CN113185466A - Novel low-carbon-emission flucytosine production process - Google Patents
Novel low-carbon-emission flucytosine production process Download PDFInfo
- Publication number
- CN113185466A CN113185466A CN202110458400.7A CN202110458400A CN113185466A CN 113185466 A CN113185466 A CN 113185466A CN 202110458400 A CN202110458400 A CN 202110458400A CN 113185466 A CN113185466 A CN 113185466A
- Authority
- CN
- China
- Prior art keywords
- fluorocytosine
- cytosine
- product
- fluorosuccinimide
- crude
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- 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
Abstract
The invention belongs to the field of fluorine-containing fine chemicals, and particularly relates to a novel process for producing flucytosine with low carbon emission; preparing fluorinating agent N-fluorosuccinimide from N-chlorosuccinimide and potassium fluoride, fluorinating cytosine by using the fluorinating agent to obtain a fluorocytosine crude product, and refining and drying the fluorocytosine crude product to obtain a fluorocytosine finished product; the production process is simple and the manufacturing cost is low.
Description
The technical field is as follows:
the invention belongs to the field of fluorine-containing fine chemicals, and particularly relates to a novel low-carbon-emission flucytosine production process.
Background art:
fluorocytimidine (also known as 5-Fluorocytosine, amethyst, 5-fluorocytidine, Anrayon, etc. with CAS number 2022-85-7, is a crystalline solid powder with appearance from off-white to white, and is a chemical product with higher added value in the field of fine chemicals containing fluorine.
Fluorocytosine is extremely widely used, and Shin et al believe that Fluorocytosine inhibits tumor growth by inhibiting DNA synthesis (anti-fungal effects of human neural stem cells expressing therapeutic genes on adaptive thyroid cells. J Cell Biochem 121(2):1586-1598.) Basnet et al report that Fluorouracil-labeled RNA sequencing (Flura-seq) can be used as a transcriptional analysis of a rapidly isolated rare Cell population in the primary microenvironment (laboratory and Isolation of Fluorouracil Tagged RNA by cellular uracil expression. BioProtoc 9(22): e3433.) Leontdt et al construct a Fluorocytosine-phosphate transferase (UPP) gene by fusing the bacterial uracil phosphoribosyltransferase (UPP) gene to achieve the therapeutic effect of Fluorocytosine by Cell precursor (FC5-fluoro Cytosine) 2. F-5. F-uracil-2. F-2. Leontto convert Fluorocytosine into a fluoro-Cytosine precursor 3) 731-741.), Zimbres et al consider fluorocytosine to be a potent pigmentation inhibitor in the C.gattii model (Pharmacological inhibition of pigmentation in cryptography. "FEMS Yeast Res 19(1).
In addition to the above uses, flucytosine is only in a situation of being in short supply and demand in the field of key raw material subdivision for preparing an anti-cancer drug Capecitabine (Capecitabine) and an anti-AIDS drug Emtricitabine (Emtricitabine) in the market at present, and a production process of flucytosine which meets the supervision requirement, is safe and controllable, is environment-friendly and has low carbon emission is urgently to be developed.
The production process routes for fluorocytosine are currently mainly divided into the following:
(1) the Corning reactor (Chinese) technical team published in 2017 (https:// www.sohu.com/a/146392732_337733) reports that cheap cytosine is directly fluorinated by fluorine gas to prepare flucytosine, the technology currently stays in a small test stage, and fluorine gas with extremely strong toxicity is used in the technology, so that the technology has great safety hazard, and Swedish chemical Housexle, British chemist David, French scientist Gaussa and Tyner, Scotland chemist Nordheim brother, French scientist Movalsa and the like all die of fluorine gas. CN110483414, CN110746360 and CN110615767 report that the process route also uses fluorine gas as a fluorinating agent, and industrial scale production brings about greater potential safety hazard and does not meet the current strict safety supervision requirements.
(2) The production process of fluorocytosine reported in CN104086489 only changes the production method of cytosine and does not change the essence of fluorine gas for preparing fluorocytosine by fluorinating cytosine.
