Method for introducing C-13 methyl on pyrimidine ring through ethyl acetoacetate alpha-alkylation

Abstract

The invention relates to a method for introducing C-13 methyl on a pyrimidine ring through ethyl acetoacetate alpha-alkylation, which comprises the following steps: (1) carrying out H extraction treatment on an ethyl acetoacetate compound by adopting NaH, and then carrying out substitution reaction on the ethyl acetoacetate compound and a C-13 labeled iodo-alkyl compound to obtain an ethyl acetoacetate alpha-alkyl (C-13) intermediate; and (2) carrying out cyclization reaction on the ethyl acetoacetate alpha-alkyl (C-13) intermediate obtained in the step (1) and a benzamidine compound to obtain the C-13 labeled methylpyrimidine ring compound. According to the method, ethyl acetoacetate is marked with C-13, then a heterocyclic ring is synthesized through ring removal, the reaction step of introducing a C-13 marking group on the heterocyclic ring is obviously shortened, and the C-13 marking yield and time efficiency are obviously improved.

Description

Technical Field

[0001] The invention belongs to the field of isotope labeling, and specifically relates to a method for introducing a C-13 methyl group on a pyrimidine ring through α-alkylation of ethyl acetoacetate. Background Art

[0002] Ethyl acetoacetate is an important raw material for organic synthesis. It is widely used in organic synthesis and can be used to synthesize heterocyclic compounds such as pyridine, pyrrole, pyrazolone, pyrimidine, purine and cyclic lactone.

[0003] In the process of C-13 labeling heterocyclic compounds, due to the complex nature of heterocyclic compounds, it is generally necessary to introduce C-13 labeling sites by constructing heterocyclic skeletons. The synthetic route is generally long, the reaction control is complex, and the yield is not high. Therefore, the idea of ​​C-13 labeling the alkyl group on the heterocyclic ring is also necessary. However, due to the complex nature of heterocyclic compounds, it is generally difficult to directly introduce C-13 labeling groups on the heterocyclic ring. Summary of the invention

[0004] The invention provides a method for introducing a C-13 methyl group on a pyrimidine ring through α-alkylation of ethyl acetoacetate. The method can introduce a C-13 labeling group on the pyrimidine ring, shorten the reaction steps, and improve the reaction yield and time efficiency.

[0005] The technical solution of the present invention is as follows:

[0006] A method for introducing a C-13 methyl group on a pyrimidine ring by α-alkylation of ethyl acetoacetate, comprising the following steps:

[0007] (1) using NaH to remove H from ethyl acetoacetate compounds, and then performing a substitution reaction with a C-13 labeled iodinated alkyl compound to obtain an ethyl acetoacetate α-alkyl (C-13) intermediate;

[0008] (2) the ethyl acetoacetate α-alkyl (C-13) intermediate obtained in step (1) undergoes a cyclization reaction with a benzamidine compound to obtain a C-13 labeled methyl pyrimidine ring compound;

[0009] The reaction formula is as follows:

[0010]

[0011] Among them, R1 is C1~C4 alkyl; R2 is C1~C4 alkoxy.

[0012] The invention performs alkylation (C-13) on the α-carbon of ethyl acetoacetate, then synthesizes a heterocycle, and finally introduces an alkyl marked with C-13 on the heterocycle, thereby avoiding the difficulty of directly introducing the alkyl on the heterocycle.

[0013] Preferably, R1=CH3, CH3CH2; R2=OCH3, OCH2CH3, OCH2CH2CH3, OiPr.

[0014] Preferably, in step (1), the solvent for the H-extraction treatment is tetrahydrofuran, and the temperature for the H-extraction treatment is 0 to 30°C.

[0015] Preferably, in step (1), the temperature of the substitution reaction is 35-45° C., and the reaction time is 12-24 h.

[0016] Preferably, in step (1), the substitution reaction is carried out under sealing conditions, which can effectively avoid the volatilization of the C-13 labeled iodinated alkyl compound and improve the reaction yield.

[0017] Preferably, in step (2), the base used in the alkaline condition is NaOMe, and the solvent used in the reaction is methanol.

[0018] Preferably, in step (2), the temperature of the cyclization reaction is 65-75° C., and the reaction time is 10-24 h.

[0019] Preferably, in step (2), the following post-treatment method is adopted: stop the reaction, cool naturally to room temperature, evaporate the reaction solution under reduced pressure, add water, then adjust the pH of the reaction solution to 3-4, extract with ethyl acetate, combine the organic phases, wash, dry and column chromatograph to obtain the C-13 labeled methyl pyrimidine ring compound.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0021] The invention firstly uses C-13 to label ethyl acetoacetate, and then decyclizes to synthesize a heterocycle. The reaction steps of introducing a C-13 labeling group on the heterocycle are significantly shortened, and the labeling yield and time efficiency of C-13 are significantly improved. DETAILED DESCRIPTION

[0022] Example 1

[0023] The reaction formula is as follows:

[0024]

[0025] 1.0 g of ethyl propionyl acetate (compound 1, 6.94 mmol, 1.0 eq) was dissolved in 10 ml of THF, cooled at 0 °C under nitrogen atmosphere, and the solution turned into white turbidity; 0.28 g of NaH (60% in oil, 6.94 mmol, 1.0 eq) was slowly added, and then stirred at room temperature, stirred for 30 min at naturally elevated temperature, and then 1.1 g of 13C-iodomethane (7.64mmol, 1.1eq), then sealed and stirred at 40°C overnight, TLC monitoring the completion of the reaction. Stop the reaction, cool to room temperature, add 20ml of water to the reaction system, extract twice with EtOAc, dry and evaporate the organic phase to obtain 1.86g of light yellow oily liquid, column purification to obtain 0.85g of colorless oily liquid (Compound 2), 69.9% yield (based on 13 The purity was acceptable by TLC and it was directly used in the next step.

