Method for full-automatically synthesizing <18>F-marked pyrimidine acrylamide based EGFR positive-electron tracer agent through one-step method

Abstract

The invention discloses a method for full-automatically synthesizing a <18>F-marked pyrimidine acrylamide based EGFR positive-electron tracer agent through a one-step method, and belongs to the fieldof chemical synthesis. The method sequentially comprises the following steps that (1) <18>F ions from an accelerator and water are conveyed to a receiving bottle and guided into an anion exchange column; (2) <18>F ions in the anion exchange column are eluted with a mixed solution formed by strong alkali and weak acid salt, acetonitrile and ionic liquid, and then are conveyed to a reaction bottle;(3) precursor is dissolved in a DMSO or acetonitrile or DMF solution, a buffer solution is added into the former solution to enable pH of the former solution to be 2, and the obtained solution is added into the reaction bottle and heated under protection of inert gas; (4) the temperature is lowered, and coarse products in the reaction bottle are purified through a solid-phase extraction C18 pillaret; and (5) target products of a solution obtained in the step (4) are separated and collected, so that the positive-electron tracer agent is obtained. The method has the characteristics of multi-purpose, large yield, high efficiency, short synthesis time, low cost and the like, and can meet the requirement for large-scale production.

Description

technical field

[0001] The invention relates to a compound synthesized by fluorination substitution reaction 18 F-labeled pyrimidine acrylamide EGFR positron tracer and preparation method thereof, the invention belongs to the field of chemical synthesis, Background technique

[0002] Epidermal growth factor receptor (EGFR, ErbB) is a cell surface receptor of the extracellular protein ligand of class I epidermal growth factor family. It has tyrosine kinase activity and is an important transmembrane receptor. The high expression of EGFR can promote the proliferation, angiogenesis, adhesion, invasion and metastasis of tumor cells, so EGFR tyrosine kinase inhibitors have become a hot spot in the research of anti-tumor drugs. Studies have shown that the mutation at the T790M site of the EGFR gene is the main cause of drug resistance. In order to overcome the drug resistance of existing drugs, this paper uses the EGFR inhibitor AZD-9291 as a lead compound for structural modificat...

Examples

Embodiment 1E

[0067] Embodiment 1EGFR TKI-BF 3 - Preparation of AZD9291

[0068] The BF 3 -The molecular structural formula of AZD9291 is as shown in formula I:

[0069]

[0070] The preparation flow chart is as figure 1 As shown, the specific preparation method is as follows:

[0071] (1) Under nitrogen protection, 50g (2-chloropyrimidin-4-yl)-1-methyl-3a, 7a-dihydro-1H-indole, 38.03g 4-fluoro-2-methoxy-5- Nitroaniline and 37.09g p-toluenesulfonic acid were mixed in 580ml 2-pentanol, stirred mechanically at 105°C for 2.5h, cooled to room temperature, filtered with suction, the filter cake was washed with 2-pentanol, and dried to obtain a light brown solid , separated and purified by column chromatography, and eluted with an eluent obtained by mixing methanol and dichloromethane according to a volume ratio of 1:100, and finally obtained a light yellow needle-shaped solid, namely compound 1, with a yield of 85%;

[0072] (2) Mix 65g of compound 1, 19.65g of N,N,N'-trimethylethylenedi...

Embodiment 2

[0078] Embodiment 2 one-step synthesis 18 F-labeled pyrimidine acrylamide EGFR positron tracer ( 18 F-BF 3 -AZD9291)

[0079] Flowchart such as Figure 5 As shown, the synthesis steps are as follows:

[0080] 1. Will be transmitted from the medical cyclotron 18 F ions and water pass to the receiving bottle (1-4Ci), and are introduced into the anion exchange column QMA;

[0081] 2. Using 0.15mL K 2 CO 3 (0.9mg)+0.5mL acetonitrile was eluted from the QMA column 18 F ions are sent to the reaction bottle;

[0082] 3. Dissolve 3 mg of the precursor (prepared in Example 1) in 0.5 mL of 50% (v / v) DMF aqueous solution, add o-diazepine hydrochloric acid buffer solution to make the solution pH = 2, and add the mixed solution to the reaction bottle; heated in a water bath at 80°C for 15 minutes under the protection of nitrogen or helium;

[0083]

[0084] 4. Cool the temperature to 25°C, then pass the reaction solution through a C18 column to separate and purify the product,...

