CN112500446A

CN112500446A - Synthetic method of 2 '-fluoro-2' -deoxyuridine

Info

Publication number: CN112500446A
Application number: CN202011452956.7A
Authority: CN
Inventors: 刘助武; 廖福爱
Original assignee: Pingjiang Jicheng Technology Co ltd
Current assignee: Pingjiang Jicheng Technology Co ltd
Priority date: 2020-12-11
Filing date: 2020-12-11
Publication date: 2021-03-16
Anticipated expiration: 2040-12-11
Also published as: CN112500446B

Abstract

The application discloses a method for synthesizing 2 '-fluoro-2' -deoxyuridine, which comprises the following steps: step 1) adding uridine and diphenyl carbonate into dimethylformamide, heating to dissolve, clarifying the solution, adding a catalyst sodium bicarbonate under the condition of keeping the temperature, heating for reaction for the second time, naturally cooling to room temperature after the reaction is finished, stirring, filtering, and drying a filter cake to obtain a compound 2; and 2) dissolving the compound 2, anhydrous potassium fluoride and a catalyst boron trifluoride diethyl etherate in a solvent, heating for reaction, filtering and concentrating after the reaction is finished, and obtaining a compound 3, namely 2 '-fluoro-2' -deoxyuridine. The method has the advantages of higher reaction conversion rate and better yield, and avoids using highly toxic reagents such as pyridine hydrogen fluoride, fluorine gas and the like.

Description

Synthetic method of 2 '-fluoro-2' -deoxyuridine

Technical Field

The invention belongs to the field of organic chemistry, and particularly relates to a synthetic method of 2 '-fluoro-2' -deoxyuridine.

Background

2 ' -fluoro-2 ' -deoxyuridine is an important pharmaceutical and chemical intermediate, and is generally synthesized by uridine, wherein 2 ' -position and 1-position keto group are subjected to dehydration condensation, and then a fluorinating reagent is used for introducing a fluorine group into the 2 ' -position, and US 2004/77567A 1 reports that after dehydration condensation of the 2 ' -position and the 1-position keto group of uridine, 2 ' -fluoro-2 ' -deoxyuridine is synthesized by reaction in a pyridine solution of 70% hydrogen fluoride.

Disclosure of Invention

The main purpose of the present application is to provide a method for synthesizing 2 '-fluoro-2' -deoxyuridine.

The technical scheme is as follows:

a method of synthesizing 2 '-fluoro-2' -deoxyuridine, comprising the steps of:

step 1) adding uridine and diphenyl carbonate into dimethylformamide, heating to dissolve, clarifying the solution, adding a catalyst sodium bicarbonate under the condition of keeping the temperature, heating for reaction for the second time, naturally cooling to room temperature after the reaction is finished, stirring, filtering, and drying a filter cake to obtain a compound 2;

and 2) dissolving the compound 2, anhydrous potassium fluoride and a catalyst boron trifluoride diethyl etherate in a solvent, heating for reaction, filtering and concentrating after the reaction is finished, and obtaining a compound 3, namely 2 '-fluoro-2' -deoxyuridine.

Further, compound 1 in the step 1): the molar ratio of diphenyl carbonate is 1: 1.1.

further, the temperature for heating and dissolving in the step 1) is 58-62 ℃.

Further, the temperature of the second heating in the step 1) is 78-82 ℃.

Further, the room temperature in the step 1) is 20-30 ℃.

Further, the stirring time in the step 1) is 1-3 hours.

Further, the solvent in the step 2) is dimethylformamide or chlorobenzene.

Further, compound 2 in step 2): the weight ratio of the anhydrous potassium fluoride is 1-2: 1.

Further, in the step 2), the reaction temperature is increased to 120 ℃.

Further, the reaction time in the step 2) is 10-14 hours.