[0026] Compound 3 (947 mg, 5.31 mmol, 1.0 eq) was dissolved in 8 ml MeOH, and NaOMe (372 mg, 6.90 mmol, 1.3 eq) was added under nitrogen atmosphere and stirred to form a white turbid liquid. 0.85 g of compound 2 (5.31 mmol, 1.0 eq, dissolved in 4 ml MeOH) was added dropwise, and stirred overnight at 70 ° C. TLC showed that the reaction was complete. Post-treatment: stop the reaction, cool to room temperature naturally, evaporate the reaction solution under reduced pressure at 40 ° C, add 20 ml of deionized water, cool in an ice water bath, adjust the pH of the reaction solution from 12 to 3-4 with concentrated hydrochloric acid, extract with EA, wash the combined organic phases with saturated brine, dry with Na2SO4, evaporate to dryness under reduced pressure to obtain 1.5 g of light yellow viscous, and column purification to obtain 0.95 g of light yellow oily liquid 4 with a purity of more than 98%. 13 C abundance is more than 99%, [M+H] + :274.20, 65.4% yield.

[0027] Comparative Example 1

[0028] 1.0 g of ethyl propionyl acetate (compound 1, 6.94 mmol, 1.0 eq) was dissolved in 10 ml of THF, cooled at 0 °C under nitrogen atmosphere, and the solution turned into white turbidity; 0.28 g of NaH (60% in oil, 6.94 mmol, 1.0 eq) was slowly added, and then stirred at room temperature, stirred for 30 min at naturally elevated temperature, and then 1.1 g of 13 C-iodomethane (7.64mmol, 1.1eq) was added to the mixture and then reacted at 40°C for 24 hours under a nitrogen atmosphere. The reaction was stopped and cooled to room temperature. 20ml of water was added to the reaction system and extracted twice with EtOAc. The organic phase was dried and evaporated to obtain 1.58g of a light yellow oily liquid. Column purification gave 0.17g of a colorless oily liquid with a yield of 14.0% (based on 13 The TLC purity showed that the product contained a small amount of compound 1, which had a poor effect in the next step reaction.

[0029] This comparative example used reflux of the condenser tube instead of the sealing operation. The results showed that the yield of compound 2 was significantly reduced. The reason may be that the sealing reaction made the volatile 13CH3I cannot escape from the reaction system, and the reaction efficiency is greatly improved.

Claims

1. A method for introducing a C-13 methyl group on a pyrimidine ring by α-alkylation with ethyl acetoacetate, characterized in that: The following steps are involved: (1) using NaH to remove H from ethyl acetoacetate compounds, and then performing a substitution reaction with a C-13 labeled iodinated alkyl compound to obtain an ethyl acetoacetate α-alkyl (C-13) intermediate; (2) Under alkaline conditions, the ethyl acetoacetate α-alkyl (C-13) intermediate obtained in step (1) undergoes a cyclization reaction with a benzamidine compound to obtain a C-13 labeled methyl pyrimidine ring compound; The reaction formula is as follows: Among them, R1 is C1~C4 alkyl; R2 is C1~C4 alkoxy.

2. The method according to claim 1, characterized in that: R1=CH3, CH3CH2; R2=OCH3, OCH2CH3, OCH2CH2CH3, OiPr.

3. The method according to claim 1, characterized in that: In step (1), the solvent for the H-extraction treatment is tetrahydrofuran or diethyl ether, and the temperature for the H-extraction treatment is 0 to 30°C.

4. The method according to claim 1, characterized in that In step (1), the temperature of the substitution reaction is 35 to 45° C., and the reaction time is 12 to 24 hours.

5. The method according to claim 1, characterized in that: In step (1), the substitution reaction is carried out under sealing conditions.

6. The method according to claim 1, characterized in that In step (2), the base used in the alkaline condition is NaOMe or NaOEt, and the solvent used in the reaction is methanol or ethanol.

7. The method according to claim 1, characterized in that In step (2), the temperature of the cyclization reaction is 65 to 75° C., and the reaction time is 10 to 24 hours.

8. The method according to claim 1, characterized in that In step (2), the following post-treatment method is adopted: stop the reaction, cool naturally to room temperature, evaporate the reaction solution under reduced pressure, add water, then adjust the pH of the reaction solution to 3-4, extract with ethyl acetate, combine the organic phases, wash, dry and column chromatograph to obtain the C-13 labeled methyl pyrimidine ring compound.

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