CN104447570A - Synthesis method for 5-bromo-2-fluoropyrimidine - Google Patents

Abstract

The invention discloses a synthesis method for 5-bromo-2-fluoropyrimidine. The synthesis method comprises the following steps: dissolving 2-hydroxypyrimidine salt as a raw material through deionized water, and regulating the pH to 6 with saturated sodium bicarbonate solution, so as to prepare 2-hydroxypyrimidine; enabling bromine to react with 2-hydroxypyrimidine below 5 DEG C, and preparing 2-hydroxy-5-bromopyrimidine through methyl alcohol recrystallization; carrying out temperature control reaction on 2-hydroxy-5-bromopyrimidine, POCl3 and triethylamine for 8 hours; and cooling to room temperature, reacting with fluorine, carrying out suction filtration under adjustment of a sodium hydroxide solution, washing, drying and carrying out chromatography, so as to obtain white solid, wherein the yield can reach over 91%.

Description

The synthetic method of the bromo-2-5-FU of a kind of 5-

Technical field

The present invention relates to a kind of synthetic method of compound, the synthetic method of the bromo-2-5-FU of a kind of 5-.

Background technology

Pyrimidines causes the extensive concern of people as the elementary cell of new drug molecular designing and synthesis, pyrimidines is widely used in the preparation of agricultural chemicals and medicine at present, synthesis agrochemicals weedicides, the intermediate of the medicines such as medical pain killer and dyestuff.5-halogenated pyrimidine derivative has chemotherapy significantly because of it, biological chemistry isoreactivity, has synthesized the nucleoside analog in a large number with physiologically active have vast potential for future development as pharmaceutical intermediate in pharmaceutical industry and genetically engineered.As; 5 FU 5 fluorouracil is applied to clinical as good cancer therapy drug, and 5-bromo pyrimi piperidine liquid is used to inflammatory cells etc.

Summary of the invention

The invention provides a kind ofly to consume less, the synthetic method of cheaper starting materials is easy to get, yield the is high bromo-2-5-FU of 5-.

For achieving the above object, the synthetic route of the bromo-2-5-FU of 5-of the present invention is:

The building-up process of the bromo-2-5-FU of the 5-that the present invention relates to comprises the following steps:

1, the synthesis of 2-hydroxy pyrimidine

(1) by 23g2-hydroxy pyrimidine salt 100mL deionized water dissolving, ice-water bath degraded is to less than 0 DEG C, and dripping saturated sodium bicarbonate aqueous solution adjust pH is 6, and temperature control less than 0 DEG C continues to stir 20min;

(2) use 100mL dichloromethane extraction 3 times, merge organic phase, 25mL saturated salt washes three times, adds 0.5g gac, anhydrous sodium sulfate drying, suction filtration, and 30mL methylene dichloride divides 3 washing leaching cakes, and evaporate to dryness methylene dichloride, obtains white solid.

2, the synthesis of 2-hydroxyl-5-bromo pyrimi piperidine

1) in the deionized water of 250mL, add 35g2-hydroxy pyrimidine, ice-water bath is cooled to less than 5 DEG C, slowly adds 40g bromine;

(2) rise to room temperature, continue to stir 45min, suction filtration, be washed to filtrate and become neutral, anhydrous magnesium sulfate drying, steams solvent, residue on neutral alumina column chromatography for separation, then uses 52g white powder solid after the ethyl alcohol recrystallization of 20mL85%.

3, the synthesis of the bromo-2-5-FU of 5-

(1) in reaction flask, 8g2-hydroxyl-5-bromo pyrimi piperidine is added, 70mLPOCl ₃, slowly drip 3.2g triethylamine, be warming up to backflow, temperature control reaction 8h, reclaims POCl ₃50mL;

(2) be cooled to room temperature, add methylene dichloride 30mL wherein and pour trash ice into, being cooled to-8 DEG C, drip the fluorine 30g that massfraction is 50%, insulation 4-5h;

(3) adjust pH=7, suction filtration, washing with the aqueous sodium hydroxide solution that 20mL massfraction is 10%, dry, steaming desolventizes, residue by silicagel column chromatography, and obtain white solid 9.2g, yield reaches 91%.

