four-step reaction, and the total yield is 33%. Dewkar et al, in the literature, microfluidic radio synthesis and biodisturbation of 18 F]2- (5-fluoro-pental) -2-methyl malonic acid (J. Label company. Radiopharm 2013,56 289-294) discloses that 1, 5-dibromopentane and 2-methyl diethyl malonate are used as starting materials, a target product is generated through a two-step reaction, the total yield is 69%, but a noble metal reagent p-toluenesulfonyl is required in the reactionAnd (4) participating in the silver sulfate.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: in order to solve the problems of low synthesis yield of 5-p-toluenesulfonylpentyl-2-methylmalonic acid diethyl ester and use of a noble metal reagent in the prior art, the synthesis method of 5-p-toluenesulfonylpentyl-2-methylmalonic acid diethyl ester has high yield and does not use the noble metal reagent.
The technical scheme adopted by the invention for solving the technical problem is as follows:
a method for synthesizing 5-p-toluenesulfonylpentyl-2-methyl diethyl malonate comprises the following steps: under the protection of inert gas, reacting diethyl methylmalonate with sodium hydride in an organic solvent, and then adding 1, 5-pentanediol di (p-toluenesulfonic acid) ester to react to generate 5-p-toluenesulfonylpentyl-2-diethyl methylmalonate;
the synthetic route is as follows:
preferably, the reaction temperature of the diethyl methylmalonate and the sodium hydride is-15 ℃ to 10 ℃; the reaction time of the diethyl methylmalonate and the sodium hydride is preferably 30-90min.
Preferably, the temperature for adding 1, 5-pentanediol di (p-toluenesulfonic acid) ester is 50-100 ℃, and the reaction time is preferably 12-24h.
Preferably, the organic solvent is at least one of N, N-dimethylformamide, tetrahydrofuran, acetonitrile, N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide.
Preferably, the molar ratio of the diethyl methylmalonate, the sodium hydride and the 1, 5-pentanediol di (p-toluenesulfonic acid) ester is 1.
Preferably, the inert gas is at least one or more of nitrogen, helium and argon.
Preferably, after the formation of diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate, the reaction solution is extracted to remove the organic solvent from the organic phase and purified by column chromatography.
Preferably, the solvent used for extraction is a mixture of water and an organic extraction solvent, said organic extraction solvent being at least one of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, dichloromethane, chloroform.
The invention has the beneficial effects that:
according to the invention, diethyl methyl malonate, sodium hydride and 1, 5-pentanediol di (p-toluenesulfonic acid) are used as raw materials to prepare diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate, the diethyl methyl malonate and the sodium hydride do not need to be subjected to post-treatment after reaction, and the 1, 5-pentanediol di (p-toluenesulfonic acid) ester can be directly added into a reaction system to be subjected to reaction to obtain a target product, a noble metal reagent is not needed in the preparation process, and the preparation method for the diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate has the advantages of simple process, low cost and high yield.
Drawings
The technical solution of the present application is further explained below with reference to the drawings and the embodiments.
FIG. 1 is a mass spectrum of diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate prepared in example 1 of the present application;
FIG. 2 is a nuclear magnetic diagram of diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate prepared in example 1 of the present application.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict.
The technical solutions of the present application will be described in detail below with reference to the accompanying drawings in combination with embodiments.
Example 1
This example provides a method for synthesizing diethyl 5-tosylpentyl-2-methylmalonate, including the following steps: 50mg of diethyl methylmalonate and 12mg of sodium hydride in 20mL of N, N-Dimethylformamide (DMF) were reacted under nitrogen protection at-15 ℃ for 30min, and then 120mg of 1, 5-pentanediol bis (p-toluenesulfonic acid) was added) Performing ester reaction, stirring at 50 ℃ for 12h, cooling the reaction solution to room temperature, adding water and ethyl acetate for extraction, drying, evaporating an organic phase, and performing column chromatography purification to obtain a target product of 108mg, wherein the yield is 90.78%; MS:453 (M + K); 1 H NMR(400MHz，CDCl 3 )δ7.78-7.83(d,2H,Ar-H),7.33-7.38(d,2H,Ar-H),4.13-4.22(q,4H,CH 3 CH 2 -),3.98-4.04(t,2H,-CH 2 OTs),2.44-2.48(s,3H,Ar-CH 3 ),1.77-1.83(m,2H,-CH 2 -),1.61-1.70(m,3H,-CCH 3 ),1.33-1.39(m,4H,-CH 2 -,),1.16-1.29(m,8H,-CH 2 -,CH 2 CH 3 )。
example 2
The embodiment provides a method for synthesizing diethyl 5-tosylpentyl-2-methylmalonate, which comprises the following steps: under the protection of helium and under the condition of ice-water bath, 250mg of diethyl methylmalonate and 200mg of sodium hydride react for 60min in 30mL of Tetrahydrofuran (THF), 1000mg of 1, 5-pentanediol di (p-toluenesulfonic acid) ester is added to react, the mixture is stirred at 70 ℃ for 18h, the reaction liquid is cooled to room temperature, water and dichloromethane are added to extract, the organic phase is dried and evaporated to dryness, and the product is purified by a column to obtain 565mg of a target product, wherein the yield is 94.98%; and (2) MS:453 (M + K).
