CN103819412B - A kind of preparation method of 5-flurocytosine - Google Patents

A kind of preparation method of 5-flurocytosine Download PDF

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CN103819412B
CN103819412B CN201310667782.XA CN201310667782A CN103819412B CN 103819412 B CN103819412 B CN 103819412B CN 201310667782 A CN201310667782 A CN 201310667782A CN 103819412 B CN103819412 B CN 103819412B
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fluoride
flurocytosine
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fluoro
cyt
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CN103819412A (en
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陈小平
姚福友
卢娓
肖木杰
高飞飞
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Zhejiang Pioneer Technology Group Co.,Ltd.
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Abstract

The invention discloses a kind of preparation method of 5-flurocytosine, described method comprises the steps: 1) cytosine(Cyt) and halogenating agent carry out halogenating reaction and obtain intermediate (I) at 0 ~ 80 DEG C in organic solvent; 2) intermediate (I) and amino protecting agent react obtained intermediate (II) at 0 ~ 120 DEG C; 3) intermediate (II) and fluoro reagent are carried out fluoro-reaction and are obtained intermediate (III) at 70 ~ 200 DEG C in polar aprotic solvent or hydrogen fluoride, and intermediate (III) directly carries out amino deprotection reaction, obtained 5-flurocytosine after being separated, purifying.Operational path in present method is reasonable, and product yield is high, quality good, and fluoro reagent production security is high, simple to operate, is suitable for suitability for industrialized production.

Description

A kind of preparation method of 5-flurocytosine
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, be specifically related to the preparation method of a kind of antifungal drug or medicine intermediate 5-flurocytosine, this intermediate is for the preparation of antineoplastic medicine capecitabine and antiviral emtricitabine.
Background technology
5-flurocytosine is a kind of antimycotic medicine of chemosynthesis, higher anti-mycotic activity is had to hiding Coccus, Candida, choice drug abroad as treatment serious systemic Candida albicans and Cryptococcus infections takes in " American Pharmacopeia " (the 19 edition), for fungoid meningitis, the treatment of fungoid respiratory tract infection and black fungi disease.Meanwhile, 5-flurocytosine is also the important intermediate preparing antineoplastic medicine capecitabine and antiviral emtricitabine.
In existing technology, the preparation method of 5-flurocytosine is as follows:
With 5 FU 5 fluorouracil (F.Hoffmann-LaRoche & Co.5-Fluorocytosines.Br877,318: cA1962:56:8724a) or 5 FU 5 fluorouracil precursor 2-methoxyl group-4-hydroxyl-5-fluorine pyrimidine (Chinese Journal of Pharmaceuticals 1982-08-29, China Medicine University's journal 1989,20 (1), 35) for starting raw material obtains 5-flurocytosine through chlorination, ammonification, hydrolysis.The former cost is high, yield low (not comprising refining 56.4%), the latter needs pressurization to carry out aminating reaction and uses a large amount of anhydrous methanol as solvent, be unfavorable for suitability for industrialized production, in addition, final step hydrolysis easily makes the amino on pyrimidine ring be converted into hydroxyl, becomes 5 FU 5 fluorouracil again again, causes unstable product quality.
JP37553/1979 reports cytosine(Cyt) directly prepares 5-flurocytosine method with fluorine gas fluoro, and products obtained therefrom yield and purity are all lower.Cytosine(Cyt) generates hydrogen fluoride salts and carries out fluoro-reaction under fluorine gas/hydrogen fluoride effect, then in and the hydrogen fluoride method of preparing 5-flurocytosine (US4473691, EP0063352) all increase on yield and purity compared with the method for the direct fluoro of fluorine gas.But use highly corrosive, hypertoxic fluorine gas require high to production operation and production unit etc., may cause larger injury to environment and operator, production security is poor, and industrial production has certain difficulty.
