CN111217867A - Method for preparing trifluridine - Google Patents

Method for preparing trifluridine Download PDF

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CN111217867A
CN111217867A CN202010098718.4A CN202010098718A CN111217867A CN 111217867 A CN111217867 A CN 111217867A CN 202010098718 A CN202010098718 A CN 202010098718A CN 111217867 A CN111217867 A CN 111217867A
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CN111217867B (en
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周观燊
李亚周
陈振昌
张红娟
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Fujian Ruibo Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

the invention discloses a method for preparing trifluridine, which comprises the following steps of halogenating hydroxyl fully-protected ribose, condensing with 5-trifluoromethyl uracil, deprotecting to generate intermediate 5-trifluoromethyl uridine, and carrying out dehydration, halogenation and reduction reactions to obtain the trifluridine.

Description

Method for preparing trifluridine
Technical Field
The invention relates to a method for preparing trifluridine, and belongs to the technical field of medicine preparation.
Background
Trifluridine, also known as trifluridine, trifluromethyl glycoside, trifluorothymidine, trifluromethyl uridine, triflurolidine, triflurothymidine or 5-trifluoromethyl-2-deoxyuridine, has the molecular formula C10H11F3N2O5Are a class used for preventing and treating viral infectionsThe antiviral drug of (1) has an inhibiting effect on herpes simplex virus, and the effect is similar to that of iodoglycoside. The antiviral mechanism may be inhibition of certain dnase activities or phosphorylation by thymidine kinase to mono-, di-and triphosphates, the mono-phosphate being able to intercalate into viral DNA, thereby interfering with DNA synthesis and viral replication. The existing medical research shows that the medicine taking trifluridine as a main active ingredient can also be used as an anticancer nucleoside medicine and is mainly used for treating colorectal cancer, particularly for early treatment of colon cancer patients, the trifluridine can directly interact with cancer DNA, so that the DNA cannot normally perform functions, the action mechanism of the medicine is different from that of fluoropyrimidine, oxaliplatin and irinotecan, and second-phase clinical tests show that the medicine containing the trifluridine active ingredient has different curative effects on the colon cancer patients who cannot be effectively treated by the three medicines. The chemical structure of the compound is shown as the following formula I:
Figure BDA0002386129510000011
currently, there are two main types of processes for preparing trifluridine:
the first method mainly uses 2' -deoxyuridine as a raw material, after hydroxyl protection, trifluoroacetic acid, trifluoroiodomethane or sodium trifluoromethylsulfinate is used as a trifluoromethylation reagent to carry out trifluoromethylation to generate hydroxyl-protected trifluridine, and then deprotection reaction is carried out to obtain the trifluridine; the method also comprises the steps of carrying out 3 '-position and 5' -hydroxyl protection and 2 '-halogenation by using uridine as a raw material, reducing and dehalogenating to obtain hydroxyl-protected 2' -deoxyuridine, and then carrying out trifluoromethylation. The trifluoromethylation reagent used in the method has high toxicity and high cost, and the yield is between 21% and about 70%.
The second method uses 5-trifluoromethyl uracil and 2-deoxy-D-ribose as raw materials, firstly, silicon-based protection is carried out on 5-trifluoromethyl uracil, then 2-deoxy-D-ribose is subjected to methylation, p-chlorobenzoyl and chlorination, and then, the 2-deoxy-D-ribose is condensed with the silicon-based protected 5-trifluoromethyl uracil, and finally, a protecting group is removed to obtain trifluridine.
In view of the foregoing, there is still a need in the art for a safe, green and easy-to-operate process for preparing trifluridine.
Disclosure of Invention
The invention aims to provide a method for preparing trifluridine, which is safe, green and simple to operate.
In order to achieve the above object, the present invention prepares trifluridine by the following steps: halogenating ribose fully protected by hydroxyl, condensing with 5-trifluoromethyl uracil, deprotecting to generate an intermediate 5-trifluoromethyl uridine, and preparing trifluridine through dehydration, halogenation and reduction reactions.
