CN106349169A - Flucytosine preparation method applicable to industrial production - Google Patents
Flucytosine preparation method applicable to industrial production Download PDFInfo
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- CN106349169A CN106349169A CN201610720465.3A CN201610720465A CN106349169A CN 106349169 A CN106349169 A CN 106349169A CN 201610720465 A CN201610720465 A CN 201610720465A CN 106349169 A CN106349169 A CN 106349169A
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- Prior art keywords
- flucytosine
- preparation
- industrial
- stirring
- filter
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a flucytosine preparation method applicable to industrial production. The method comprises the following steps: performing chlorination on fluorouracil, performing ammonification, and performing hydrolysis, thereby obtaining flucytosine. To solve defects, the invention provides the flucytosine preparation method applicable to industrial production, and the method is small in process procedure, simple in operation, low in investment cost, relatively good in prospect and applicable to large-scale industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis technical field is and in particular to a kind of be applied to industrial flucytosine
Preparation method.
Background technology
Flucytosine, for treating the fungal infection caused by cryptococcus and candidiasises etc., such as mycotic septicemia, endocardium
Inflammation, meningitiss and pulmonary and urinary tract infection antifungal agent.Be mainly used in skin mucosa candidiasiss, candidiasises endocarditiss,
Candida arthritis, crypotococcal and chromomycosis.Hemogram should be made regular check on during medication.Liver and kidney function not whole blood
Liquid patient and anemia of pregnant woman use with caution；Serious potential renal insufficiency patient disabling.This product contains as treatment serious systemic white abroad
Pearl bacterium and the choice drug of Cryptococcus infections, for fungoids meningitis, the controlling of fungoids respiratory tract infection and black funguses disease
Treat.
But the existing production process producing chlorine cytosine is more complicated and the flucytosine purity produced and
Yield is relatively low, improve input cost.
Content of the invention
The present invention is to solve above-mentioned deficiency, provides a kind of preparation method being applied to industrial flucytosine, technique
Process is few, simple to operate, input cost is low, have preferable prospect, suitably big commercial scale.
The technical solution of the present invention:
A kind of preparation method being applied to industrial flucytosine, described preparation method comprises the following steps:
(1) chlorination process
Fluorouracil and phosphorus oxychloride are added in chlorination pot, is stirred, control temperature, Deca n, n- dimethylaniline；Drip
Add after finishing, be warmed up to 110 DEG C about reaction 2h;It is cooled to room temperature, puts to ice solution in brine ice, maintain temperature to be 15 DEG C, stir；
Filter, washing obtains the chloro- fluoropyrimidine of 2,4- bis-；
(2) ammonifying process
Chloro- for 2,4- bis- fluoropyrimidine is dissolved in ethanol, stirring, control Deca ammonia below 35 DEG C, drip and finish, be cooled to 25 DEG C
React some hours, to doing, the stirring that adds water is warmed up to 20 DEG C to decompression chief culprit's ethanol；Filter, wash crystallization with water, be dried, draw
4- amino -2- chlorine-fluorine pyrimidine；
(3) hydrolytic process
By 4- amino -2- chlorine-fluorine pyrimidine and mixed in hydrochloric acid, stirring heats up, and after reaction 2h, is evaporated to dry, be dissolved in water knot
Crystalline substance, plus activated carbon decolorizing, filter, and filtrate adjusts ph to 7-8 with ammonia, stands overnight；Rejection filter, washes crystallization with water, through exquisiteness is
Can get flucytosine.
As control temperature in the optimization further of this programme, described step (1) below 15 DEG C.
As the optimization further of this programme, in described step (1), mixing time is 1.5h.
As the optimization further of this programme, in described step (2), the response time is 3.5h.
It is warming up to 85 DEG C -95 DEG C as stirring in the optimization further of this programme, described step (3).
Beneficial effects of the present invention:
The present invention passes through flucytosine to be obtained by fluorouracil through chlorination process, ammonifying process, hydrolytic process, technical process is few,
Yield reaches 85%, and simple to operate, input cost is low, safe and reliable, have preferable prospect, suitable for large-scale industrialized production.
Specific embodiment
All features disclosed in this specification, or disclosed all methods or during step, except mutually exclusive
Feature and/or step beyond, all can combine by any way.
Any feature disclosed in this specification (including any accessory claim, summary), unless specifically stated otherwise,
Replaced by other alternative features equivalent or that there is similar purpose.I.e., unless specifically stated otherwise, each feature is a series of
One of equivalent or similar characteristics example.
Embodiment:
A kind of preparation method being applied to industrial flucytosine, described preparation method comprises the following steps:
(1) chlorination process
Fluorouracil and phosphorus oxychloride are added in chlorination pot, is stirred, control temperature below 15 DEG C, low price n, n- diformazan
Base aniline；After completion of dropping, it is warmed up to 110 DEG C about reaction 2h;It is cooled to room temperature, put to ice solution in brine ice, maintenance temperature is
15 DEG C, stirring 1.5h；Filter, washing obtains the chloro- fluoropyrimidine of 2,4- bis-；
(2) ammonifying process
Chloro- for 2,4- bis- fluoropyrimidine is dissolved in ethanol, stirring, control Deca ammonia below 35 DEG C, drip and finish, be cooled to 25 DEG C
Reaction 3.5h, to doing, the stirring that adds water is warmed up to 20 DEG C to decompression chief culprit's ethanol；Filter, wash crystallization with water, be dried, draw 4- ammonia
Base -2- chlorine-fluorine pyrimidine；
(3) hydrolytic process
By 4- amino -2- chlorine-fluorine pyrimidine and mixed in hydrochloric acid, stirring is warming up to 85 DEG C -95 DEG C, after reaction 2h, is evaporated to dry,
Be dissolved in water crystallization, plus activated carbon decolorizing, filters, and filtrate adjusts ph to 7-8 with ammonia, stands overnight；Rejection filter, washes knot with water
Crystalline substance, can get flucytosine through exquisiteness.