The invention firstly dehydrates and condenses uridine (compound 1 in the following formula) 2 ' -position and 1-position ketone group to generate compound 2, adds high-activity potassium fluoride and boron trifluoride diethyl etherate into solvent, and opens ring at high temperature to generate 2 ' -fluoro-2 ' -deoxyuridine (compound 3 in the following formula), the method has higher reaction conversion rate and better yield, and avoids using high-toxicity reagents such as hydrogen fluoride pyridine, fluorine gas and the like, and the reaction formula is as follows:

Detailed Description

In order to make those skilled in the art better understand the technical solutions in the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.

EXAMPLE 1 Synthesis of Compound 2

Adding 69.0g of uridine into a reaction bottle, adding 69.0g (1.1eq) of diphenyl carbonate, adding 163.0g of DMF, starting stirring, gradually heating to 58-62 ℃, continuously dissolving solids in the heating process, controlling the temperature to be 58-62 ℃ after a clear solution of the solution is clarified at about 60 ℃, adding 1.7g of sodium bicarbonate, gradually heating to 78-82 ℃, naturally cooling to 20-30 ℃ after the reaction is finished, stirring for 1-3 hours, filtering, drying a filter cake to obtain 57.2g of compound 2, wherein the yield is as follows: 89.5 percent and the purity is 99.57 percent.

EXAMPLE 2 Synthesis of Compound 3

20g of the compound 2 was charged into a reaction flask, 12.5g of high-activity anhydrous potassium fluoride, 0.2g of boron trifluoride diethyl ether and 200ml of DMF were added, the temperature was raised to 120 ℃ to react for 12 hours, after the reaction was completed, filtration was carried out, the filtrate was concentrated and recrystallized from tetrahydrofuran and ethyl acetate to obtain 11.6g of 2 '-fluoro-2' -deoxyuridine with a yield of 53.2% and a purity of 98.2%.

EXAMPLE 3 Synthesis of Compound 3

20g of the compound 2 was charged into a reaction flask, 12.5g of high-activity anhydrous potassium fluoride, 0.2g of boron trifluoride diethyl etherate and 200ml of chlorobenzene were added, the temperature was raised to 130 ℃ to react for 12 hours, after the reaction was completed, filtration was performed, the filtrate was concentrated and recrystallized from tetrahydrofuran and ethyl acetate to obtain 10.8g of 2 '-fluoro-2' -deoxyuridine with a yield of 49.8% and a purity of 99.0%.

The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for synthesizing 2 '-fluoro-2' -deoxyuridine, which is characterized by comprising the following steps:

step 1) adding a compound 1 and diphenyl carbonate into dimethylformamide, heating to dissolve, clarifying the solution, adding a catalyst sodium bicarbonate under the condition of keeping the temperature, heating for reaction for the second time, naturally cooling to room temperature after the reaction is finished, stirring, filtering, and drying a filter cake to obtain a compound 2;

step 2) dissolving the compound 2, anhydrous potassium fluoride and a catalyst boron trifluoride diethyl etherate in a solvent, heating for reaction, filtering and concentrating after the reaction is finished to obtain a compound 3, namely 2 '-fluoro-2' -deoxyuridine;

the reaction formula is as follows:

2. the method of synthesis according to claim 1, wherein in step 1) compound 1: the molar ratio of diphenyl carbonate is 1: 1.1.

3. the synthesis method according to claim 1, wherein the temperature for heating and dissolving in the step 1) is 58-62 ℃.

4. The synthesis method according to claim 1, wherein the second temperature rise in step 1) is 78-82 ℃.

5. The synthesis method according to claim 1, wherein the room temperature in step 1) is 20-30 ℃.

6. The synthesis method according to claim 1, wherein the stirring time in step 1) is 1 to 3 hours.

7. The synthesis method of claim 1, wherein the solvent in step 2) is dimethylformamide or chlorobenzene.

8. The method of synthesis of claim 1, wherein in step 2) compound 2: the weight ratio of the anhydrous potassium fluoride is 1-2: 1.

9. The method of claim 1, wherein the reaction temperature in step 2) is 120 ℃.

10. The method of claim 1, wherein the reaction time in step 2) is 10 to 14 hours.