(3) CN103435557 reports a process for producing fluorocytosine, which comprises condensing ethyl formate and methyl fluoroacetate, reacting the condensate with urea to produce 5-fluorouracil, chlorinating with thionyl chloride, and aminolyzing with ammonia water. The market supply of the starting material methyl fluoroacetate of the process is in short supply, the selectivity of chlorine in the ammonolysis process is difficult to control, and the industrialization difficulty is high.
(4) CN105153041, CN108033917 and CN104356071 report that the fluorocytosine production process takes 2-methoxy-4-chloro-5-fluorouracil as raw material, and is prepared by steps of chlorination, amination, hydrolysis and the like. Regardless of the phosphorus pentachloride which is difficult to treat by waste gas and waste water, the large amount of organic solvent such as toluene, N-dimethylaniline, xylene, DMF and the like involved in the process can cause a huge carbon emission. In addition, because the total yield of the process is low, organic residues generated in production need to be incinerated and disposed, and serious carbon emission problems also can be caused.
In recent years, along with the increasing of the inclination of governments to common people's medical policies and the formal implementation of the national carbon emission right trade management method (trial implementation), the market competitiveness is gradually weakened and the elimination is only a time problem due to the overhigh manufacturing cost and huge carbon emission in the conventional flucytosine production process, so that the significance of developing a novel low-carbon-emission and low-cost flucytosine production process is great.
The purpose of the invention is as follows:
aiming at the defects and shortcomings in the prior art, the invention provides a novel flucytosine production process which is low in carbon emission, simple in production process and low in manufacturing cost.
The technical scheme adopted is as follows: in order to achieve the purpose, the invention is realized by the following technical scheme:
the invention relates to a novel process for producing low-carbon-emission fluorocytosine, which comprises the steps of preparing fluorinating agent N-fluorosuccinimide from N-chlorosuccinimide and potassium fluoride, fluorinating cytosine by using the fluorinating agent to obtain a crude fluorocytosine product, and refining and drying the crude fluorocytosine product to obtain a finished fluorocytosine product.
The preparation process of fluorinating agent N-fluorosuccinimide related by the invention is that N-chlorosuccinimide and potassium fluoride directly carry out dry reaction, and the feeding proportion is N (N-chlorosuccinimide): n (potassium fluoride) ═ 1: 1.04, incomplete replacement of N-chlorosuccinimide fluorine and chlorine is easily caused by too small amount of potassium fluoride, and the quality and yield are affected by impurities generated in the cytosine fluorination process due to too large amount of potassium fluoride.
The new preparation fluorinating agent N-fluoro succinimide related by the invention does not need special treatment, and can be directly used for the fluorination of cytosine, and the feeding proportion is N (N-fluoro succinimide): n (cytosine) ═ 1.14: 1, the replacement of N-chlorosuccinimide fluorine and chlorine in the previous step is completely performed. The fluorination of cytosine needs to be carried out according to the proportion, and other feeding proportions can not achieve good reaction effect.
The fluorination process of cytosine and N-fluorosuccinimide is a dry reaction without using a solvent. The charging speed of cytosine in the process needs to be adjusted in real time according to the viscosity of a reaction system to ensure uniform mixing, and the recommended charging speed is 100-150 kg/h.
The product of the fluorination of cytosine by N-fluorosuccinimide is a mixture of fluorocytosine and 2, 5-pyrrolidine diketone, the mixture needs to be separated by utilizing the characteristic that the fluorocytosine is slightly soluble in water and the 2, 5-pyrrolidine diketone is easily soluble in water, and a filter cake obtained in the centrifugal separation process needs to be fully rinsed. The crude flucytosine product obtained in the step has yellow appearance and can meet the quality requirement only by further refining.