The present invention passes through flucytosine, technical process to be obtained by fluorouracil through chlorination process, ammonifying process, hydrolytic process
Few, yield reaches 85%, simple to operate, input cost is low, safe and reliable, have preferable prospect, suitable industrialization to give birth on a large scale
Produce.
The basic teaching of the present invention is illustrated, and for having the people of the usual technical ability in this area, many extends and becomes
Change will be aobvious and the person of being apparent from.Because the present invention that description discloses can be in the other spies without departing from present invention spirit or general characteristics
Setting formula is implementing, and some forms of these particular forms have been noted, so, description embodiments of the disclosure should be regarded as
Illustrate rather than restriction.The scope of the present invention is to be defined by appended claim, rather than by described above institute circle
Calmly, within the scope of all changes of the impartial meaning and scope that fall into claim still being will be contained in it.
Claims (5)
1. a kind of preparation method being applied to industrial flucytosine it is characterised in that described preparation method include following
Step:
(1) chlorination process
Fluorouracil and phosphorus oxychloride are added in chlorination pot, is stirred, control temperature, Deca n, n- dimethylaniline；Drip
Add after finishing, be warmed up to 110 DEG C about reaction 2h;It is cooled to room temperature, puts to ice solution in brine ice, maintain temperature to be 15 DEG C, stir；
Filter, washing obtains the chloro- fluoropyrimidine of 2,4- bis-；
(2) ammonifying process
Chloro- for 2,4- bis- fluoropyrimidine is dissolved in ethanol, stirring, control Deca ammonia below 35 DEG C, drip and finish, be cooled to 25 DEG C
React some hours, to doing, the stirring that adds water is warmed up to 20 DEG C to decompression chief culprit's ethanol；Filter, wash crystallization with water, be dried, draw
4- amino -2- chlorine-fluorine pyrimidine；
(3) hydrolytic process
By 4- amino -2- chlorine-fluorine pyrimidine and mixed in hydrochloric acid, stirring heats up, and after reaction 2h, is evaporated to dry, be dissolved in water knot
Crystalline substance, plus activated carbon decolorizing, filter, and filtrate adjusts ph to 7-8 with ammonia, stands overnight；Rejection filter, washes crystallization with water, through exquisiteness is
Can get flucytosine.
2. a kind of preparation method being applied to industrial flucytosine according to claim 1 is it is characterised in that institute
State and control temperature in step (1) below 15 DEG C.
3. a kind of preparation method being applied to industrial flucytosine according to claim 1 is it is characterised in that institute
Stating in step (1) mixing time is 1.5h.
4. a kind of preparation method being applied to industrial flucytosine according to claim 1 is it is characterised in that institute
Stating in step (2) response time is 3.5h.
5. a kind of preparation method being applied to industrial flucytosine according to claim 1 is it is characterised in that institute
State stirring in step (3) and be warming up to 85 DEG C -95 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610720465.3A CN106349169A (en) | 2016-08-25 | 2016-08-25 | Flucytosine preparation method applicable to industrial production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610720465.3A CN106349169A (en) | 2016-08-25 | 2016-08-25 | Flucytosine preparation method applicable to industrial production |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106349169A true CN106349169A (en) | 2017-01-25 |
Family
ID=57854313
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610720465.3A Pending CN106349169A (en) | 2016-08-25 | 2016-08-25 | Flucytosine preparation method applicable to industrial production |
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| Country | Link |
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| CN (1) | CN106349169A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632080A (en) * | 2016-08-25 | 2017-05-10 | 宿迁市万和泰化工有限公司 | Flucytosine manufacturing process |
| CN114853682A (en) * | 2022-06-10 | 2022-08-05 | 江苏中渊化学品有限公司 | Production equipment and method of bulk drug intermediate 4, 6-dichloro-5-fluoropyrimidine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3040026A (en) * | 1959-06-03 | 1962-06-19 | Hoffmann La Roche | Processes and intermediates for deoxyfluorocytidine |
| PL115858B1 (en) * | 1978-06-22 | 1981-05-30 | Pabianickie Zaklad Farma | Process for preparing 5-fluorocytosine starting from 5-fluorouracil |
| JPH08127569A (en) * | 1994-10-31 | 1996-05-21 | Sumika Fine Chem Kk | Production of flucytosine |
-
2016
- 2016-08-25 CN CN201610720465.3A patent/CN106349169A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3040026A (en) * | 1959-06-03 | 1962-06-19 | Hoffmann La Roche | Processes and intermediates for deoxyfluorocytidine |
| US3185690A (en) * | 1959-06-03 | 1965-05-25 | Hoffmann La Roche | 2-chloro-4-amino-5-fluoropyrimidine |
| PL115858B1 (en) * | 1978-06-22 | 1981-05-30 | Pabianickie Zaklad Farma | Process for preparing 5-fluorocytosine starting from 5-fluorouracil |
| JPH08127569A (en) * | 1994-10-31 | 1996-05-21 | Sumika Fine Chem Kk | Production of flucytosine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632080A (en) * | 2016-08-25 | 2017-05-10 | 宿迁市万和泰化工有限公司 | Flucytosine manufacturing process |
| CN114853682A (en) * | 2022-06-10 | 2022-08-05 | 江苏中渊化学品有限公司 | Production equipment and method of bulk drug intermediate 4, 6-dichloro-5-fluoropyrimidine |
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Application publication date: 20170125 |