CN104356071A - Preparation method for 5-fluorocytosine - Google Patents
Preparation method for 5-fluorocytosine Download PDFInfo
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- CN104356071A CN104356071A CN201410676436.2A CN201410676436A CN104356071A CN 104356071 A CN104356071 A CN 104356071A CN 201410676436 A CN201410676436 A CN 201410676436A CN 104356071 A CN104356071 A CN 104356071A
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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
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicinal chemical synthesis, and particularly relates to a preparation method for 5-fluorocytosine. The preparation method comprises the following steps of: dropwise adding ethyl formate in xylene, carrying out a condensation reaction with methyl fluoroacetate under the action of a metal catalyst, and heating, stirring and carrying out heating heat preservation to obtain an intermediate; carrying out chlorination substitution on the intermediate with a chlorinating agent in the presence of an organic amine catalyst to obtain a chlorination product; carrying out ammoniation substitution on the chlorination product in an ammonia gas pressure environment and under the action of phase transfer catalysts (N-alkyl phosphoramide, methylene bridged phosphate and tetrabutylammonium bromide to obtain an ammoniation product; carrying out acidic hydrolysis on the ammoniation product to obtain 5-fluorocytosine. The 5-fluorocytosine prepared by the preparation method disclosed by the invention is high in yield and high in purity; use of highly-toxic fluorine is avoided during the preparation process, thus reducing damage and injury to equipment and operating personnel during a production process.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, be specifically related to a kind of preparation method of 5-flurocytosine.
Background technology
5-flurocytosine, is used for the treatment of the fungi infestation that cryptococcus and candidiasis etc. are caused, as mycotic septicemia, endocarditis, meningitis and lung and urinary tract infection antifungal drug.Be mainly used in skin mucosa moniliosis, candidiasis endocarditis, candida arthritis, crypotococcal and chromomycosis.Blood picture should be made regular check on during medication.Liver and kidney function not whole blood patient and pregnant woman is cautious use of; Severe renal functional defect patient is forbidden.These product abroad as treatment serious systemic white bead-containing bacteria and the choice drug of Cryptococcus infections, for fungoid meningitis, the treatment of fungoid respiratory tract infection and black fungi disease.
JP37553/1979 reports the method that direct cytosine(Cyt) carries out fluoridizing, the method relates to the use of fluorine gas, yield and the purity of the method 5-flurocytosine are higher, but use fluorine gas to require higher to equipment and safety etc., and can damage operator.
Summary of the invention
The object of this invention is to provide a kind of preparation method of 5-flurocytosine, both can ensure yield purity and the stability of obtained 5-flurocytosine, the use of hypertoxic fluorine gas can be avoided again, reduce the injury to equipment and operator in production process.
The preparation method of 5-flurocytosine of the present invention, comprises the following steps:
(1) in dimethylbenzene, instill ethyl formate, under the effect of metal catalyst, carry out condensation reaction with methylfluoracetate, through heating up, stirring, again heating and heat preservation obtain intermediate;
(2) intermediate carries out chlorination replacement with chlorizating agent under the effect of organic amine catalyst, obtains chlorizate;
(3) chlorizate is under the effect of ammonia pressure environment and phase-transfer catalyst N-alkylphosphines acid amides, methyne bridge phosphorus, Tetrabutyl amonium bromide, carries out ammonification replacement, obtains aminate;
(4) aminate carries out acidic hydrolysis and obtains 5-flurocytosine.
Wherein:
Step (1) be warming up to 20 DEG C stir 2h, then be warming up to 42 DEG C insulation 10h obtain intermediate, metal catalyst is sodium Metal 99.5 or potassium metal, and the mol ratio of methylfluoracetate, dimethylbenzene, ethyl formate, catalyzer is 1:2.75:2.33:0.5.
Step (2) chlorizating agent is N-chlorosuccinimide, the mol ratio of intermediate and chlorizating agent is 1:4, organic amine catalyst is Isopropylamine, Di-n-Butyl Amine, 2 ethyl hexylamine, diethylamine, Diisopropylamine, isobutylamine, hexanediamine, triethylamine, 1, one or more in 2-dimethyl propylamine, quadrol, diethanolamine or trolamine, methylfluoracetate and organic amine catalyst mol ratio are 1:0.5.