Embodiment 3

[0085] Embodiment 3 adopts one-step synthesis 18 F-labeled pyrimidine acrylamide EGFR positron tracer ( 18 F-BF 3 -AZD9291)

[0086] In step 3, 70W microwave is used for heating, the heating time can be shortened by 1-2 minutes, the synthesis efficiency can reach 30%, and the radiochemical purity is greater than 98%. Other steps are the same as in embodiment 2.

technical field

[0001] The invention relates to a compound synthesized by fluorination substitution reaction 18 F-labeled pyrimidine acrylamide EGFR positron tracer and preparation method thereof, the invention belongs to the field of chemical synthesis, Background technique

[0002] Epidermal growth factor receptor (EGFR, ErbB) is a cell surface receptor of the extracellular protein ligand of class I epidermal growth factor family. It has tyrosine kinase activity and is an important transmembrane receptor. The high expression of EGFR can promote the proliferation, angiogenesis, adhesion, invasion and metastasis of tumor cells, so EGFR tyrosine kinase inhibitors have become a hot spot in the research of anti-tumor drugs. Studies have shown that the mutation at the T790M site of the EGFR gene is the main cause of drug resistance. In order to overcome the drug resistance of existing drugs, this paper uses the EGFR inhibitor AZD-9291 as a lead compound for structural modificat...

Examples

Embodiment 1E

[0067] Embodiment 1EGFR TKI-BF 3 - Preparation of AZD9291

[0068] The BF 3 -The molecular structural formula of AZD9291 is as shown in formula I:

[0069]

[0070] The preparation flow chart is as figure 1 As shown, the specific preparation method is as follows:

[0071] (1) Under nitrogen protection, 50g (2-chloropyrimidin-4-yl)-1-methyl-3a, 7a-dihydro-1H-indole, 38.03g 4-fluoro-2-methoxy-5- Nitroaniline and 37.09g p-toluenesulfonic acid were mixed in 580ml 2-pentanol, stirred mechanically at 105°C for 2.5h, cooled to room temperature, filtered with suction, the filter cake was washed with 2-pentanol, and dried to obtain a light brown solid , separated and purified by column chromatography, and eluted with an eluent obtained by mixing methanol and dichloromethane according to a volume ratio of 1:100, and finally obtained a light yellow needle-shaped solid, namely compound 1, with a yield of 85%;

[0072] (2) Mix 65g of compound 1, 19.65g of N,N,N'-trimethylethylenedi...

Embodiment 2

[0078] Embodiment 2 one-step synthesis 18 F-labeled pyrimidine acrylamide EGFR positron tracer ( 18 F-BF 3 -AZD9291)

[0079] Flowchart such as Figure 5 As shown, the synthesis steps are as follows:

[0080] 1. Will be transmitted from the medical cyclotron 18 F ions and water pass to the receiving bottle (1-4Ci), and are introduced into the anion exchange column QMA;

[0081] 2. Using 0.15mL K 2 CO 3 (0.9mg)+0.5mL acetonitrile was eluted from the QMA column 18 F ions are sent to the reaction bottle;

[0082] 3. Dissolve 3 mg of the precursor (prepared in Example 1) in 0.5 mL of 50% (v / v) DMF aqueous solution, add o-diazepine hydrochloric acid buffer solution to make the solution pH = 2, and add the mixed solution to the reaction bottle; heated in a water bath at 80°C for 15 minutes under the protection of nitrogen or helium;

[0083]

[0084] 4. Cool the temperature to 25°C, then pass the reaction solution through a C18 column to separate and purify the product,...

Embodiment 3

[0085] Embodiment 3 adopts one-step synthesis 18 F-labeled pyrimidine acrylamide EGFR positron tracer ( 18 F-BF 3 -AZD9291)

[0086] In step 3, 70W microwave is used for heating, the heating time can be shortened by 1-2 minutes, the synthesis efficiency can reach 30%, and the radiochemical purity is greater than 98%. Other steps are the same as in embodiment 2.

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