The invention provides a method for preparing trifluridine, which comprises the following steps:
1) carrying out halogenation reaction on the ribose protected by the total acyl group shown in the formula II to generate a compound shown in the formula III;
Figure BDA0002386129510000021
2) carrying out condensation reaction on a compound shown as a formula III and 5-trifluoromethyl uracil shown as a formula IV to generate a compound shown as a formula V;
Figure BDA0002386129510000022
3) carrying out deprotection reaction on the compound shown as the formula V to remove acyl, and generating a compound shown as a formula VI;
4) the compound shown as the formula VI is dehydrated and halogenated for the second time to respectively obtain compounds shown as formulas VII and VIII, and then the compound shown as the formula VIII is subjected to reduction reaction to obtain trifluridine shown as the formula I;
Figure BDA0002386129510000023
in the formula II, III and V, R is C2～C18Straight-chain or branched-chain alkyl acyl containing mono-, di-, tri-or unsubstituted aromatic cyclic formyl, C1～C18Straight or branched hydrocarbon radical, C1～C18Straight-chain or branched hydrocarbyloxy radicals, C1～C18Straight-chain or branched hydrocarbon acyl radical, C1～C18Linear or branched perfluoroalkyl, nitro, cyano, amino;
in the formula III and the formula VIII, X is halogen.
In the above method, the substituent in the mono-substituted, di-substituted, tri-substituted or unsubstituted aromatic cyclic formyl group is halogen.
In the above method, in step 1), the halogenation reaction is carried out under the action of acyl halide and alcohol;
the conditions for the halogenation are as follows: the temperature can be-20-5 ℃, specifically 0 ℃, 0-5 ℃, 20-0 ℃, 10-1 ℃ or-15-5 ℃, and the time can be 1-4 hours, specifically 2 hours, 1-2 hours, 2-4 hours or 1.5-3.5 hours.
In the above method, the acyl halide is a straight-chain or branched acyl chloride or acyl bromide containing 2 to 8 carbon atoms, and specifically may be acetyl chloride; the alcohol is straight chain or branched chain aliphatic alcohol containing 1-8 carbon atoms, and can be ethanol specifically;
the molar ratio of the total acyl protected ribose to the acyl halide represented by formula II can be 1: 1-3, specifically 1:2. 1: 1-2 and 1: 2-3 or 1: 1.5 to 2.5.
In the above method, the molar ratio of the compound represented by the formula III to the 5-trifluoromethyluracil represented by the formula IV may be 0.8 to 1.2:1, preferably 0.9 to 1.1:1, and more preferably 1: 1;
the conditions of the condensation reaction are as follows: the temperature can be 20-70 ℃, preferably 35-55 ℃, more preferably 45 ℃, the time can be 0.5-8 h, preferably 2-4 h, more preferably 3h, and the solvent is a polar aprotic solvent, and specifically can be 1, 2-dichloroethane or acetonitrile.
In the above method, the deprotection reaction is carried out in the presence of acetyl chloride and methanol;
the conditions for the deprotection reaction are as follows: the temperature can be-20 to 20 ℃, and the time can be 4 to 16 hours; preferably, the temperature can be-10 ℃, and the reaction time can be 8-12 h; more preferably, the reaction temperature can be 0 ℃ and the reaction time can be 10 h;
the molar ratio of the compound of formula v to acetyl chloride may be 1: 1.5-3.5, specifically 1:2.5, 1: 1.5-2.5, 1: 2.5-3.5 or 1:2 to 3.
In the above method, the dehydration reaction is carried out in the presence of a dehydrating agent and an inorganic base;
adding a halogenating reagent for the second halogenating reaction;
hydrogenation and metal catalyst are carried out in the reduction reaction;
the solvent for the reaction in the step 4) is N, N-dimethylformamide, N-dimethylacetamide, alcohol or tetrahydrofuran.
In the above method, the dehydration reaction conditions are as follows: the temperature can be 90-160 ℃, and the time can be 2-12 h; preferably, the temperature of the dehydration reaction can be 110-130 ℃, and the dehydration time can be 5-9 h; more preferably, the temperature may be 120 ℃ and the dehydration time may be 8 hours.
