CN116425815A - Cytidine acid production process - Google Patents
Cytidine acid production process Download PDFInfo
- Publication number
- CN116425815A CN116425815A CN202310415006.4A CN202310415006A CN116425815A CN 116425815 A CN116425815 A CN 116425815A CN 202310415006 A CN202310415006 A CN 202310415006A CN 116425815 A CN116425815 A CN 116425815A
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- CN
- China
- Prior art keywords
- cytidine
- production process
- acid production
- process according
- cytidine acid
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- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 title claims abstract description 41
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 title claims abstract description 41
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 title claims abstract description 41
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 37
- 239000002253 acid Substances 0.000 title claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000001816 cooling Methods 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000007788 liquid Substances 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 5
- 230000001105 regulatory effect Effects 0.000 claims abstract description 4
- 238000003825 pressing Methods 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000003916 acid precipitation Methods 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 238000005202 decontamination Methods 0.000 claims description 2
- 230000003588 decontaminative effect Effects 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 abstract description 10
- 230000008569 process Effects 0.000 abstract description 9
- 239000002910 solid waste Substances 0.000 abstract description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 abstract description 5
- 238000006386 neutralization reaction Methods 0.000 abstract description 3
- 238000011112 process operation Methods 0.000 abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 231100000206 health hazard Toxicity 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a cytidine acid production process in the technical field of cytidine acid production, which comprises the following steps: cooling triethyl phosphate, and then adding cytidine and phosphorus oxychloride; step two: adding water to hydrolyze and delaminate after the reaction is finished; step three: regulating pH of the water layer to 2-2.5 with liquid alkali, cooling to-5-10 deg.c and crystallizing for 6 hr; the existing liquid alkali is used for replacing sodium carbonate for neutralization, the process operation is simple, the difficult problem of generation of a large amount of solid waste is directly solved, the whole process pipeline operation can be realized, and the production safety is ensured to a great extent.
Description
Technical Field
The invention relates to the technical field of cytidine acid production, in particular to a cytidine acid production process.
Background
The cytidine acid has the appearance and the character of fine off-white crystalline powder, and is mainly used as a food additive, a genetic engineering reagent and a pharmaceutical raw material, and is also used for biochemical research.
The original method for extracting the organic phase in the cytidine acid production process is to recover the triethylamine through drying sodium carbonate, which can cause a large amount of solid waste salt to be generated, and volatilize a large amount of organic solvent in the suction filtration process to cause occupational health hazard and potential safety hazard.
Disclosure of Invention
The present invention is directed to a cytidine acid production process, which solves the problems set forth in the background art.
In order to achieve the above purpose, the present invention provides the following technical solutions: the cytidine acid production process comprises the following steps,
step one: cooling triethyl phosphate, and then adding cytidine and phosphorus oxychloride;
step two: adding water to hydrolyze and delaminate after the reaction is finished;
step three: regulating pH of the water layer to 2-2.5 with liquid alkali, cooling to-5-10 deg.c and crystallizing for 6 hr;
step four: press filtration;
step five: adding 4 times of water into the wet product, heating for dissolving, cooling, and adding 95% ethanol;
step six: cooling to 5 ℃ and centrifugally spin-drying, and drying the wet product in a drying oven at 75 ℃ to obtain a cytidine acid finished product.
As a preferable scheme of the cytidine acid production process, the invention comprises the following steps: in the first step, the triethyl phosphate is cooled to about minus 10 ℃, and then cytidine is added.
As a preferable scheme of the cytidine acid production process, the invention comprises the following steps: in the first step, phosphorus oxychloride is added in a dropwise manner, the temperature is controlled to be-8 to-10 ℃, and the dropwise addition is carried out for 3-4 hours.
As a preferable scheme of the cytidine acid production process, the invention comprises the following steps: and the first step, the second step and the third step are provided with tail gas treatment devices.
As a preferable scheme of the cytidine acid production process, the invention comprises the following steps: in the step six, the wet product is crushed after being dried in an oven, and the finished product is packaged after the crushing.
As a preferable scheme of the cytidine acid production process, the invention comprises the following steps: in the fourth step, distillation concentration, centrifugal separation, acid precipitation, crystallization and secondary filter pressing are carried out after filter pressing.
As a preferable scheme of the cytidine acid production process, the invention comprises the following steps: and (5) carrying out recrystallization after secondary filter pressing.
As a preferable scheme of the cytidine acid production process, the invention comprises the following steps: and (5) carrying out tail gas removal treatment after the acid precipitation.
As a preferable scheme of the cytidine acid production process, the invention comprises the following steps: and carrying out decontamination water treatment after secondary filter pressing.
Compared with the prior art, the invention has the beneficial effects that: the existing liquid alkali is used for replacing sodium carbonate for neutralization, the process operation is simple, the difficult problem of generation of a large amount of solid waste is directly solved, the whole process pipeline operation can be realized, and the production safety is ensured to a great extent. And the product has the advantages of good quality stability, greatly reduced production cost, more contribution to large-scale production and the like.
Drawings
FIG. 1 is a process flow diagram of the cytidine acid production process of the present invention;
FIG. 2 is a diagram showing the reaction equation of the cytidine acid production process according to the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
As mentioned in the background art, the method aims at the defects that a large amount of solid waste salt is generated in the prior art, and a large amount of organic solvent is volatilized in the suction filtration process, so that occupational health hazard and potential safety hazard are caused. The invention provides a cytidine acid production process which directly solves the problem of generation of a large amount of solid wastes, can realize the pipeline operation of the whole process and ensures the production safety to a great extent.
