CN105153041B - A kind of preparation method of 5 Flucytosines suitable for industrialized production - Google Patents
A kind of preparation method of 5 Flucytosines suitable for industrialized production Download PDFInfo
- Publication number
- CN105153041B CN105153041B CN201510678299.0A CN201510678299A CN105153041B CN 105153041 B CN105153041 B CN 105153041B CN 201510678299 A CN201510678299 A CN 201510678299A CN 105153041 B CN105153041 B CN 105153041B
- Authority
- CN
- China
- Prior art keywords
- preparation
- methoxyl groups
- industrialized production
- flurocytosine
- reaction
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 27
- 229960002949 fluorouracil Drugs 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 21
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000008346 aqueous phase Substances 0.000 claims abstract description 13
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims abstract description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract 3
- 239000000460 chlorine Substances 0.000 claims abstract 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract 3
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 239000012141 concentrate Substances 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- 238000004176 ammonification Methods 0.000 claims description 8
- 239000012320 chlorinating reagent Substances 0.000 claims description 8
- 230000003301 hydrolyzing effect Effects 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 238000005576 amination reaction Methods 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- -1 methoxyl group Chemical group 0.000 abstract description 11
- 238000005660 chlorination reaction Methods 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- 125000003368 amide group Chemical group 0.000 abstract description 5
- 238000011084 recovery Methods 0.000 abstract description 5
- 239000002699 waste material Substances 0.000 abstract description 5
- 238000005903 acid hydrolysis reaction Methods 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 4
- 230000002378 acidificating effect Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000012545 processing Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 239000002912 waste gas Substances 0.000 abstract description 2
- WAVYAFBQOXCGSZ-UHFFFAOYSA-N 2-fluoropyrimidine Chemical compound FC1=NC=CC=N1 WAVYAFBQOXCGSZ-UHFFFAOYSA-N 0.000 abstract 4
- 238000012805 post-processing Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 230000007547 defect Effects 0.000 description 3
- 230000007717 exclusion Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- RJBYSQHLLIHSLT-UHFFFAOYSA-N methyl 2-fluoroacetate Chemical compound COC(=O)CF RJBYSQHLLIHSLT-UHFFFAOYSA-N 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000007096 poisonous effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical class ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- ZXVOCOLRQJZVBW-UHFFFAOYSA-N azane;ethanol Chemical class N.CCO ZXVOCOLRQJZVBW-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of preparation method of 5 Flucytosines suitable for industrialized production, belongs to pharmaceutical chemistry synthesis technical field.It carries out chlorination using the fluorouracil of 2 methoxyl group 5 as raw material, with phosphorus pentachloride and obtains the fluoropyrimidine of 2 methoxyl group, 4 chlorine 5, and the acid aqueous phase concentration of post processing gained is standby；The fluoropyrimidine of 2 methoxyl group, 4 chlorine 5 and aminating agent carry out aminating reaction and obtain the fluoropyrimidine of 2 methoxyl group, 4 amido 5, and the concentrated acidic aqueous phase that the fluoropyrimidine of 2 methoxyl group, 4 amido 5 is reclaimed with chlorination carries out acidic hydrolysis and obtains 5 Flucytosines.5 Flucytosines that the present invention is obtained by using above-mentioned technology, high income, convenient post-treatment, three-waste pollution is few, the problems such as toxic articles consumption in traditional handicraft is big, acid waste gas processing is difficult, pollution is big, cost is high is solved, its mole of total recovery is up to more than 70%, suitable for industrialized production and application.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, and in particular to a kind of 5- fluorine born of the same parents suitable for industrialized production are phonetic
The preparation method of pyridine.