Example 3
This example provides a method for synthesizing diethyl 5-tosylpentyl-2-methylmalonate, including the following steps: reacting 500mg of diethyl methylmalonate and 2000mg of sodium hydride in 200mL of N, N-Dimethylformamide (DMF) for 90min under the protection of argon and at the temperature of 10 ℃, then adding 50g of 1, 5-pentanediol di (p-toluenesulfonic acid) ester for reaction, stirring at the temperature of 100 ℃ for 24h, cooling the reaction liquid to room temperature, adding water and ethyl acetate for extraction, drying and evaporating an organic phase, and purifying by passing through a column to obtain 1142mg of a target product with the yield of 95.99%; MS:453 (M + K).
In light of the foregoing description of the preferred embodiments according to the present application, it is to be understood that various changes and modifications may be made without departing from the spirit and scope of the invention. The technical scope of the present application is not limited to the contents of the specification, and must be determined according to the scope of the claims.
Claims (10)
1. A method for synthesizing 5-p-toluenesulfonylpentyl-2-methyl diethyl malonate is characterized by comprising the following steps: reacting diethyl methylmalonate and sodium hydride in an organic solvent under the protection of inert gas, and then adding 1, 5-pentanediol di (p-toluenesulfonic acid) ester for reaction to generate 5-p-toluenesulfonylpentyl-2-diethyl methylmalonate.
2. The method for synthesizing diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate according to claim 1, wherein the reaction temperature of the diethyl methylmalonate with sodium hydride is-15 ℃ to 10 ℃.
3. The method for synthesizing diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate according to claim 1 or 2, wherein the reaction time of the diethyl methylmalonate with the sodium hydride is 30 to 90min.
4. The method for synthesizing diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate according to any one of claims 1 to 3, wherein the temperature of the reaction of adding 1, 5-pentanediol bis (p-toluenesulfonate) is 50 to 100 ℃.
5. The method for synthesizing diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate according to any one of claims 1 to 4, wherein the reaction time for adding 1, 5-pentanediol bis (p-toluenesulfonate) is 12 to 24 hours.
6. The method for synthesizing diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate according to any one of claims 1 to 5, wherein the organic solvent is at least one of N, N-dimethylformamide, tetrahydrofuran, acetonitrile, N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide.
7. The method for synthesizing diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate according to any one of claims 1 to 6, wherein the molar ratio of diethyl methylmalonate, sodium hydride and 1, 5-pentanediol bis (p-toluenesulfonate) is 1.
8. The method for synthesizing diethyl 5-tosylpentyl-2-methylmalonate according to any one of claims 1 to 7, characterized in that the inert gas is at least one of nitrogen, helium and argon.
9. The method for synthesizing diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate according to any one of claims 1 to 8, wherein after the formation of diethyl 5-p-toluenesulfonylpentyl-2-methylmalonate, the reaction solution is extracted to remove the organic solvent from the organic phase, and the resultant is purified by column chromatography.
10. The method for synthesizing diethyl 5-tosylpentyl-2-methylmalonate according to claim 9, wherein the solvent used for extraction is a mixture of water and an organic extraction solvent, and the organic extraction solvent is at least one of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, dichloromethane, and chloroform.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120029223A1 (en) * | 2010-07-27 | 2012-02-02 | Gad Friedman | Method for production of substituted alkyl malonic esters and derivatives thereof |
| CN103601658A (en) * | 2013-11-07 | 2014-02-26 | 江苏华益科技有限公司 | Precursors of novel PET (polyethylene terephthalate) precursor-fluoride standard ML-10 and preparation method thereof |
| US20210111346A1 (en) * | 2017-03-30 | 2021-04-15 | Georgia Tech Research Corporation | Conjugated polymers with multistage side-chain cleavage |
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- 2022-12-06 CN CN202211553667.5A patent/CN115806511A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120029223A1 (en) * | 2010-07-27 | 2012-02-02 | Gad Friedman | Method for production of substituted alkyl malonic esters and derivatives thereof |
| CN103601658A (en) * | 2013-11-07 | 2014-02-26 | 江苏华益科技有限公司 | Precursors of novel PET (polyethylene terephthalate) precursor-fluoride standard ML-10 and preparation method thereof |
| US20210111346A1 (en) * | 2017-03-30 | 2021-04-15 | Georgia Tech Research Corporation | Conjugated polymers with multistage side-chain cleavage |
Non-Patent Citations (1)
| Title |
|---|
| BRIAN SCHMATZ等: "Aqueous Processing for Printed Organic Electronics: Conjugated Polymers with Multistage Cleavable Side Chains", 《ACS CENT. SCI.》, pages 961 - 967 * |
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