Specific embodiments

The building-up process of the bromo-2-5-FU of a kind of 5-that the present invention relates to comprises the following steps:

By 23g2-hydroxy pyrimidine salt 100mL deionized water dissolving, ice-water bath degraded is to less than 0 DEG C, and dripping saturated sodium bicarbonate aqueous solution adjust pH is 6, and temperature control less than 0 DEG C continues to stir 20min; With 100mL dichloromethane extraction 3 times, merge organic phase, 25mL saturated salt washes three times, adds 0.5g gac, anhydrous sodium sulfate drying, suction filtration, and 30mL methylene dichloride divides 3 washing leaching cakes, and evaporate to dryness methylene dichloride, obtains white solid.In the deionized water of 250mL, add 35g2-hydroxy pyrimidine, ice-water bath is cooled to less than 5 DEG C, slowly adds 40g bromine; Rise to room temperature, continue to stir 45min, suction filtration, be washed to filtrate and become neutral, anhydrous magnesium sulfate drying, steams solvent, residue on neutral alumina column chromatography for separation, then uses 52g white powder solid after the ethyl alcohol recrystallization of 20mL85%.8g2-hydroxyl-5-bromo pyrimi piperidine is added, 70mLPOCl in reaction flask ₃, slowly drip 3.2g triethylamine, be warming up to backflow, temperature control reaction 8h, reclaims POCl ₃50mL; Be cooled to room temperature, add methylene dichloride 30mL wherein and pour trash ice into, being cooled to-8 DEG C, drip the fluorine 30g that massfraction is 50%, insulation 4-5h; Adjust pH=7, suction filtration with the aqueous sodium hydroxide solution that 20mL massfraction is 10%, washing, dry, steaming desolventizes, residue by silicagel column chromatography, obtains white solid 9.2g, calculated yield.

Example 1

By 23g2-hydroxy pyrimidine salt 100mL deionized water dissolving, ice-water bath degraded is to less than 0 DEG C, and dripping saturated sodium bicarbonate aqueous solution adjust pH is 6, and temperature control less than 0 DEG C continues to stir 20min; With 100mL dichloromethane extraction 3 times, merge organic phase, 25mL saturated salt washes three times, adds 0.5g gac, anhydrous sodium sulfate drying, suction filtration, and 30mL methylene dichloride divides 3 washing leaching cakes, and evaporate to dryness methylene dichloride, obtains white solid.In the deionized water of 250mL, add 35g2-hydroxy pyrimidine, ice-water bath is cooled to less than 5 DEG C, slowly adds 40g bromine; Rise to room temperature, continue to stir 45min, suction filtration, be washed to filtrate and become neutral, anhydrous magnesium sulfate drying, steams solvent, residue on neutral alumina column chromatography for separation, then uses 52g white powder solid after the ethyl alcohol recrystallization of 20mL85%.8g2-hydroxyl-5-bromo pyrimi piperidine is added, 70mLPOCl in reaction flask ₃, slowly drip 3.2g triethylamine, be warming up to backflow, temperature control reaction 8h, reclaims POCl ₃50mL; Be cooled to room temperature, add methylene dichloride 30mL wherein and pour trash ice into, being cooled to-8 DEG C, drip the fluorine 30g that massfraction is 50%, insulation 4h; Adjust pH=7, suction filtration with the aqueous sodium hydroxide solution that 20mL massfraction is 10%, washing, dry, steaming desolventizes, residue by silicagel column chromatography, and obtain white solid 9.2g, yield reaches more than 91%.

Example 2

By 23g2-hydroxy pyrimidine salt 100mL deionized water dissolving, ice-water bath degraded is to less than 0 DEG C, and dripping saturated sodium bicarbonate aqueous solution adjust pH is 6, and temperature control less than 0 DEG C continues to stir 20min; With 100mL dichloromethane extraction 3 times, merge organic phase, 25mL saturated salt washes three times, adds 0.5g gac, anhydrous sodium sulfate drying, suction filtration, and 30mL methylene dichloride divides 3 washing leaching cakes, and evaporate to dryness methylene dichloride, obtains white solid.In the deionized water of 250mL, add 35g2-hydroxy pyrimidine, ice-water bath is cooled to less than 5 DEG C, slowly adds 40g bromine; Rise to room temperature, continue to stir 45min, suction filtration, be washed to filtrate and become neutral, anhydrous magnesium sulfate drying, steams solvent, residue on neutral alumina column chromatography for separation, then uses 52g white powder solid after the ethyl alcohol recrystallization of 20mL85%.8g2-hydroxyl-5-bromo pyrimi piperidine is added, 70mLPOCl in reaction flask ₃, slowly drip 3.2g triethylamine, be warming up to backflow, temperature control reaction 8h, reclaims POCl ₃50mL; Be cooled to room temperature, add methylene dichloride 30mL wherein and pour trash ice into, being cooled to-8 DEG C, drip the fluorine 30g that massfraction is 50%, insulation 4.5h; Adjust pH=7, suction filtration with the aqueous sodium hydroxide solution that 20mL massfraction is 10%, washing, dry, steaming desolventizes, residue by silicagel column chromatography, and obtain white solid 9.2g, yield reaches more than 91%.