Step (3) ammonia pressure is 0.8 ~ 1MPa, and the mol ratio of chlorizate and phase-transfer catalyst is 1:0.45, N-alkylphosphines acid amides, methyne bridge phosphorus, mass ratio between Tetrabutyl amonium bromide three are 1:1:0.83.
Step (4) acidic hydrolysis carries out in the sour environment of pH=5, preferably adopts sulfuric acid control pH, other acid also can be adopted to control.
Compared with prior art, the present invention has following beneficial effect:
The 5-flurocytosine that the present invention obtains, yield is high, and purity is good, avoids using hypertoxic fluorine gas in preparation process, reduces the injury to equipment and operator in production process.
Embodiment
Below in conjunction with embodiment, the invention will be further described.
Embodiment 1
In 1L reaction flask, add 200ml dimethylbenzene, in dimethylbenzene, instill 200g ethyl formate, then add 5g sodium Metal 99.5,80g methylfluoracetate carries out condensation reaction, through be warming up to 20 DEG C stir 2h, then be warming up to 42 DEG C insulation 10h obtain intermediate; In intermediate, add 27g Isopropylamine, 50g N-chlorosuccinimide, 100 DEG C of reaction 5h obtain chlorizate; Chlorizate, under the effect of 0.8MPa ammonia pressure environment, phase-transfer catalyst N-alkylphosphines acid amides 3g, methyne bridge phosphorus 3g, Tetrabutyl amonium bromide 2.5g, carries out ammonification replacement, obtains aminate; Aminate is hydrolyzed and obtains 5-flurocytosine in the sour environment of pH=5, obtains 5-flurocytosine 58.2g, purity 99.99% after refining.
Embodiment 2
In 1L reaction flask, add 200ml dimethylbenzene, in dimethylbenzene, instill 200g ethyl formate, then add 5g sodium Metal 99.5,80g methylfluoracetate carries out condensation reaction, through be warming up to 20 DEG C stir 2h, then be warming up to 42 DEG C insulation 10h obtain intermediate; In intermediate, add 25g diethylamine, 50g N-chlorosuccinimide, 95 DEG C of reaction 5h obtain chlorizate; Chlorizate, under the effect of 0.8MPa ammonia pressure environment, phase-transfer catalyst N-alkylphosphines acid amides 3g, methyne bridge phosphorus 3g, Tetrabutyl amonium bromide 2.5g, carries out ammonification replacement, obtains aminate; Aminate is hydrolyzed and obtains 5-flurocytosine in the sour environment of pH=5, obtains 5-flurocytosine 56.1g, purity 99.99% after refining.
Embodiment 3
In 1L reaction flask, add 200ml dimethylbenzene, in dimethylbenzene, instill 200g ethyl formate, then add 5g sodium Metal 99.5,80g methylfluoracetate carries out condensation reaction, through be warming up to 20 DEG C stir 2h, then be warming up to 42 DEG C insulation 10h obtain intermediate; In intermediate, add 28g triethylamine, 50g N-chlorosuccinimide, 105 DEG C of reaction 5h obtain chlorizate; Chlorizate, under the effect of 0.9MPa ammonia pressure environment, phase-transfer catalyst N-alkylphosphines acid amides 3g, methyne bridge phosphorus 3g, Tetrabutyl amonium bromide 2.5g, carries out ammonification replacement, obtains aminate; Aminate is hydrolyzed and obtains 5-flurocytosine in the sour environment of pH=5, obtains 5-flurocytosine 57.2g, purity 99.99% after refining.
Embodiment 4
In 1L reaction flask, add 200ml dimethylbenzene, in dimethylbenzene, instill 200g ethyl formate, then add 5g sodium Metal 99.5,80g methylfluoracetate carries out condensation reaction, through be warming up to 20 DEG C stir 2h, then be warming up to 42 DEG C insulation 10h obtain intermediate; In intermediate, add 30 diethanolamine, 50g N-chlorosuccinimide, 100 DEG C of reaction 5h obtain chlorizate; Chlorizate, under the effect of 0.9MPa ammonia pressure environment, phase-transfer catalyst N-alkylphosphines acid amides 3g, methyne bridge phosphorus 3g, Tetrabutyl amonium bromide 2.5g, carries out ammonification replacement, obtains aminate; Aminate is hydrolyzed and obtains 5-flurocytosine in the sour environment of pH=5, obtains 5-flurocytosine 56.6g, purity 99.99% after refining.