The crude cytosine is yellow in appearance, and by virtue of the amino characteristics of the molecular structure of the crude cytosine, the crude cytosine is salified by using dilute acid, decolored and dissociated by using alkali to obtain a wet refined flucytosine product meeting the quality requirement, and the wet refined flucytosine product is dried to obtain a finished flucytosine product. The acid is hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like, preferably hydrochloric acid, and the concentration of the hydrochloric acid is preferably 10%; the alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide, and the concentration of the sodium hydroxide is preferably 32%. The temperature of the dilute acid salt formation process needs to be strictly controlled to be lower than 5 ℃, and the temperature is too high, so that the molecular ring opening is easily caused; the temperature of the alkali dissociation process needs to be strictly controlled to be lower than 5 ℃, and the temperature is too high, so that the ring opening of molecules is easily caused. The end point of the base liberation is pH 8, the pH is too low to liberate completely, and the pH is too high to cause the ring opening of the fluorocytosine molecules.
The beneficial results are as follows:
the raw materials involved in the invention have wide sources and low price, and the manufacturing cost is low.
The invention has the advantages of less industrial equipment, less investment of fixed assets and contribution to quickly expanding the fluorocytosine capacity.
All the procedures of the invention do not need to use any organic solvent, and the waste gas without VOCs does not relate to the incineration of organic waste gas, so the problem of carbon emission caused by waste gas is not generated.
The 2, 5-pyrrolidine diketone byproduct can be widely applied to the fields of organic synthesis, pharmacy, electroplating, chemical analysis and the like, and can create additional economic income.
The invention has high total yield and less organic residue, so the problem of carbon emission caused by burning the organic residue is only slightly involved.
Drawings
The invention is further illustrated below with reference to the accompanying drawings:
FIG. 1 is a liquid phase chromatogram of a fluorocytosine finished product;
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Preparation of N-fluorosuccinimide
Putting N-chlorosuccinimide (550.00kg, 4.12kmol) and potassium fluoride (250.00kg, 4.30kmol) into a 2000L dry-type stirring high-pressure reaction kettle, sealing and heating to 205-. After the reaction end point is reached, the materials in the reaction kettle are a mixture of N-fluorosuccinimide, potassium chloride and a small amount of N-chlorosuccinimide, are in a light brown paste shape, are not treated at all, and directly enter the next working procedure.
Example 2
Preparation of fluorocytosine:
controlling the temperature at 205 ℃ and 215 ℃, adding cytosine (400.00kg, 3.60kmol) in batches into the 2000L dry-type stirring high-pressure reaction kettle mentioned in the previous step, wherein the reaction system is firstly agglomerated and is continuously dispersed along with the stirring, and finally the reaction system is a uniform light yellow fine particle solid. After the cytosine feeding is finished, the temperature is raised to 250-260 ℃ and the temperature is kept for 5h in the temperature interval. After the heat preservation reaction is finished, sampling is controlled, and the end point of the reaction is considered to be reached when the cytosine residue is less than 0.5%. After completion of the reaction, the heating was turned off, and water (950.00kg, 52.78kmol) was added to the 2000L dry stirred autoclave, and the water loss due to steam was timely replenished. After water is added, the temperature of a reaction system is about 80-90 ℃ (if the temperature is too high, the temperature of the reaction system needs to be properly reduced in the water adding process), the reaction system is transferred to a crystallization kettle when the reaction system is hot, the reaction system is light yellow suspension at the moment, the reaction system is stirred and cooled to be lower than 25 ℃, the mixture is discharged and centrifuged, a filter cake is fully rinsed to obtain light yellow solid powder which is a flucytosine crude product, the wet weight is 518.36kg, and the next refining process is carried out; the filtrate is the aqueous solution of 2, 5-pyrrolidine diketone, and 2, 5-pyrrolidine diketone byproduct is prepared by dehydration.
And (3) controlling the temperature to be lower than 5 ℃, dissolving the obtained crude flucytosine with a proper amount of dilute hydrochloric acid, adding activated carbon accounting for 0.5 percent of the total weight of the crude flucytosine for decoloring, and controlling the temperature of a decoloring solution to be lower than 5 ℃ and adjusting the pH value to be 8 by using 32 percent sodium hydroxide. After the pH is adjusted, discharging and centrifuging, and desalting filtrate to prepare a sodium chloride byproduct; the filter cake is a flucytosine wet refined product, 416.52kg of bright white crystalline solid powder is obtained by drying, the bright white crystalline solid powder is a flucytosine finished product, the molar yield is 89.62% (calculated by cytosine), HPLC (area normalization method) is adopted, the analytical data is shown in table 1, and the liquid phase spectrogram is shown in figure 1.