The conditions for the second halogenation are as follows: the temperature is 25-85 ℃, and the time is 6-12 h; preferably, the temperature of the second halogenation reaction is 45-65 ℃, and the halogenation time is 8-12 h; more preferably, the temperature is 55 ℃, and the halogenation time is 10 h;
the conditions of the reduction reaction are as follows: the pH value is 6-9, the temperature is 0-30 ℃, the hydrogen pressure is 0.1-1 Mpa, and the time can be 8-16 h; preferably, the pH value of the reduction reaction is 6.5-8.5, the reduction temperature is 10-20 ℃, the hydrogen pressure is 0.3-0.8 Mpa, and the time can be 10-14 h; more preferably, the pH value is 7-8, the reduction temperature is 15 ℃, the hydrogen pressure is 0.6Mpa, and the time can be 12 h.
In the method, the dehydrating agent is a di-aliphatic carbonate, and an aliphatic chain in the di-aliphatic carbonate is a straight chain or a branched chain containing 1-8 carbon atoms, and specifically can be dimethyl carbonate;
the inorganic base is a hydroxide or bicarbonate of an alkali metal, wherein the alkali metal is lithium, sodium or potassium; the inorganic base can be sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate;
the halogenating agent is hydrogen halide, and specifically can be hydrogen chloride or hydrogen bromide;
the metal catalyst is nickel, palladium or zinc; preferably nickel or palladium; more preferably palladium.
The molar ratio of the compound shown in the formula VI in the step 4) to the dehydrating agent and the inorganic base can be 1: 1-3: 0.02-0.2, specifically 1:2:0.05, 1: 1-2: 0.02-0.05, 1: 2-3: 0.05-0.2 or 1: 1.5-2.5: 0.05 to 0.1.
In the present invention, the amount of the halogenating agent and the metal catalyst to be used is an amount known to those skilled in the art.
The invention has the following advantages:
firstly, the use of fully protected ribose as raw material significantly reduces the cost of raw materials, and the 2-acyl protected ribose significantly improves the β -stereoselectivity of the condensation reaction due to the effect of the participation of ortho-group in the condensation reaction process.
Secondly, 5-trifluoromethyl uracil is used as a raw material, so that a highly toxic trifluoromethylation reagent is avoided, and the method is environment-friendly.
Thirdly, the compound shown in the formula VI is continuously operated, the intermediate does not need to be separated and purified, the final product can be directly generated, the production operation is greatly facilitated, the production efficiency is improved, and the labor cost is reduced.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1 Synthesis of 1-chloro-2, 3, 5-O-triacetyl-D-ribose
100g of tetraacetyl-D-ribose is dissolved in 49.3g of acetyl chloride (the molar ratio of the two is 1:2) at 0 ℃, 218g of ethanol is slowly dripped while maintaining the temperature at 0 ℃, the temperature is kept for 2 hours after dripping, and after the reaction is finished, the solvent is decompressed and dried in a spinning mode to obtain 103g of 1-chloro-2, 3, 5-O-triacetyl-D-ribose which is oily and can be directly used for the next reaction without purification.