Example 1
Referring to fig. 1 to 2, the cytidine acid production process includes the steps of,
step one: cooling triethyl phosphate, and then adding cytidine and phosphorus oxychloride;
step two: adding water to hydrolyze and delaminate after the reaction is finished;
step three: the pH value of the water layer is regulated to 2-2.5 by liquid caustic soda, the temperature is about 10 ℃, the water layer is cooled to minus 5-10 ℃ for crystallization for 6 hours, sodium carbonate is adopted for drying, distillation recovery is carried out after extraction in the prior art, and the recovered triethyl phosphate is reused, so that a large amount of solid waste salt is generated, a large amount of organic solvent is volatilized in the suction filtration process, occupational health hazard and potential safety hazard are caused, the existing liquid caustic soda is used for replacing sodium carbonate for neutralization, the process operation is simple, the problem of the generation of a large amount of solid waste is directly solved, the whole process pipeline operation can be realized, and the production safety is ensured to a large extent. The product has the advantages of good quality stability, greatly reduced production cost, more contribution to large-scale production and the like;
step four: press filtration;
step five: adding 4 times of water into the wet product, heating for dissolving, cooling, and adding 95% ethanol;
step six: cooling to 5deg.C, centrifuging, drying at 75deg.C to obtain cytidine acid product with yield of above 100%, HPLC of above 99%, and UV of above 98%.
In the first step, triethyl phosphate is cooled to about-10 ℃ and cytidine is added.
In the first step, phosphorus oxychloride is added in a dropwise manner, the temperature is controlled to be-8 to-10 ℃, and the dropwise addition is carried out for 3-4 hours.
In order to reduce pollution, the tail gas treatment device is arranged in the first step, the second step and the third step.
In order to facilitate production, in the step six, wet products are crushed after being dried in an oven, and finished products are packaged after being crushed.
And step four, carrying out distillation concentration, centrifugal separation, acid precipitation, crystallization and secondary filter pressing after filter pressing, and carrying out recrystallization after secondary filter pressing, thus repeating the process of the step six for drying.
Example 2
Referring to fig. 1, the tail gas is treated after acid precipitation, and the decontaminated water is treated after pressure filtration again, so that the pollution to the environment can be reduced.
The rest of the structure is the same as in embodiment 1.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (9)
1. The cytidine acid production process is characterized in that: comprises the following steps of the method,
step one: cooling triethyl phosphate, and then adding cytidine and phosphorus oxychloride;
step two: adding water to hydrolyze and delaminate after the reaction is finished;
step three: regulating pH of the water layer to 2-2.5 with liquid alkali, cooling to-5-10 deg.c and crystallizing for 6 hr;
step four: press filtration;
step five: adding 4 times of water into the wet product, heating for dissolving, cooling, and adding 95% ethanol;
step six: cooling to 5 ℃ and centrifugally spin-drying, and drying the wet product in a drying oven at 75 ℃ to obtain a cytidine acid finished product.
2. The cytidine acid production process according to claim 1, characterized in that: in the first step, the triethyl phosphate is cooled to about minus 10 ℃, and then cytidine is added.
3. The cytidine acid production process according to claim 1, characterized in that: in the first step, phosphorus oxychloride is added in a dropwise manner, the temperature is controlled to be-8 to-10 ℃, and the dropwise addition is carried out for 3-4 hours.
4. The cytidine acid production process according to claim 1, characterized in that: and the first step, the second step and the third step are provided with tail gas treatment devices.
5. The cytidine acid production process according to claim 1, characterized in that: in the step six, the wet product is crushed after being dried in an oven, and the finished product is packaged after the crushing.
6. The cytidine acid production process according to claim 1, characterized in that: in the fourth step, distillation concentration, centrifugal separation, acid precipitation, crystallization and secondary filter pressing are carried out after filter pressing.
7. The cytidine acid production process according to claim 6, characterized in that: and (5) carrying out recrystallization after secondary filter pressing.
8. The cytidine acid production process according to claim 6, characterized in that: and (5) carrying out tail gas removal treatment after the acid precipitation.
9. The cytidine acid production process according to claim 6, characterized in that: and carrying out decontamination water treatment after secondary filter pressing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310415006.4A CN116425815A (en) | 2023-04-18 | 2023-04-18 | Cytidine acid production process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310415006.4A CN116425815A (en) | 2023-04-18 | 2023-04-18 | Cytidine acid production process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116425815A true CN116425815A (en) | 2023-07-14 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310415006.4A Withdrawn CN116425815A (en) | 2023-04-18 | 2023-04-18 | Cytidine acid production process |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114315934A (en) * | 2021-12-22 | 2022-04-12 | 成都市海通药业有限公司 | Synthesis and refining method of citicoline important intermediate cytidylic acid |
-
2023
- 2023-04-18 CN CN202310415006.4A patent/CN116425815A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114315934A (en) * | 2021-12-22 | 2022-04-12 | 成都市海通药业有限公司 | Synthesis and refining method of citicoline important intermediate cytidylic acid |
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Legal Events
| Date | Code | Title | Description |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20230714 |
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| WW01 | Invention patent application withdrawn after publication |