Example 3

By 23g2-hydroxy pyrimidine salt 100mL deionized water dissolving, ice-water bath degraded is to less than 0 DEG C, and dripping saturated sodium bicarbonate aqueous solution adjust pH is 6, and temperature control less than 0 DEG C continues to stir 20min; With 100mL dichloromethane extraction 3 times, merge organic phase, 25mL saturated salt washes three times, adds 0.5g gac, anhydrous sodium sulfate drying, suction filtration, and 30mL methylene dichloride divides 3 washing leaching cakes, and evaporate to dryness methylene dichloride, obtains white solid.In the deionized water of 250mL, add 35g2-hydroxy pyrimidine, ice-water bath is cooled to less than 5 DEG C, slowly adds 40g bromine; Rise to room temperature, continue to stir 45min, suction filtration, be washed to filtrate and become neutral, anhydrous magnesium sulfate drying, steams solvent, residue on neutral alumina column chromatography for separation, then uses 52g white powder solid after the ethyl alcohol recrystallization of 20mL85%.8g2-hydroxyl-5-bromo pyrimi piperidine is added, 70mLPOCl in reaction flask ₃, slowly drip 3.2g triethylamine, be warming up to backflow, temperature control reaction 8h, reclaims POCl ₃50mL; Be cooled to room temperature, add methylene dichloride 30mL wherein and pour trash ice into, being cooled to-8 DEG C, drip the fluorine 30g that massfraction is 50%, insulation 5h; Adjust pH=7, suction filtration with the aqueous sodium hydroxide solution that 20mL massfraction is 10%, washing, dry, steaming desolventizes, residue by silicagel column chromatography, and obtain white solid 9.2g, yield reaches more than 91%.

Claims (3)

1. a synthetic method for the bromo-2-5-FU of 5-, is characterized in that the synthesis of 2-hydroxy pyrimidine:

(1) by 23g2-hydroxy pyrimidine salt 100mL deionized water dissolving, ice-water bath degraded is to less than 0 DEG C, and dripping saturated sodium bicarbonate aqueous solution adjust pH is 6, and temperature control less than 0 DEG C continues to stir 20min;

(2) use 100mL dichloromethane extraction 3 times, merge organic phase, 25mL saturated salt washes three times, adds 0.5g gac, anhydrous sodium sulfate drying, suction filtration, and 30mL methylene dichloride divides 3 washing leaching cakes, and evaporate to dryness methylene dichloride, obtains white solid.

2. the synthetic method of the bromo-2-5-FU of a kind of 5-according to claim 1, is characterized in that the synthesis of 2-hydroxyl-5-bromo pyrimi piperidine:

(1) in the deionized water of 250mL, add 35g2-hydroxy pyrimidine, ice-water bath is cooled to less than 5 DEG C, slowly adds 40g bromine;

(2) rise to room temperature, continue to stir 45min, suction filtration, be washed to filtrate and become neutral, anhydrous magnesium sulfate drying, steams solvent, residue on neutral alumina column chromatography for separation, then uses 52g white powder solid after the ethyl alcohol recrystallization of 20mL85%.

3. the synthetic method of the bromo-2-5-FU of a kind of 5-according to claim 1, is characterized in that:

(1) in reaction flask, 8g2-hydroxyl-5-bromo pyrimi piperidine is added, 70mLPOCl ₃, slowly drip 3.2g triethylamine, be warming up to backflow, temperature control reaction 8h, reclaims POCl ₃50mL;

(2) be cooled to room temperature, add methylene dichloride 30mL wherein and pour trash ice into, being cooled to-8 DEG C, drip the fluorine 30g that massfraction is 50%, insulation 4-5h;

(3) adjust pH=7, suction filtration, washing with the aqueous sodium hydroxide solution that 20mL massfraction is 10%, dry, steaming desolventizes, residue by silicagel column chromatography, and obtain white solid 9.2g, yield reaches 91%.