example 2 Synthesis of 2 ', 3 ', 5 ' -O-triacetyl- β -D-5-trifluoromethyluridine
dissolving 1-chloro-2, 3,5-O- β -D-ribose obtained in example 1 of the invention and 56.6g of 5-trifluoromethyluracil (molar ratio of the two is 1:1) in 100mL of acetonitrile, heating to 45 ℃, keeping the temperature and reacting for 3h, after TLC monitoring reaction is finished, carrying out reduced pressure rotary evaporation on reaction liquid until the reaction liquid is dry, dissolving residues by using ethyl acetate, washing the residues by using water and saturated NaCl solution for 2 times respectively, discarding an aqueous phase, carrying out reduced pressure rotary evaporation on an organic phase until the organic phase is dry, recrystallizing the residues by using ethyl acetate-ethanol to separate out a solid, filtering and rinsing a filter cake by using a proper amount of ethanol, drying to obtain 112g of 2 ', 3 ', 5 ' -O- β -beta-D-5-trifluoromethyluridine which is white to white-like solid, wherein the yield is 81.3% (based on tetraacetyl-D-ribose),1H NMR(400MHz，CDCl3)δ2.11(s,3H),2.13(s,3H),2.14(s,3H),4.33(d,J＝13.6Hz,1H),4.43(m,2H),5.34(t,J＝5.4Hz,1H),5.37(t,J＝5.4Hz,1H),6.07(d,J＝5.4Hz,1H),8.00(s,1H),9.09(s,1H)，19F NMR(376MHz，CDCl3)δ-64.0。
EXAMPLE 3 Synthesis of β -D-5-trifluoromethyluridine
dissolving 20g of 2 ', 3', 5 '-O-triacetyl- β -D-5-trifluoromethyl uridine in 150mL of methanol, cooling to 0 ℃, starting to dropwise add 9g of acetyl chloride (the molar ratio of 2', 3 ', 5' -O-triacetyl- β -D-5-trifluoromethyl uridine to acetyl chloride is 1:2.5), keeping the temperature at 0 ℃ after dropwise adding for reaction for 10 hours, after TLC detection reaction is completed, drying the solvent at low temperature under reduced pressure, recrystallizing the residue with ethanol-acetone to separate out a solid, filtering, rinsing the filter cake with an appropriate amount of acetone, and drying to obtain 13.7g of β -D-5-trifluoromethyl uridine which is a white solid and has the yield of 96.2%。1H NMR(400MHz，DMSO-d6)δ3.60(m,1H),3.75(m,1H),3.90(dt,J＝6.0,2.0Hz,1H),4.00(dd,J＝9.2,5.3Hz,1H),4.06(dd,J＝7.2,4.0Hz,1H),5.08(d,J＝4.6Hz,1H),5.35(t,J＝4.2Hz,1H),5.51(d,J＝4.6Hz,1H),5.70(d,J＝3.2Hz,1H),8.88(s,1H),11.85(s,1H)，19F NMR(376MHz，DMSO-d6)δ-61.2。
Example 4 Synthesis of trifluridine
dissolving 10g of β -D-5-trifluoromethyl uridine in 20mL of N, N-dimethylformamide, adding 5.77g of dimethyl carbonate and 0.14g of sodium bicarbonate (the molar ratio of the β -D-5-trifluoromethyl uridine to the dimethyl carbonate to the sodium bicarbonate is 1:2:0.05), heating the reaction solution to 120 ℃ for 8 hours, after the reaction is finished, cooling to room temperature, adding 20mL of N, N-dimethylformamide solution with 2mol/L of hydrogen chloride, heating to 55 ℃ for 10 hours, after the reaction is finished, adjusting the pH value to 7-8 by using 2mol/L of sodium hydroxide aqueous solution, then cooling to 15 ℃ and adding 1g of Pd/C, introducing hydrogen and keeping the hydrogen pressure at 0.6MPa, simultaneously dropwise adding 2mol/L of sodium hydroxide aqueous solution to keep the pH value stable, keeping the hydrogen pressure and the temperature for 12 hours, filtering the reaction solution, carrying out reduced pressure rotary evaporation to dryness, and carrying out two-time recrystallization by using water and methanol respectively to obtain 8.2g of white uridine, wherein the yield of the uridine is 4.86.1H NMR(400MHz，DMSO-d6)δ2.20(m,2H),3.57(d,J＝11.2Hz,1H),3.66(d,J＝11.6Hz,1H),3.82(m,1H),4.26(m,1H),5.20(t,J＝4.0Hz,1H),5.25(t,J＝4.4Hz,1H),6.08(t,J＝6.2Hz,1H),8.73(s,1H),11.80(s,1H)，13C NMR(100MHz，DMSO-d6)δ40.5,60.2,69.4,85.5,87.8,102.8,122.6,142.2,149.7,159.1，19F NMR(376MHz，DMSO-d6)δ-65.9。

Claims (9)

1. A process for preparing trifluridine, comprising the steps of:
1) carrying out halogenation reaction on the ribose protected by the total acyl group shown in the formula II to generate a compound shown in the formula III;
Figure FDA0002386129500000011
2) carrying out condensation reaction on a compound shown as a formula III and 5-trifluoromethyl uracil shown as a formula IV to generate a compound shown as a formula V;
Figure FDA0002386129500000012
3) carrying out deprotection reaction on the compound shown as the formula V to remove acyl, and generating a compound shown as a formula VI;
4) the compound shown as the formula VI is dehydrated and halogenated for the second time to respectively obtain compounds shown as formulas VII and VIII, and then the compound shown as the formula VIII is subjected to reduction reaction to obtain trifluridine shown as the formula I;
Figure FDA0002386129500000013
in the formula II, III and V, R is C2～C18Straight-chain or branched-chain alkyl acyl containing mono-, di-, tri-or unsubstituted aromatic cyclic formyl, C1～C18Straight or branched hydrocarbon radical, C1～C18Straight-chain or branched hydrocarbyloxy radicals, C1～C18Straight-chain or branched hydrocarbon acyl radical, C1～C18Linear or branched perfluoroalkyl, nitro, cyano, amino;
in the formula III and the formula VIII, X is halogen.