Summary of the invention
For the above-mentioned problems in the prior art, the object of the present invention is to provide a kind of chemical preparation process of 5-flurocytosine, with to solve in prior art that product cost is high, quality is unstable or use highly corrosive, hypertoxic fluorine gas requires high to production operation and production unit etc., larger injury may be caused to environment and operator, production security is poor, is unfavorable for industrial defect.
The preparation method of described a kind of 5-flurocytosine, is characterized in that said method comprising the steps of:
1) cytosine(Cyt) and halogenating agent react obtained intermediate (I) at 0 ~ 80 DEG C in organic solvent;
2) intermediate (I) that step 1) obtains reacts obtained intermediate (II) with amino protecting agent at 0 ~ 120 DEG C;
3) step 2) intermediate (II) that obtains carries out fluoro-reaction with fluoro reagent and obtains intermediate (III) at 70 ~ 200 DEG C in polar aprotic solvent or hydrogen fluoride; intermediate (III) directly carries out amino deprotection reaction; obtained 5-flurocytosine after being separated, purifying again, syntheti c route is as follows:
Above-mentioned intermediate (I), intermediate (II) and intermediate (III) are respectively (I), (II) and (III) in syntheti c route;
Wherein X is one or more in halogen Cl, Br, I;
R is amino protecting group.
The preparation method of described a kind of 5-flurocytosine, it is characterized in that the halogenating agent described in step 1) be chlorine, bromine, iodine, n-chlorosuccinimide, n-bromo-succinimide, none or more mixtures in-N-iodosuccinimide, tetrabutylammonium tribromide, tetrabromo cyclic ketones, cupric bromide; The molar feed ratio of cytosine(Cyt) and halogenating agent is 1:1 ~ 3.
The preparation method of described a kind of 5-flurocytosine, it is characterized in that the organic solvent described in step 1) is one or more mixtures in tetracol phenixin, chloroform, methylene dichloride, 1,2-ethylene dichloride, toluene, dimethylbenzene, DMF, DMSO, acetonitrile, ethyl acetate, acetic acid, ethanol.
The preparation method of described a kind of 5-flurocytosine, is characterized in that described amino protecting group is one or more mixtures in formyl radical, ethanoyl, benzoyl, trifluoroacetyl group, phthaloyl, p-toluenesulfonyl, tertbutyloxycarbonyl, biphenylisopropyloxycarbonyl, carbobenzoxy-(Cbz), diisopropyl methoxycarbonyl, fluorenylmethyloxycarbonyl, benzyl, trityl.
The preparation method of described a kind of 5-flurocytosine, it is characterized in that the fluoro reagent described in step 3) is one or more mixtures in inorganic fluoride salt, organic villiaumite, fluoro quaternary ammonium salt or carrier villiaumite, intermediate (II) is 1:1 ~ 3 with the molar feed ratio of fluoro reagent.
The preparation method of described a kind of 5-flurocytosine, is characterized in that inorganic fluoride salt is Sodium Fluoride, Potassium monofluoride, cesium fluoride, lithium fluoride, antimony trifluoride, antimony pentafluoride, Mercury difluoride, silver fluoride, cupric fluoride, cobaltous fluoride or cerium fluoride; Organic villiaumite is pyridine hydrogen fluoride salts; Fluoro quaternary ammonium salt is tetrabutyl ammonium fluoride or Methanaminium, N,N,N-trimethyl-, fluoride; Carrier villiaumite is carrier Potassium monofluoride.
The preparation method of described a kind of 5-flurocytosine, it is characterized in that the polar aprotic solvent described in step 3) be DMF, n,N-N,N-DIMETHYLACETAMIDE, DMSO, tetramethylene sulfone, none or more mixtures in-methyl-2-pyrrolidone, ethanamide, acetonitrile, benzyl cyanide, crown ether, polyoxyethylene glycol.