Claims (10)
1. a preparation method for 5-flurocytosine, is characterized in that comprising the following steps:
(1) in dimethylbenzene, instill ethyl formate, under the effect of metal catalyst, carry out condensation reaction with methylfluoracetate, through heating up, stirring, again heating and heat preservation obtain intermediate;
(2) intermediate carries out chlorination replacement with chlorizating agent under the effect of organic amine catalyst, obtains chlorizate;
(3) chlorizate is under the effect of ammonia pressure environment and phase-transfer catalyst N-alkylphosphines acid amides, methyne bridge phosphorus, Tetrabutyl amonium bromide, carries out ammonification replacement, obtains aminate;
(4) aminate carries out acidic hydrolysis and obtains 5-flurocytosine.
2. the preparation method of 5-flurocytosine according to claim 1, is characterized in that: step (1) be warming up to 20 DEG C stir 2h, then be warming up to 42 DEG C insulation 10h obtain intermediate.
3. the preparation method of 5-flurocytosine according to claim 1, is characterized in that: step (1) metal catalyst is sodium Metal 99.5 or potassium metal.
4. the preparation method of 5-flurocytosine according to claim 1, is characterized in that: the mol ratio of step (1) methylfluoracetate, dimethylbenzene, ethyl formate, catalyzer is 1:2.75:2.33:0.5.
5. the preparation method of 5-flurocytosine according to claim 1, is characterized in that: step (2) chlorizating agent is N-chlorosuccinimide.
6. the preparation method of 5-flurocytosine according to claim 1 or 5, is characterized in that: the mol ratio of step (2) intermediate and chlorizating agent is 1:4.
7. the preparation method of 5-flurocytosine according to claim 1, it is characterized in that: step (2) organic amine catalyst is Isopropylamine, Di-n-Butyl Amine, 2 ethyl hexylamine, diethylamine, Diisopropylamine, isobutylamine, hexanediamine, triethylamine, 1, one or more in 2-dimethyl propylamine, quadrol, diethanolamine or trolamine, methylfluoracetate and organic amine catalyst mol ratio are 1:0.5.
8. the preparation method of 5-flurocytosine according to claim 1, is characterized in that: step (3) ammonia pressure is 0.8 ~ 1MPa.
9. the preparation method of 5-flurocytosine according to claim 1, it is characterized in that: the mol ratio of step (3) chlorizate and phase-transfer catalyst is 1:0.45, N-alkylphosphines acid amides, methyne bridge phosphorus, mass ratio between Tetrabutyl amonium bromide three are 1:1:0.83.
10. the preparation method of 5-flurocytosine according to claim 1, is characterized in that: step (4) acidic hydrolysis carries out in the sour environment of pH=5.
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| CN201410676436.2A CN104356071A (en) | 2014-11-21 | 2014-11-21 | Preparation method for 5-fluorocytosine |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153041A (en) * | 2015-10-20 | 2015-12-16 | 浙江先锋科技股份有限公司 | 5-fluctyosine preparation method suitable for industrial production |
| CN106632080A (en) * | 2016-08-25 | 2017-05-10 | 宿迁市万和泰化工有限公司 | Flucytosine manufacturing process |
| CN110105290A (en) * | 2019-05-14 | 2019-08-09 | 浙江伟锋药业有限公司 | A kind of preparation method of 5-flurocytosine |
-
2014
- 2014-11-21 CN CN201410676436.2A patent/CN104356071A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153041A (en) * | 2015-10-20 | 2015-12-16 | 浙江先锋科技股份有限公司 | 5-fluctyosine preparation method suitable for industrial production |
| CN106632080A (en) * | 2016-08-25 | 2017-05-10 | 宿迁市万和泰化工有限公司 | Flucytosine manufacturing process |
| CN110105290A (en) * | 2019-05-14 | 2019-08-09 | 浙江伟锋药业有限公司 | A kind of preparation method of 5-flurocytosine |
| CN110105290B (en) * | 2019-05-14 | 2020-06-23 | 浙江伟锋药业有限公司 | Preparation method of 5-fluorocytosine |
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