TABLE 1 liquid phase analysis data for fluorocytosine end products
While the basic teachings of the present invention have been described, numerous extensions and variations will be apparent to those of ordinary skill in the art. As the present invention disclosed in the specification may be embodied in other specific forms without departing from the spirit or general characteristics thereof, and it is noted that some of these specific forms have been set forth, the embodiments disclosed in the specification should be considered as illustrative and not restrictive. The scope of the invention is indicated by the appended claims, rather than the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.
Claims (6)
1. A novel process for producing low-carbon-emission flucytosine is characterized by comprising the following steps: preparing fluorinating agent N-fluorosuccinimide from N-chlorosuccinimide and potassium fluoride, fluorinating cytosine by using the fluorinating agent to obtain a fluorocytosine crude product, and refining and drying the fluorocytosine crude product to obtain a fluorocytosine finished product.
2. The novel process for producing fluorocytosine with low carbon emission as claimed in claim 1, wherein the preparation process of fluorinating agent N-fluorosuccinimide comprises the following steps: directly carrying out dry reaction on N-chlorosuccinimide and potassium fluoride, wherein the feeding proportion is N (N-chlorosuccinimide): n (potassium fluoride) ═ 1: 1.04.
3. the novel process for producing fluorocytosine with low carbon emission as claimed in claim 2, wherein the fluorinating agent N-fluorosuccinimide is used for the fluorination of cytosine directly without special treatment, and the feeding ratio is N (N-fluorosuccinimide): n (cytosine) ═ 1.14: 1, completely replacing N-chlorosuccinimide fluorine and chlorine in the previous step; the fluorination of cytosine needs to be carried out according to the proportion, and other feeding proportions can not achieve good reaction effect.
4. The novel process for producing fluorocytosine with low carbon emission as claimed in claim 3, wherein the fluorination process of cytosine and N-fluorosuccinimide is a dry reaction without using a solvent; the charging speed of cytosine in the process needs to be adjusted in real time according to the viscosity of a reaction system so as to ensure uniform mixing, and the charging speed is between 100 and 150 kg/h.
5. The novel process for producing fluorocytosine with low carbon emission as claimed in claim 4, wherein the product of fluorination of cytosine by N-fluorosuccinimide is a mixture of fluorocytosine and 2, 5-pyrrolidinedione, which is separated by taking advantage of the property that fluorocytosine is slightly soluble in water and 2, 5-pyrrolidinedione is easily soluble in water, and the filter cake obtained by the centrifugal separation process needs to be thoroughly rinsed; the crude flucytosine product obtained in the step has yellow appearance and can meet the quality requirement only by further refining.
6. The novel process for producing fluorocytosine with low carbon emission as claimed in claim 5, wherein the crude cytosine product is yellowish in appearance, and by virtue of amino characteristics of the molecular structure of the crude cytosine product, the crude cytosine product is salified with a dilute acid, then decolored, dissociated with an alkali to obtain a wet refined fluorocytosine product meeting quality requirements, and dried to obtain a finished fluorocytosine product;
the acid is hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like, preferably hydrochloric acid, and the concentration of the hydrochloric acid is preferably 10%;
the alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide, and the concentration of the sodium hydroxide is preferably 32%;
the temperature of the dilute acid salt formation process needs to be strictly controlled to be lower than 5 ℃, and the temperature is too high, so that the molecular ring opening is easily caused;
the temperature of the alkali dissociation process needs to be strictly controlled to be lower than 5 ℃, and the temperature is too high, so that the ring opening of molecules is easily caused;