Compared with prior art, the present invention adopts the first halo of cytosine(Cyt), amido protecting, again fluoro, the method of last deprotection prepares 5-flurocytosine, prepare compared with 5-flurocytosine with 5 FU 5 fluorouracil or its precursor 2-methoxyl group-4-hydroxyl-5-fluorine pyrimidine through the technology of chlorination, ammonification, hydrolysis, cheaper starting materials of the present invention is easy to get, yield is high, cost is low, constant product quality; Compared with the technology of directly cytosine(Cyt) being carried out to fluoro with fluorine gas; avoid the use of highly corrosive, hypertoxic fluorine gas; reduce the requirement to production operation and production unit; decrease the injury to environment and operator; use common fluoro reagent; production security is good, is applicable to the industrial production of mass-producing.
Embodiment
Below in conjunction with concrete case study on implementation, the present invention is further described.Be construed as; the preparation method of the invention process case is only for illustration of the present invention, instead of limitation of the present invention, and protection scope of the present invention is not limited in this; under concept thereof of the present invention, all the scope of protection of present invention is belonged to the simple modifications of preparation method of the present invention.
The preparation of embodiment 1:5-bromine cytosine(Cyt)
By cytosine(Cyt) (55.6g, 0.5mol) be suspended in 120mL acetic acid, bromine (87.9g is slowly dripped under room temperature, 0.55mol) with the mixing solutions of 80mL acetic acid, TLC tracks to cytosine(Cyt) and reacts completely, and ice-water bath is cooled to 10 DEG C, filter, filter cake washs with acetic acid 20mL and water 20mL successively, dries and obtains 5-bromine cytosine(Cyt) (89.7g, 94.3%).
In this embodiment, halogenating agent chlorine, iodine, n-chlorosuccinimide, n-bromo-succinimide, none or more mixtures in-N-iodosuccinimide, tetrabutylammonium tribromide, tetrabromo cyclic ketones, cupric bromide replace bromine; One or more mixtures in organic solvent tetracol phenixin, chloroform, methylene dichloride, 1,2-ethylene dichloride, toluene, dimethylbenzene, DMF, DMSO, acetonitrile, ethyl acetate, ethanol replace acetic acid, all can obtain similar technique effect.
Embodiment 2: nthe preparation of-ethanoyl-5-bromine cytosine(Cyt)
5-bromine cytosine(Cyt) (95g, 0.5mol), aceticanhydride (306.3g, 3mol) are added in reaction flask, is warming up to 70 DEG C of reaction 4h, decompression steams solvent, adds 200mL methyl alcohol and is warming up to backflow 30min, be cooled to room temperature, filter, filter cake methyl alcohol 30mL washs, and oven dry obtains n-ethanoyl-5-bromine cytosine(Cyt) (114.3g, 98.5%).
The preparation of embodiment 3:5-flucytosine
Will n-ethanoyl-5-bromine cytosine(Cyt) (69.6g, 0.3mol) drop in dry reaction flask, anhydrous potassium fluoride (23.2g is added under nitrogen protection, 0.4mol), ethanamide (29.5g, 0.5mol), DMF150mL, be warming up to 130 DEG C of reaction 5h, decompression steams solvent, be cooled to 40 DEG C and add 150mL ammonia methyl alcohol and insulation reaction 12h, TLC tracks to intermediate (III) and reacts completely, decompression steams methyl alcohol, adding 400mL water is heated to clearly molten, be cooled to 10 DEG C, filter, oven dry obtains White crystalline solid 5-flurocytosine (36g, 93%), HPLC content 99.5%.
In this embodiment, fluoro reagent Sodium Fluoride, cesium fluoride, lithium fluoride, antimony trifluoride, antimony pentafluoride, Mercury difluoride, silver fluoride, cupric fluoride, cobaltous fluoride, cerium fluoride, pyridine hydrogen fluoride salts, tetrabutyl ammonium fluoride, Methanaminium, N,N,N-trimethyl-, fluoride or carrier Potassium monofluoride replace anhydrous potassium fluoride, and polar aprotic solvent is used n,N-N,N-DIMETHYLACETAMIDE, DMSO, tetramethylene sulfone, none or more mixtures in-methyl-2-pyrrolidone, ethanamide, acetonitrile, benzyl cyanide, crown ether, polyoxyethylene glycol, hydrogen fluoride replace n,N-dimethyl formamide, all can obtain similar technique effect.