2. The method of claim 1, wherein: the substituent in the mono-substituted, di-substituted, tri-substituted or unsubstituted aromatic ring formyl is halogen.
3. The method according to claim 1 or 2, characterized in that: in the step 1), the halogenation reaction is carried out under the action of acyl halide and alcohol;
the conditions for the halogenation are as follows: the temperature is-20 to 5 ℃, and the time is 1 to 4 hours.
The molar ratio of the total acyl protected ribose represented by formula II to the acyl halide and the alcohol is 1:1 to 3.
4. The method of claim 4, wherein: the acyl halide is straight-chain or branched acyl chloride or acyl bromide containing 2-8 carbon atoms; the alcohol is a straight chain or branched chain aliphatic alcohol containing 1-8 carbon atoms;
the molar ratio of the total acyl protected ribose to the acyl halide shown in the formula II is 1:1 to 3.
5. The method according to any one of claims 1-4, wherein: the molar ratio of the compound shown in the formula III to the 5-trifluoromethyl uracil shown in the formula IV is 0.8-1.2: 1;
the conditions of the condensation reaction are as follows: the temperature is 20-70 ℃, the time is 0.5-8 h, and the solvent is a polar aprotic solvent.
6. The method according to any one of claims 1-5, wherein: the deprotection reaction is carried out in the presence of acetyl chloride and methanol;
the conditions for the deprotection reaction are as follows: the temperature is-20 to 20 ℃, and the time is 4 to 16 hours;
the molar ratio of the compound of formula v to acetyl chloride is 1: 1.5 to 3.5.
7. The method according to any one of claims 1-6, wherein: the dehydration reaction is carried out in the presence of a dehydrating agent and an inorganic base;
adding a halogenating reagent for the second halogenating reaction;
hydrogenation and metal catalyst are carried out in the reduction reaction;
the solvent for the reaction in the step 4) is N, N-dimethylformamide, N-dimethylacetamide, alcohol or tetrahydrofuran.
8. The method according to any one of claims 1-7, wherein: the conditions of the dehydration reaction are as follows: the temperature is 90-160 ℃, and the time is 2-12 h.
The conditions for the second halogenation are as follows: the temperature is 25-85 ℃, and the time is 6-12 h;
the conditions of the reduction reaction are as follows: the pH value is 6-9, the temperature is 0-30 ℃, the hydrogen pressure is 0.1-1 Mpa, and the time is 8-16 h.
9. The method according to claim 7 or 8, characterized in that: the dehydrating agent is a di-aliphatic carbonate, and an aliphatic chain in the di-aliphatic carbonate is a straight chain or a branched chain containing 1-8 carbon atoms;
the inorganic base is hydroxide or bicarbonate of alkali metal, wherein the alkali metal is lithium, sodium or potassium;
the halogenating agent is hydrogen halide;
the metal catalyst is nickel, palladium or zinc;
the molar ratio of the compound shown in the formula VI in the step 4) to the dehydrating agent and the inorganic base is 1: 1-3: 0.02 to 0.2.
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