the end point of the base liberation is pH 8, the pH is too low to liberate completely, and the pH is too high to cause the ring opening of the fluorocytosine molecules.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110458400.7A CN113185466B (en) | 2021-04-27 | 2021-04-27 | Novel low-carbon-emission flucytosine production process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110458400.7A CN113185466B (en) | 2021-04-27 | 2021-04-27 | Novel low-carbon-emission flucytosine production process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113185466A true CN113185466A (en) | 2021-07-30 |
| CN113185466B CN113185466B (en) | 2022-09-06 |
Family
ID=76979400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110458400.7A Active CN113185466B (en) | 2021-04-27 | 2021-04-27 | Novel low-carbon-emission flucytosine production process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113185466B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016030662A1 (en) * | 2014-08-29 | 2016-03-03 | University Of Durham | Process for producing fluorocytosine and fluorocytosine derivatives |
| CN107089952A (en) * | 2017-05-09 | 2017-08-25 | 宁夏蓝博思化学技术有限公司 | The method that 5 Flucytosines are prepared using micro passage reaction |
| CN110483414A (en) * | 2019-08-14 | 2019-11-22 | 贵州永诺菲特生物制药有限公司 | A method of synthesis capecitabine intermediate 5-flurocytosine |
-
2021
- 2021-04-27 CN CN202110458400.7A patent/CN113185466B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016030662A1 (en) * | 2014-08-29 | 2016-03-03 | University Of Durham | Process for producing fluorocytosine and fluorocytosine derivatives |
| CN107089952A (en) * | 2017-05-09 | 2017-08-25 | 宁夏蓝博思化学技术有限公司 | The method that 5 Flucytosines are prepared using micro passage reaction |
| CN110483414A (en) * | 2019-08-14 | 2019-11-22 | 贵州永诺菲特生物制药有限公司 | A method of synthesis capecitabine intermediate 5-flurocytosine |
Non-Patent Citations (1)
| Title |
|---|
| ANTAL HARSANYI等: "One-Step Continuous Flow Synthesis of Antifungal WHO Essential Medicine Flucytosine Using Fluorine", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113185466B (en) | 2022-09-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1313742A1 (en) | Process for preparation of hydrates of olanzapine and their conversion into crystalline forms of olanzapine | |
| CN113185466B (en) | Novel low-carbon-emission flucytosine production process | |
| CN113929622B (en) | Synthesis method of 2,5, 6-trichloro-cyanogen | |
| CN102887902B (en) | Preparation process for synthesizing high-purity Pemedolac | |
| CN109694354B (en) | Synthesis method of 4-chloro-2-methylthiopyrimidine-5-ethyl formate | |
| CN103012288B (en) | Preparation method of 6-chloro-1,3-dimethyluracil | |
| Ross | The preparation of some 4-substituted nicotinic acids and nicotinamides | |
| CN106831648B (en) | The synthetic method of diazoxiide | |
| CN109761916A (en) | A kind of improvement synthetic method of orotic acid | |
| CN108675946A (en) | A method of preparing 2,4- diamino benzene sulfonic acids | |
| CN108794468A (en) | A kind of preparation method of Tetrahydropyridoindocompounds compounds | |
| CN111333650A (en) | Method for preparing hypoxanthine by inosine hydrolysis method | |
| CN111620875B (en) | Preparation process of imidazopyrazine compound | |
| CH632748A5 (en) | METHOD FOR PRODUCING URACIL DERIVATIVES. | |
| CN111303045A (en) | Production process of 2-ethoxy-4, 6-difluoropyrimidine | |
| US3642815A (en) | Process for preparing copper phthalocyanine | |
| CN105175294A (en) | Method for synthesizing sulfanilamide by using chlorobenzene as raw material | |
| CN106432067A (en) | Environment-friendly chemical synthetic method for 3-pyridine sulfonyl chloride | |
| CN108752271A (en) | A kind of synthetic method of oxyquinoline | |
| CN117069663B (en) | Synthesis method of rebaudinib intermediate V and synthesis method of rebaudinib | |
| CN108863900A (en) | A kind of preparation method of 5- fluoro indole -2- ketone | |
| CN103936766B (en) | A kind of 5(4H)-pyridone the synthetic method of furazan oxide | |
| CN108084183A (en) | A kind of caffeine purifying process | |
| CN114230525B (en) | Preparation method of 2-amino-4, 6-dimethoxypyrimidine | |
| CN111362957B (en) | Preparation method of icotinib key intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |