CN103601686A - Method for synthesizing fluorine-containing pyrimidine compounds by virtue of one-pot method - Google Patents
Method for synthesizing fluorine-containing pyrimidine compounds by virtue of one-pot method Download PDFInfo
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- CN103601686A CN103601686A CN201310557467.1A CN201310557467A CN103601686A CN 103601686 A CN103601686 A CN 103601686A CN 201310557467 A CN201310557467 A CN 201310557467A CN 103601686 A CN103601686 A CN 103601686A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/56—One oxygen atom and one sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
Abstract
The invention discloses a method for synthesizing fluorine-containing pyrimidine compounds by virtue of a one-pot method, and belongs to the field of organic synthesis. The fluorine-containing pyrimidine compounds have wide application, and mainly serve as organic reagents, pesticide intermediates, medicaments and medical intermediates. According to the method for synthesizing the fluorine-containing pyrimidine compounds by virtue of the one-pot method, a condensation reaction and a cyclization reaction are combined into a one-step reaction, so that unit operation is reduced, the preparation process is simple, the reaction conditions are mild, and the method is applicable to large-scale industrial production.
Description
Technical field
The method that the present invention relates to the synthetic fluorine-containing pyrimidines of a kind of one kettle way, belongs to pharmaceutical chemistry field.
Background technology
Fluorine-containing pyrimidine compound is the important intermediate of the fluorine-containing sulphur grass of synthetic herbicide amine agricultural chemicals on the one hand, and the sulphur grass amine of fluorinated is inner-adsorption conduction-type herbicide, can conduct to weeds complete stool, thereby herbicide is thorough, can not recur.Efficacy stability at low temperatures, even still can guarantee to stablize at low temperatures drug effect, this point is that other not fluorine-containing sulphurs grass amine weedicides are incomparable.On the other hand, 5 FU 5 fluorouracil and derivative thereof are medicine or medicine intermediate, that wide spectrum is applied to is antitumor, anticancer medication synthetic.
The synthetic cost of industry that reduces fluorinated pyrimidine compound is all significant for synthesizing of agricultural chemicals and medicine.
The general formula of fluorine-containing pyrimidines is as shown in the formula shown in (1):
R
1for OH; R
2for H, OH, SH ,-OCH
3, – OCH
2cH
3,-SCH
3.
Its similar structures compound synthesis technology has been reported, and Tetrahedron Letters for example mentions the method for compound shown in the compound preparation formula (1) shown in following formula (2) in 1980,4605-4606.
It is raw material that compound shown in its Chinese style (1) be take uridylic (2), and ethanol or methyl alcohol are made solvent, add a little acetic acid, under room temperature, pass into fluorine gas, directly fluoridize and obtain.
Yet the yield of aforesaid method only has 40-50% conventionally, can produce a large amount of three wastes, the corrodibility of fluorine gas is strong especially, high especially to equipment requirement of strength, and danger potential in suitability for industrialized production is larger.
Summary of the invention
It is lower that the present invention is intended to overcome the fluorine-containing pyrimidine compound yield of existing preparation, and environmental pollution is large, the defect of raw material danger, the method of the synthetic fluorine-containing pyrimidine compound of a kind of one kettle way is provided, the method raw materials cost is low, and processing condition are simple to operation, and product yield is higher.
The technical solution used in the present invention is: the method for the pyrimidines that a kind of one kettle way is synthetic fluorine-containing, under nitrogen protection, in 1000mL four-hole boiling flask, add raw material, the mol ratio of the formic acid ester compound in raw material and fluorinated ester compound is 1-3:1, be cooled to 0-5 ℃, add in batches the aromatic solvent containing alkali, after adding, be warming up to 25 ℃, reaction 3h, reaction solution becomes faint yellow turbid solution; Under nitrogen protection, the faint yellow turbid solution in described 1000mL four-hole boiling flask adds described alkali, alcoholic solvent successively, is cooled to 0-5 ℃; start to add urea phosphate compounds and alcoholic solvent, urea hydrochlorate and described fluorine ester contained mol ratio are 0.5-1:1, after adding, are warming up to 25-45 ℃; continue reaction 3-5h, stopped reaction, concentrating under reduced pressure solvent; add deionized water making beating to stir; with concentrated hydrochloric acid, being adjusted to pH is 4-5, and adularescent solid is separated out, and filters; dry, obtain fluorine-containing pyrimidines solid.
Ester cpds in described raw material is a kind of in methyl-formiate, ethyl formate, propyl formate; Fluorinated ester compound in described raw material is a kind of in methylfluoracetate, ethyl fluoroacetate;
Described urea phosphate compounds is a kind of in O-Methyl Isourea Sulfate, S-methyl-isourea, S-ethyl isothiourea vitriol, O-methyl-isourea methyl sulfate salt, O-methyl-isourea hydrochloride.
Described alkali is sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium Metal 99.5, sodium hydroxide, potassium hydroxide, sodium hydride.
Described benzene solvent is one or both in toluene, dimethylbenzene; Described alcoholic solvent is one or both in methyl alcohol, ethanol.
The invention has the beneficial effects as follows: the method is combined into single step reaction by condensation and ring-closure reaction, has reduced unit operation, and preparation process is simple, be applicable to large-scale industrial production.Related raw material is all easy to get, and reaction conditions gentleness is easy to control.
Embodiment
The invention provides a kind of synthetic method of fluorine-containing pyrimidine compound, the general formula of this compound as the formula (1):
Wherein, R
1for OH; R
2for H, OH, SH ,-OCH
3, – OCH
2cH
3,-SCH
3.
Fluorine-containing pyrimidine compound shown in described formula (1) is 5 FU 5 fluorouracil, 2-methoxyl group-5 FU 5 fluorouracil, 2-first sulfydryl-5 FU 5 fluorouracil, 4-methoxyl group-5 FU 5 fluorouracil, 2-sulfydryl-5 FU 5 fluorouracil, 4-sulfydryl-5 FU 5 fluorouracil, 4-first sulfydryl-5 FU 5 fluorouracil etc.
According to described method provided by the invention, described reaction conditions comprises: temperature of reaction 0-80 ℃, and the reaction times is preferably 1-5h, and the fluorinated ester of using in reacting of take is 1eq, the ester of using in reaction, alkali, urea hydrochlorate institute consumption is respectively 1-3eq; 1-3eq; 0.5-1eq.Preferred reaction conditions comprises: temperature of reaction 25-45 ℃, and reaction times 3-5h, the ester of using in reaction, alkali, urea hydrochlorate consumption is 1.5-2.5eq; 1-2eq; 0.5-0.8eq.
According to the invention provides described method, described alkali can be sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium Metal 99.5, sodium hydroxide, potassium hydroxide, one or more in sodium hydride.
According to the invention provides described method, described reaction is carried out under organic solvent exists, and described organic solvent can be toluene, dimethylbenzene, methyl alcohol, ethanol, one or both mixed solvents such as methyl tertiary butyl ether.Described organic solvent and fluorine ester contained consumption mass ratio are 3-20:1.
Below by example, the present invention will be further described.
In following instance, the purity of synthesized compound is according to high effective liquid chromatography for measuring.
The preparation of embodiment 1 2-first sulfydryl-5 FU 5 fluorouracil
Under nitrogen protection, in 1000mL four-hole boiling flask, add successively methylfluoracetate 27.6g (0.3moL; 1.0eq) with ethyl formate 44.4g(0.6mol; 2.0eq); be cooled to 0-5 ℃; add in batches the 75g xylene solution containing sodium ethylate 22.4g (0.33mol, 1.1eq), after adding, be warming up to 25 ℃ of reaction 3h; reaction solution becomes faint yellow turbid solution, stand-by.Under nitrogen protection; in above-mentioned 1000mL four-hole boiling flask, add successively sodium ethylate 22.4g (0.33mol; 1.1eq), ethanol 320g, is cooled to 0-5 ℃; start to add S-methyl-isourea 50.4g (0.18mol; 0.6eq), with 240g ethanolic soln, after adding, be warming up to 35-40 ℃, continue reaction 4h; stopped reaction; concentrating under reduced pressure solvent, adds deionized water 500g making beating to stir, and with concentrated hydrochloric acid, being adjusted to pH is 4-5; adularescent solid is separated out; filter, dry, obtain solid 89.8g; purity is 98.2%, and product yield is 55.1%.