The preparation of embodiment 4:5-bromine cytosine(Cyt)
By cytosine(Cyt) (55.6g, 0.5mol), n-bromo-succinimide (106.8g, 0.6mol) and DMF150mL add in reaction flask, are cooled to 15 DEG C of ultrasonic reaction 1h, and TLC raw material reaction is complete, filter, and filter cake use water (20mL × 2) washs, and drying obtains 5-bromine cytosine(Cyt) (90.9g, 95.6%).
Embodiment 5: nthe preparation of-fluorenylmethyloxycarbonyl-5-bromine cytosine(Cyt)
By 5-bromine cytosine(Cyt) (95g, 0.5mol), saturated sodium carbonate solution 200mL, dioxane 100mL add in reaction flask, be cooled to 10-15 DEG C and drip fluorenylmethyloxycarbonyl chlorine (155.2g, 0.6mol) and the mixing solutions of 100mL dioxane, dropwise, be warming up to room temperature reaction 3h, filter, filter cake water (50mL × 2) washs, and oven dry obtains n-fluorenylmethyloxycarbonyl-5-bromine cytosine(Cyt) (196.7g, 95.4%).
The preparation of embodiment 6:5-flucytosine
Will n-fluorenylmethyloxycarbonyl-5-bromine cytosine(Cyt) (123.7g, 0.3mol) drop in dry reaction flask, anhydrous potassium fluoride (23.2g is added under nitrogen protection, 0.4mol), tetrabutyl ammonium fluoride (7.8g, 0.03mol), DMF150mL, be warming up to 110 DEG C of reaction 10h, decompression steams solvent, be cooled to room temperature, add the sodium hydroxide solution 80mL of 240mL dioxane and 4mol/L, be warming up to 50 DEG C of reaction 2h, be cooled to room temperature, adding 1mol/L dilute hydrochloric acid regulates pH in neutral, continue to be cooled to 10 DEG C, filter, filter cake 320mL water recrystallization obtains White crystalline solid 5-flurocytosine (35.3g, 91.1%), HPLC content 99.2%.
The preparation of embodiment 7:5-bromine cytosine(Cyt)
By cytosine(Cyt) (55.6g, 0.5mol), n-bromo-succinimide (133.5g, 0.75mol) and 240mL chloroform add in reaction flask, are warming up to back flow reaction 4h, steam solvent, add 120mL water, be cooled to 10 DEG C, filter, filter cake use water 30mL washs, and drying obtains 5-bromine cytosine(Cyt) (90.5g, 95.2%).Drying obtains 5-bromine cytosine(Cyt) (90.9g, 95.6%).
Embodiment 8: nthe preparation of-ethanoyl-5-bromine cytosine(Cyt)
5-bromine cytosine(Cyt) (95g, 0.5mol), aceticanhydride (71.5g, 0.7mol), toluene 200mL are added in reaction flask, is warming up to back flow reaction 8h, decompression steams solvent, adds 150mL methyl alcohol and is warming up to backflow 15min, be cooled to room temperature, filter, filter cake methyl alcohol 30mL washs, and oven dry obtains n-ethanoyl-5-bromine cytosine(Cyt) (113.8g, 98.1%).
The preparation of embodiment 9:5-flucytosine
Will n-ethanoyl-5-bromine cytosine(Cyt) (69.6g, 0.3mol) drop in dry reaction flask, anhydrous potassium fluoride (29.1g is added under nitrogen protection, 0.5mol), DMSO200mL, be warming up to 170 DEG C of reaction 8h, decompression steams solvent, be cooled to room temperature, add 100mL water dispersed with stirring, be cooled to 10 DEG C, filter, filter cake adds in the hydrochloric acid 100mL of 150mL methyl alcohol and 6mol/L, be warming up to backflow 2h, be cooled to room temperature, adding 2mol/L sodium hydroxide solution regulates pH in neutral, continue to be cooled to 10 DEG C, filter, filter cake 320mL water recrystallization obtains White crystalline solid 5-flurocytosine (35.7g, 92.1%), HPLC content 99.3%.