Background technology
In the prior art, it is anti-that US447369, EP0063352 carry out on cytimidine fluoro in the method for fluorine gas/hydrogen fluoride
Should, but high is required to production operation and production equipment etc. using highly corrosive, hypertoxic fluorine gas, production is dangerous high,
Exist in industrialization compared with difficulty；CN103435557A with methylfluoracetate and Ethyl formate condensation after, then with urea reaction generate
5 FU 5 fluorouracil, 5 FU 5 fluorouracil obtains the chloro- 5-FUs of 2.4- bis- with thionyl chloride chlorination, then is obtained through ammonification and sulphuric acid hydrolysis
5-flurocytosine.Urea cyclization 5 FU 5 fluorouracil yield is low in this method, and thionyl chloride chlorination produce sulfur dioxide and
Hydrogen chloride gas produces larger pollution.CN104356071A is carried out Ethyl formate and methylfluoracetate using sodium as catalyst
Condensation reaction, intermediate carries out chlorination reaction with chlorinating agent, then through ammonification, acidic hydrolysis obtains institute in 5-flurocytosine, this method
With metallic sodium is expensive and dangerous height, the same cost of chlorinating agent N- chlorosuccinimides used is too high, Atom economy
Lowly, it is not suitable for industrial production.
The content of the invention
For above technical problem, the invention provides a kind of preparation side of the 5-flurocytosine suitable for industrialized production
Method, it solves cost of material height in existing process without using severe poisonous chemicals raw material POCl3, and production safety hidden danger is big,
The too high defect of three wastes rate.
The preparation method of described a kind of 5-flurocytosine suitable for industrialized production, it is characterised in that including following step
Suddenly：
1）Chlorinating step：In the presence of a catalyst, in organic solvent, 2- methoxyl groups -5 FU 5 fluorouracil is entered with chlorinating agent
Row chlorination reaction, after reaction terminates, adds water and is quenched, after layering, organic phase processor obtains the chloro- 5-FUs of 2- methoxyl groups -4-
（I）, acid water is mutually concentrated under reduced pressure with standby；
2）Amination steps：Under the conditions of certain pressure, by step 1）The chloro- 5-FUs of obtained 2- methoxyl groups -4-（I）With
Aminating agent carries out aminating reaction and obtains 2- methoxyl groups -4- amidos -5-FU（Ⅱ）, ammonification filtrate is for hydrolysing step regulation pH
Value；
3）Hydrolysing step：By step 2）Obtained 2- methoxyl groups -4- amidos -5-FU（Ⅱ）With acid system in catalysis
Agent effect is lower to carry out acid hydrolytic reaction, and reaction adjusts pH=8.0-8.5 after terminating, separates out solid 5-flurocytosine, specific route is such as
Under：
。
A kind of preparation method of described 5-flurocytosine suitable for industrialized production, it is characterised in that step 1）In
The chlorinating agent is phosphorus pentachloride, and the molar ratio of chlorinating agent and 2- methoxyl groups -5 FU 5 fluorouracil is 2-3: 1.
A kind of preparation method of described 5-flurocytosine suitable for industrialized production, it is characterised in that step 1）In
The catalyst is DMF, DMA, diisopropylethylamine or pyridine, catalyst and 2- first
The molar ratio of epoxide -5 FU 5 fluorouracil is 0.1-1:1.
A kind of preparation method of described 5-flurocytosine suitable for industrialized production, it is characterised in that step 1）In
The organic solvent is benzene, toluene or dimethylbenzene.
A kind of preparation method of described 5-flurocytosine suitable for industrialized production, it is characterised in that step 2）Middle institute
Aminating agent is stated for saturation methanolic ammonia solution, saturated ammonia ethanol solution or ammoniacal liquor, aminating agent and the chloro- 5-FUs of 2- methoxyl groups -4-
The mass ratio that feeds intake for 2-5：1.
A kind of preparation method of described 5-flurocytosine suitable for industrialized production, it is characterised in that step 2）In it is anti-
Answer pressure 0.5-1.5Mpa.
A kind of preparation method of described 5-flurocytosine suitable for industrialized production, it is characterised in that step 3）Middle institute
Acid system is stated for step 1）The acid water phase decompressed concentrate of middle gained.
A kind of preparation method of described 5-flurocytosine suitable for industrialized production, it is characterised in that step 3）Middle institute
Catalyst is stated for sodium iodide or KI, catalyst and 2- methoxyl groups -4- amidos -5-FU（Ⅱ）Molar ratio be
0.05-0.1：1.
A kind of preparation method of described 5-flurocytosine suitable for industrialized production, it is characterised in that step 3）In it is anti-
Answer 130-150 DEG C of temperature, reaction time 3-5 hour.
A kind of preparation method of described 5-flurocytosine suitable for industrialized production, it is characterised in that step 3）It is middle to adjust
PH steps 2）Obtained ammonification filtrate adjusts pH to be 8.0-8.5.
The present invention compared with prior art, has the advantages that by using above-mentioned technology：
1）The present invention obtains 5- fluorine by using 2- methoxyl groups -5 FU 5 fluorouracil raw material through chlorination, amination and acidic hydrolysis
Cytimidine, it avoid in the prior art use severe poisonous chemicals raw material POCl3, its raw material is cheap and easy to get, high income, into
This low, product quality is stable；It simultaneously solves in existing process the defect that cost of material is high, production safety hidden danger is big；
2）2- methoxyl groups -4- amidos -5-FU hydrolysis of the present invention uses step 1）Obtain acid aqueous phase concentrate
As acid system, using step 2）Obtained ammonification filtrate is used for hydrolysing step pH and adjusts liquid, not only reduces raw material, reduces
Cost, it rationally utilizes waste reaction solution, solves the too high defect of three wastes rate, reduce three-protection design cost, meet green
Environmental requirement；
3）The 5-flurocytosine that the present invention is obtained by the technology, high income, convenient post-treatment, three-waste pollution is few, solves
The problems such as toxic articles consumption is big in traditional handicraft, acid waste gas processing is difficult, pollution is big, cost is high, its total recovery up to 70% with
On, suitable for industrialized production and application.
Embodiment
Following case study on implementation is specific descriptions of the invention.The preparation method of case study on implementation of the present invention is merely to illustrate this
Invention, rather than limitation of the present invention, protection scope of the present invention are not limited to that, under the concept thereof of the present invention,
Simple modifications to preparation method of the present invention belong to the scope of protection of present invention.
The chloro- 5-FUs of 2- methoxyl groups -4- of example 1（I）Preparation
2- methoxyl groups -5 FU 5 fluorouracil（144g, 1mol）, toluene 500g, DMA（110g, 0.92mol）,
Phosphorus pentachloride is added portionwise in 35-40 DEG C in temperature control（412g, 2mol）, every crowd of about 20g, every 3 minutes are a collection of, add within about 1 hour.
Charging is finished, and is warming up to 85 DEG C, is continued to stir 3 hours, is cooled to after room temperature, reaction solution is poured into 1500g frozen water, stirs
30 minutes, layering was spin-dried for organic phase, obtains the chloro- 5-FUs of 2- methoxyl groups -4-（I）Crude product 167g, without being further purified；Will
Aqueous phase decompression is threaded to untill exclusion steams, and obtains acid aqueous phase concentrate standby.
2- methoxyl groups-4- the amidos of example 2-5-FU（Ⅱ）Preparation
By the chloro- 5-FUs of 2- methoxyl groups -4- obtained in example 1（I）Crude product 167g, is added in 1L autoclaves,
Add ammoniacal liquor 350g, it is closed after, be warming up to 100 DEG C, pressure 0.7Mpa is stirred 2 hours.Reaction solution is cooled to 0-5 DEG C, precipitation
Solid, filtering, filter cake drying obtains 128g white solids（Two step total recoverys 89.5%）, ammoniacal liquor filtrate is standby.
The preparation of the 5-flurocytosine of example 3
Acid aqueous phase concentrate, the chloro- 5-FUs of 2- methoxyl groups -4- that example 1 is obtained（I）（128g, 0.895mol）
And sodium iodide（6.7g, 0.045mol）, stir 5 hours, be cooled to after room temperature at 130 DEG C, the ammoniacal liquor filtrate in example 2 is dripped
Add in reaction solution, until pH=8.3, separate out a large amount of solids, filtering, filter cake is recrystallized with water, white 5- fluorine born of the same parents is obtained after drying phonetic
Pyridine solid 98g（Yield 84.9%, general line molar yield 77.7%）.
The chloro- 5-FUs of 2- methoxyl groups -4- of example 4（I）Preparation
2- methoxyl groups -5 FU 5 fluorouracil（144g, 1mol）, toluene 500g, anhydrous pyridine（16g, 0.2mol）, temperature control in
35-40 DEG C, it is added portionwise phosphorus pentachloride (515g, 2.5mol), every crowd of about 20g, every 3 minutes are a collection of, add within about 80 minutes.Charging
Finish, be warming up to 85 DEG C, continue to stir 5 hours, be cooled to after room temperature, reaction solution is poured into 1500g frozen water, stir 30 points
Clock, layering, is spin-dried for organic phase and obtains the chloro- 5-FUs of 2- methoxyl groups -4-（I）Crude product 164g, without being further purified；Aqueous phase is subtracted
Pressure is threaded to untill exclusion steams, and obtains acid aqueous phase concentrate standby；
2- methoxyl groups-4- the amidos of example 5-5-FU（Ⅱ）Preparation
By the chloro- 5-FUs of 2- methoxyl groups -4- obtained in example 4（I）Crude product 164g, adds 1L autoclaves, plus
Enter ammonia methanol 450g, it is closed after, be warming up to 95 DEG C, pressure 0.9Mpa is stirred 2 hours, reaction solution be cooled to 0-5 DEG C, precipitation
Solid, filtering, filter cake drying obtains 124g white solids（Two step total recoverys 86.7%）Ammonia methanol filtrate is standby.
The preparation of the 5-flurocytosine of example 6
By the acid aqueous phase concentrate of example 4, the chloro- 5-FUs of 2- methoxyl groups -4- are added（I）（124g, 0.867mol）With
And KI（14.4g, 0.0867mol）, stir 3 hours, be cooled to after room temperature, reaction solution pours into 1500g frozen water at 150 DEG C,
Ammonia methanol filtrate in example 2 is added dropwise in acidic aqueous liquid, until pH=8.5, separate out a large amount of solids, filtered, filter cake is with water weight
Crystallization, obtains white 5-flurocytosine solid 93g after drying（Yield 83.1%, general line molar yield 73.8%）.
The chloro- 5-FUs of 2- methoxyl groups -4- of example 7（I）Preparation
2- methoxyl groups -5 FU 5 fluorouracil（144g, 1mol）, dimethylbenzene 500g, DMF（7.3g, 0.1mol）, temperature control is in 35-
40 DEG C, phosphorus pentachloride is added portionwise（618g, 3mol）, every crowd of about 20g, every 3 minutes are a collection of, add within about 90 minutes.Charging is finished,
85 DEG C are warming up to, continues to stir 4 hours, is cooled to after room temperature, reaction solution is poured into 1500g frozen water, stir 30 minutes, point
Layer, is spin-dried for organic phase, obtains the chloro- 5-FUs of 2- methoxyl groups -4-（I）Crude product 160g need not be further purified；Aqueous phase is depressurized and revolved
Untill exclusion is steamed, acid aqueous phase concentrate is obtained standby.
2- methoxyl groups-4- the amidos of example 8-5-FU（Ⅱ）Preparation
By the chloro- 5-FUs of 2- methoxyl groups -4- obtained in example 7（I）Crude product 160g, adds 1L autoclaves, plus
Enter cholamine 600g, it is closed after, be warming up to 120 DEG C, pressure 1.3Mpa is stirred 2 hours.Reaction solution is cooled to 0-5 DEG C, precipitation
Solid, filtering, filter cake drying obtains 126g white solids（Two step total recoverys 88.1%）, ammoniacal liquor filtrate is standby.
The preparation of the 5-flurocytosine of example 9
Acid aqueous phase concentrate, the chloro- 5-FUs of 2- methoxyl groups -4- that example 7 is obtained embodiment 5（I）（126g,
0.881mol（And KI（7.3g, 0.044mol）, 150 DEG C are stirred 3 hours.It is cooled to after room temperature, by the ammonia in example 8
Filter liquor is added dropwise in acidic aqueous liquid, until pH=8.0, separate out a large amount of solids, filtering, filter cake is recrystallized with water, is obtained in vain after drying
Color 5-flurocytosine solid 91g（Yield 81.9%, general line molar yield 70.5%）.
Claims (5)
1. the preparation method of a kind of 5-flurocytosine suitable for industrialized production, it is characterised in that comprise the following steps：
1）Chlorinating step：In the presence of a catalyst, in organic solvent, 2- methoxyl groups -5 FU 5 fluorouracil carries out chlorine with chlorinating agent
Change reaction, after reaction terminates, add water and be quenched, after layering, organic phase processor obtains the chloro- 5-FUs of 2- methoxyl groups -4-（I）, acid
Property aqueous phase be concentrated under reduced pressure with standby, the chlorinating agent is phosphorus pentachloride, and chlorinating agent rubs with 2- methoxyl groups-feeding intake for 5 FU 5 fluorouracil
You are than being 2-3: 1；
2）Amination steps：Under the conditions of certain pressure, by step 1）The chloro- 5-FUs of obtained 2- methoxyl groups -4-（I）With ammonification
Agent NH3Carry out aminating reaction and obtain 2- methoxyl groups -4- amidos -5-FU（Ⅱ）, ammonification filtrate is for hydrolysing step regulation pH value；
3）Hydrolysing step：By step 2）Obtained 2- methoxyl groups -4- amidos -5-FU（Ⅱ）With acid body obtained by chlorinating step
Tie up to and acid hydrolytic reaction is carried out under catalyst action, the catalyst is sodium iodide, the acid system is step 1）Middle institute
The acid water phase decompressed concentrate obtained, reaction uses step 2 after terminating）Obtained ammonification filtrate adjusts pH to be 8.0-8.5, separates out solid
5-flurocytosine, specific route is as follows：
2. a kind of preparation method of 5-flurocytosine suitable for industrialized production according to claim 1, its feature exists
In step 1）Described in catalyst be DMF, DMA, diisopropylethylamine or pyridine, urge
The molar ratio of agent and 2- methoxyl groups -5 FU 5 fluorouracil is 0.1-1:1.
3. a kind of preparation method of 5-flurocytosine suitable for industrialized production according to claim 1, its feature exists
In step 1）Described in organic solvent be benzene, toluene or dimethylbenzene.
4. a kind of preparation method of 5-flurocytosine suitable for industrialized production according to claim 1, its feature exists
In step 2）Middle reaction pressure 0.5-1.5Mpa.
5. a kind of preparation method of 5-flurocytosine suitable for industrialized production according to claim 1, its feature exists
In step 3）Middle 130-150 DEG C of reaction temperature, reaction time 3-5 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510678299.0A CN105153041B (en) | 2015-10-20 | 2015-10-20 | A kind of preparation method of 5 Flucytosines suitable for industrialized production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510678299.0A CN105153041B (en) | 2015-10-20 | 2015-10-20 | A kind of preparation method of 5 Flucytosines suitable for industrialized production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105153041A CN105153041A (en) | 2015-12-16 |
| CN105153041B true CN105153041B (en) | 2017-11-07 |
Family
ID=54794139
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510678299.0A Active CN105153041B (en) | 2015-10-20 | 2015-10-20 | A kind of preparation method of 5 Flucytosines suitable for industrialized production |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105153041B (en) |
Families Citing this family (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 |
| CN108033917B (en) * | 2017-12-15 | 2019-12-10 | 浙江先锋科技股份有限公司 | Preparation method of 5-fluorocytosine |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB806584A (en) * | 1956-05-08 | 1958-12-31 | Hoffmann La Roche | Novel pyrimidine derivatives and a process for the manufacture thereof |
| CN103435557B (en) * | 2013-08-08 | 2015-05-20 | 爱斯特（成都）生物制药有限公司 | 5-fluorocytosine preparation method |
| CN103923019A (en) * | 2014-03-20 | 2014-07-16 | 蚌埠中实化学技术有限公司 | Preparation method of 2-hydroxy-4-amino-5-fluoropyrimidine |
| CN104356071A (en) * | 2014-11-21 | 2015-02-18 | 山东金城医药化工股份有限公司 | Preparation method for 5-fluorocytosine |
-
2015
- 2015-10-20 CN CN201510678299.0A patent/CN105153041B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN105153041A (en) | 2015-12-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2012163200A1 (en) | Method for separating rare earth from phosphorus ore | |
| CN103435557B (en) | 5-fluorocytosine preparation method | |
| CN105153041B (en) | A kind of preparation method of 5 Flucytosines suitable for industrialized production | |
| CN109721545A (en) | A kind of preparation method of azoxystrobin intermediate | |
| CN103359744A (en) | Method for extracting white carbon black from mine tailing | |
| CN108531718A (en) | A method of producing chrome green using tailings in vanadium extraction | |
| CN102924380B (en) | Preparation method of imidocarb | |
| CN104130194B (en) | A kind of synthetic method of 5-Amino-2-benzimidazolinone | |
| CN102964270B (en) | Method for reducing hydrazine synthesized by diazonium salt by utilizing sodium sulphite | |
| WO2021218073A1 (en) | Method for preparing benzimidazolone in aqueous solvent | |
| CN107475526A (en) | A kind of method for preparing zinc metal sheet and ammonium chloride using high chlorine smelting ash | |
| CN103952534B (en) | A kind of method utilizing nickel-molybdenum ore to prepare Sodium orthomolybdate | |
| CN104326988B (en) | A kind of synthetic method of 2,4-dichloro-5-methoxy pyrimidines | |
| CN106632014A (en) | Preparation of 2-amino-5-chloropyridine | |
| CN105858700A (en) | Novel production technique for preparing calcium chloride from carbide slag | |
| CN102560103B (en) | Method for purification production of molybdenum disulfide from molybdenum concentrate | |
| CN101429130B (en) | Method for producing 2,6-dichlorine para-nitraniline | |
| CN103950976A (en) | Method for preparing titanium dioxide by utilizing mixed alkali of sodium hydroxide and sodium nitrate | |
| CN112939893B (en) | Synthesis method of 4- (4-aminophenyl) -3-morpholinone | |
| CN103898340B (en) | A kind of method utilizing nickel-molybdenum ore to prepare barium molybdate | |
| CN104693144A (en) | Synthetic method of N-(2-chloroethyl) hexamethyleneimine hydrochloride | |
| CN108147579B (en) | Method for recycling active ingredients in Fumei production wastewater | |
| CN106316870A (en) | Synthesis method of L-glycine methyl ester salt product | |
| CN107652207B (en) | Synthetic method of 1-amino-1-cyclopropanecarbonitrile hydrochloride | |
| CN104513197A (en) | 2-aminonicotinic acid synthetic method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address |
Address after: 317021 Yongquan Houjing Yantou, Linhai City, Taizhou City, Zhejiang Province Patentee after: Zhejiang Pioneer Technology Group Co.,Ltd. Country or region after: China Address before: 317021 Hou Jing Yan Tou, Yongquan Town, Linhai City, Taizhou City, Zhejiang Province Patentee before: ZHEJIANG XIANFENG SCIENCE TECHNOLOGY Co.,Ltd. Country or region before: China |