Embodiment 2 2-methoxyl group-5 FU 5 fluorouracil preparation methods
Under nitrogen protection, in 1000mL four-hole boiling flask, add successively ethyl fluoroacetate 31.8g(0.3moL; 1.0eq) with ethyl formate 44.4g(0.6mol; 2.0eq); be cooled to 0-5 ℃; add in batches containing sodium methylate 17.8g(0.33mol; 75g toluene solution 1.1eq), is warming up to 25 ℃ of reaction 3h after adding, reaction solution becomes faint yellow turbid solution.In above-mentioned 1000mL four-hole boiling flask, add successively sodium methylate 17.8g(0.33mol, 1.1eq), methyl alcohol 400g, be cooled to 0-5 ℃, start to add O-Methyl Isourea Sulfate 44.6g (0.18mol, 0.6eq), control temperature 0-20 ℃, after adding, be warming up to 35-40 ℃, continue reaction 4h, stopped reaction, concentrating under reduced pressure solvent, add deionized water 500g making beating to stir, with concentrated hydrochloric acid, being adjusted to pH is 3-4, and adularescent solid is separated out, and filters, dry, obtain solid 95.02g, purity is 98.5%, and product yield is 60%.
Embodiment 35 FU 5 fluorouracil preparation methods
Under nitrogen protection, under nitrogen protection, in 1000mL four-hole boiling flask, add successively ethyl fluoroacetate 27.6g(0.3mol, 1.0eq) with ethyl formate 44.4g(0.6mol, 2.0eq), be cooled to 2 ℃, add in batches containing sodium ethylate 22.4g(0.33mol, 1.1eq) 75g xylene solution, at about 30 ℃, stir 3h; The condensation mixture that obtains faint yellow stiff, adds ethanol 300g and O-Methyl Isourea Sulfate 44.6g (0.18mol, 0.6eq) to condenses system, is heated with stirring to 40 ℃ of reaction 6h; Concentrating under reduced pressure, then adds water 300g, is heated to 50 ℃ of dissolvings, and filtrate is acidified to pH=3-4 with concentrated hydrochloric acid, crystallize out; Cooling, filter, with cold water leaching cake, then with the boiling water soaked overnight of sizing mixing; Through filtering, cold water drip washing, is dried, and obtains cyclization product, and above-mentioned cyclization product is added in concentrated hydrochloric acid 300g again, is heated to 60 ℃ of hydrolysis 4h, filters, and is drying to obtain 5 FU 5 fluorouracil 79.03g, and purity is 98.1%, and product yield is 60.1%.
Embodiment 42-second sulfydryl-5 FU 5 fluorouracil preparation method
Under nitrogen protection, in 1000mL four-hole boiling flask, add successively ethyl fluoroacetate 31.8g(0.3mol; 1.0eq) with ethyl formate 44.4g(0.6mol; 2.0eq); be cooled to 0-5 ℃; add in batches containing sodium methylate 17.8g(0.33mol; 75g xylene solution 1.1eq), is warming up to 25 ℃ of reaction 3h after adding, reaction solution becomes faint yellow turbid solution.In above-mentioned 1000mL four-hole boiling flask, add successively sodium methylate 17.8g (0.33moL, 1.1eq), methyl alcohol 400g, be cooled to 0-5 ℃, start to add S-ethyl isothiourea vitriol 55.08g (0.18mol, 0.6eq), control temperature 0-20 ℃, after adding, be warming up to 35-40 ℃, continue reaction 4h, stopped reaction, concentrating under reduced pressure solvent, add deionized water 500g making beating to stir, control temperature 0-10 ℃, with concentrated hydrochloric acid, being adjusted to pH is 4-5, adularescent solid is separated out, filter, dry, obtain solid 100.4g, purity is 98.3%, and product yield is 56.1%.