Claims (7)

1. a preparation method for 5-flurocytosine, is characterized in that said method comprising the steps of:
1) cytosine(Cyt) and halogenating agent react obtained intermediate (I) at 0 ~ 80 DEG C in organic solvent, described halogenating agent be chlorine, bromine, iodine, n-chlorosuccinimide, n-bromo-succinimide, none or more mixtures in-N-iodosuccinimide, tetrabutylammonium tribromide, tetrabromo cyclic ketones, cupric bromide;
2) intermediate (I) that step 1) obtains reacts obtained intermediate (II) with amino protecting agent at 0 ~ 120 DEG C;
3) step 2) intermediate (II) that obtains carries out fluoro-reaction with fluoro reagent and obtains intermediate (III) at 70 ~ 200 DEG C in polar aprotic solvent or hydrogen fluoride; intermediate (III) directly carries out amino deprotection reaction; obtained 5-flurocytosine after being separated, purifying again, syntheti c route is as follows:
Above-mentioned intermediate (I), intermediate (II) and intermediate (III) are respectively (I), (II) and (III) in syntheti c route;
Wherein X is one or more in halogen Cl, Br, I;
R is amino protecting group.
2. the preparation method of a kind of 5-flurocytosine as claimed in claim 1, is characterized in that the molar feed ratio of the cytosine(Cyt) described in step 1) and halogenating agent is 1:1 ~ 3.
3. the preparation method of a kind of 5-flurocytosine as claimed in claim 1, it is characterized in that the organic solvent described in step 1) is one or more mixtures in tetracol phenixin, chloroform, methylene dichloride, 1,2-ethylene dichloride, toluene, dimethylbenzene, DMF, DMSO, acetonitrile, ethyl acetate, acetic acid, ethanol.
4. the preparation method of a kind of 5-flurocytosine as claimed in claim 1, is characterized in that described amino protecting group is one or more mixtures in formyl radical, ethanoyl, benzoyl, trifluoroacetyl group, phthaloyl, p-toluenesulfonyl, tertbutyloxycarbonyl, biphenylisopropyloxycarbonyl, carbobenzoxy-(Cbz), diisopropyl methoxycarbonyl, fluorenylmethyloxycarbonyl, benzyl, trityl.
5. the preparation method of a kind of 5-flurocytosine as claimed in claim 1, it is characterized in that the fluoro reagent described in step 3) is one or more mixtures in inorganic fluoride salt, organic villiaumite, fluoro quaternary ammonium salt or carrier villiaumite, intermediate (II) is 1:1 ~ 3 with the molar feed ratio of fluoro reagent.
6. the preparation method of a kind of 5-flurocytosine as claimed in claim 5, is characterized in that inorganic fluoride salt is Sodium Fluoride, Potassium monofluoride, cesium fluoride, lithium fluoride, antimony trifluoride, antimony pentafluoride, Mercury difluoride, silver fluoride, cupric fluoride, cobaltous fluoride or cerium fluoride; Organic villiaumite is pyridine hydrogen fluoride salts; Fluoro quaternary ammonium salt is tetrabutyl ammonium fluoride or Methanaminium, N,N,N-trimethyl-, fluoride; Carrier villiaumite is carrier Potassium monofluoride.
7. the preparation method of a kind of 5-flurocytosine as claimed in claim 1, it is characterized in that the polar aprotic solvent described in step 3) be DMF, n,N-N,N-DIMETHYLACETAMIDE, DMSO, tetramethylene sulfone, none or more mixtures in-methyl-2-pyrrolidone, ethanamide, acetonitrile, benzyl cyanide, crown ether, polyoxyethylene glycol.
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