Claims (5)
1. the method for the synthetic fluorine-containing pyrimidines of an one kettle way, it is characterized in that: under nitrogen protection, in 1000mL four-hole boiling flask, add raw material, the mol ratio of the formic acid ester compound in raw material and fluorinated ester compound is 1-3:1, be cooled to 0-5 ℃, add in batches the aromatic solvent containing alkali, after adding, be warming up to 25 ℃, reaction 3h, reaction solution becomes faint yellow turbid solution; Under nitrogen protection, the faint yellow turbid solution in described 1000mL four-hole boiling flask adds described alkali, alcoholic solvent successively, is cooled to 0-5 ℃; start to add urea phosphate compounds and alcoholic solvent, urea hydrochlorate and described fluorine ester contained mol ratio are 0.5-1:1, after adding, are warming up to 25-45 ℃; continue reaction 3-5h, stopped reaction, concentrating under reduced pressure solvent; add deionized water making beating to stir; with concentrated hydrochloric acid, being adjusted to pH is 4-5, and adularescent solid is separated out, and filters; dry, obtain fluorine-containing pyrimidines solid.
2. the method for the synthetic fluorine-containing pyrimidines of one kettle way according to claim 1, is characterized in that: the formic acid ester compound in described raw material is a kind of in methyl-formiate, ethyl formate, propyl formate; Fluorinated ester compound in described raw material is a kind of in methylfluoracetate, ethyl fluoroacetate.
3. the method for the synthetic fluorine-containing pyrimidines of one kettle way according to claim 1, is characterized in that: described urea phosphate compounds is a kind of in O-Methyl Isourea Sulfate, S-methyl-isourea, S-ethyl isothiourea vitriol, O-methyl-isourea methyl sulfate salt, O-methyl-isourea hydrochloride.
4. one kettle way according to claim 1 synthesizes the method for fluorine-containing pyrimidines, it is characterized in that: described alkali is sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium Metal 99.5, sodium hydroxide, potassium hydroxide, sodium hydride.
5. one kettle way according to claim 1 synthesizes the method for fluorine-containing pyrimidines, it is characterized in that: described benzene solvent is one or both in toluene, dimethylbenzene; Described alcoholic solvent is one or both in methyl alcohol, ethanol.
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104447576A (en) * | 2014-11-21 | 2015-03-25 | 山东金城医药化工股份有限公司 | Method for preparing 5-fluorouracil |
CN104926735A (en) * | 2015-06-16 | 2015-09-23 | 上海合全药物研发有限公司 | Industrial preparation method for 4-chlorine-5-fluorine-2-methyl pyrimidine |
CN106632080A (en) * | 2016-08-25 | 2017-05-10 | 宿迁市万和泰化工有限公司 | Flucytosine manufacturing process |
CN109369465A (en) * | 2018-12-10 | 2019-02-22 | 黔西县黔希煤化工投资有限责任公司 | Use H2The method of S gas deep processing production antineoplastic fluorouracil medicine intermediate |
CN109651261A (en) * | 2019-01-11 | 2019-04-19 | 江苏快达农化股份有限公司 | The method of one pot process 4- amino -2,5- dimethoxypyridin |
CN111454220A (en) * | 2020-05-14 | 2020-07-28 | 常州德申环保工程有限公司 | Synthesis process of flocculant additive 5-fluoroorotic acid |
CN114210238A (en) * | 2021-12-02 | 2022-03-22 | 上海旭东海普南通药业有限公司 | Fluorouracil refining method and device |
CN114853683A (en) * | 2022-06-10 | 2022-08-05 | 江苏中渊化学品有限公司 | Fluorocytosine preparation device and process |
CN115925639A (en) * | 2023-01-31 | 2023-04-07 | 上海旭东海普南通药业有限公司 | Antineoplastic fluorouracil and preparation process thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101747282A (en) * | 2008-12-10 | 2010-06-23 | 上海特化医药科技有限公司 | Phenyl pyrimidone compounds, pharmaceutical compositions and preparation methods and uses thereof |
WO2012009666A2 (en) * | 2010-07-15 | 2012-01-19 | University Of Southern California | Synthesis of 2'-deoxy-2'-[18f]fluoro-5-methyl-1-b-d-arabinofuranosyluracil (18f-fmau) |
CN103172574A (en) * | 2011-12-26 | 2013-06-26 | 北京英力精化技术发展有限公司 | Novel synthesis process of 2-substituted-4,6-dialkoxy pyrimidine |
-
2013
- 2013-11-08 CN CN201310557467.1A patent/CN103601686A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101747282A (en) * | 2008-12-10 | 2010-06-23 | 上海特化医药科技有限公司 | Phenyl pyrimidone compounds, pharmaceutical compositions and preparation methods and uses thereof |
WO2012009666A2 (en) * | 2010-07-15 | 2012-01-19 | University Of Southern California | Synthesis of 2'-deoxy-2'-[18f]fluoro-5-methyl-1-b-d-arabinofuranosyluracil (18f-fmau) |
CN103172574A (en) * | 2011-12-26 | 2013-06-26 | 北京英力精化技术发展有限公司 | Novel synthesis process of 2-substituted-4,6-dialkoxy pyrimidine |
Non-Patent Citations (2)
Title |
---|
吕早生,等: "5-氟尿嘧啶合成工艺研究", 《化学与生物工程》, vol. 30, no. 1, 14 January 2013 (2013-01-14) * |
钟光祥: "5-氟尿嘧啶的合成方法述评", 《浙江化工》, vol. 26, no. 1, 31 December 1995 (1995-12-31) * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104447576A (en) * | 2014-11-21 | 2015-03-25 | 山东金城医药化工股份有限公司 | Method for preparing 5-fluorouracil |
CN104926735A (en) * | 2015-06-16 | 2015-09-23 | 上海合全药物研发有限公司 | Industrial preparation method for 4-chlorine-5-fluorine-2-methyl pyrimidine |
CN106632080A (en) * | 2016-08-25 | 2017-05-10 | 宿迁市万和泰化工有限公司 | Flucytosine manufacturing process |
CN109369465A (en) * | 2018-12-10 | 2019-02-22 | 黔西县黔希煤化工投资有限责任公司 | Use H2The method of S gas deep processing production antineoplastic fluorouracil medicine intermediate |
CN109651261A (en) * | 2019-01-11 | 2019-04-19 | 江苏快达农化股份有限公司 | The method of one pot process 4- amino -2,5- dimethoxypyridin |
CN109651261B (en) * | 2019-01-11 | 2022-05-20 | 江苏快达农化股份有限公司 | Method for synthesizing 4-amino-2, 5-dimethoxypyrimidine by one-pot method |
CN111454220A (en) * | 2020-05-14 | 2020-07-28 | 常州德申环保工程有限公司 | Synthesis process of flocculant additive 5-fluoroorotic acid |
CN114210238A (en) * | 2021-12-02 | 2022-03-22 | 上海旭东海普南通药业有限公司 | Fluorouracil refining method and device |
CN114853683A (en) * | 2022-06-10 | 2022-08-05 | 江苏中渊化学品有限公司 | Fluorocytosine preparation device and process |
CN115925639A (en) * | 2023-01-31 | 2023-04-07 | 上海旭东海普南通药业有限公司 | Antineoplastic fluorouracil and preparation process thereof |
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