CN108929277A - A kind of preparation method of the chloro- 5-FU of 2- methoxyl group -4- - Google Patents
A kind of preparation method of the chloro- 5-FU of 2- methoxyl group -4- Download PDFInfo
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- CN108929277A CN108929277A CN201710372486.5A CN201710372486A CN108929277A CN 108929277 A CN108929277 A CN 108929277A CN 201710372486 A CN201710372486 A CN 201710372486A CN 108929277 A CN108929277 A CN 108929277A
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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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
Abstract
The invention discloses a kind of preparation methods of the chloro- 5-FU of 2- methoxyl group -4-, belong to organic chemical intermediates chemical process technical field.Its technical process is summarised as：Alkaline matter, solvent are added into reaction vessel and stirs, phosgene, surpalite or triphosgene is then added, as chlorination reagent.It is eventually adding 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine, detection through simple aftertreatment technology, obtains the target product of high yield, high-purity after the reaction was completed.Present invention process reaction condition is mild, post-processing is simple, at low cost, and high income reaches 97-98.5%.
Description
Technical field
The invention belongs to organic chemical intermediates synthesis technology fields, and in particular to a kind of chloro- 5- of 2- methoxyl group -4-
The preparation method of fluoropyrimidine.
Background technique
The chloro- 5-FU of 2- methoxyl group -4- is a kind of important pyrimidines, is synthesis 2- hydroxyl -4- amino -5-
The important intermediate of fluoropyrimidine and florasulam.In the prior art（CN 103923019, CN 104945331, CN
105153041, CN 105272922, CN 105801492, CN104725323）Mainly with 2- methoxyl group -4- hydroxyl-5-fluorine
Pyrimidine is that raw material uses the reagents such as large excess of phosphorus oxychloride, phosphorus pentachloride as chlorination reagent to prepare 2- methoxyl group -4-
Chloro- 5-FU.But chlorination reagent dosage is very big in these preparation methods, needs to use a large amount of ice water in last handling process
System is quenched, to form a large amount of phosphorus-containing wastewaters, it is difficult to handle and be unfavorable for greenization production.Go out from the angle of green production
Hair, it is necessary to get rid of the method for relying on phosphorus oxychloride or phosphorus pentachloride etc. as chlorination reagent, explore a kind of easy to operate, economic
Effectively, it pollutes small and is easy to industrialized preparation method." a kind of chloro- 5- fluorine of 2- methoxyl group -4- is phonetic for the Chinese patent submitted on the same day
The preparation method of pyridine " overcomes disadvantages mentioned above, but yield only has 80%, and there are raw material 2- methoxyl group -4- hydroxyl-5-fluorine is phonetic
The by-product of pyridine demethylation.Therefore, it is necessary to find one kind it is possible to prevente effectively from the new 2- methoxyl group -4- of this side reaction is chloro-
The preparation method of 5-FU.
Summary of the invention
The invention reside in provide a kind of 2- methoxyl group -4- preparation method of chloro- 5-FU.Preparation provided by the present invention
The cleaning of method economy, product yield high, by-product is few, is suitble to industrialized production.
Technical scheme is as follows：
A kind of preparation method of the chloro- 5-FU of 2- methoxyl group -4-, the method includes：Chlorination is first added into alkaline matter
Reagent adds 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and carries out chlorination reaction, obtains the chloro- 5-FU of 2- methoxyl group -4-, institute
It states chlorination reagent and is selected from phosgene, surpalite, triphosgene.
Preferably, alkaline matter is dissolved in solvent, chlorination reagent is added at 0 ~ 30 DEG C, add 2- methoxyl group -4-
Hydroxyl-5-fluorine pyrimidine obtains the chloro- 5-FU of 2- methoxyl group -4-.
It is shown in formula I that the 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine can generate ketone form structure by tautomerism：
Formulas I Formula II
This tautomer can easily be turned by tautomerism each other with the 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine
It changes, both can be used as the raw material of the technical program.
Preferably, 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine is added portionwise in reaction system, when reaction system is more than 30 DEG C
In the case where, by-product 5 FU 5 fluorouracil is had, structure is as shown in Formula II.
Preferably, the ratio of the 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and alkaline matter of addition is 1mol：(5%~
2000%) mol.It is furthermore preferred that the ratio of the 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and alkaline matter that are added is 1mol：(5%
~250%) mol.It is furthermore preferred that the ratio of the 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and alkaline matter that are added is 1mol：
(100%~200%) mol.
Preferably, the concentration of 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine in a solvent is 1.0-30.0mol/L.More preferably
, the concentration of 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine in a solvent is 3.0-10.0mol/L.It is furthermore preferred that 2- methoxyl group -4-
The concentration of hydroxyl-5-fluorine pyrimidine in a solvent is 5.0-8.0mol/L.
When phosgene is as chlorination reagent, the molar ratio of 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and phosgene is 1:0.9~
20, preferably 1:1 ~ 5, more preferably 1:1~3；
When surpalite is as chlorination reagent, the molar ratio of 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and surpalite is 1:0.45~
10, preferably 1:0.5 ~ 3, more preferably 1:0.5~1.5；
When triphosgene is as chlorination reagent, the molar ratio of 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and triphosgene is 1:0.3 ~ 6,
Preferably 1:0.33 ~ 2, more preferably 1:0.33~1；
Preferably, alkaline matter used be selected from one of organic base or inorganic base or a variety of, the organic base be selected from triethylamine,
Diethylamine, trimethylamine, pyridine, triethylamine, N, N- diisopropylethylamine, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide,
4-dimethylaminopyridine or N, accelerine any one or any combination thereof two or more mixed base；It is shown
Inorganic base is selected from：Sodium hydroxide, sodium carbonate, sodium bicarbonate, ammonium carbonate, ammonium hydrogen carbonate any one or any combination thereof two kinds or
Two or more mixed bases.
Preferably, alkaline matter used is selected from triethylamine, n,N-diisopropylethylamine, n,N-Dimethylformamide, N, N-
Dimethyl acetamide, pyridine, 4-dimethylaminopyridine or N, accelerine any one or any combination.
Preferably, the solvent in nitrile, ether, halogenated alkane or aromatic hydrocarbons, halogenated aryl hydrocarbon any one or it is any
Combination.
The more preferably described solvent is selected from acetonitrile, glycol dimethyl ether, 1,4- dioxane, 1,2- dichloroethanes, 1,1,
2,2- tetrachloroethanes, toluene, tetrahydrofuran, 1,4- dioxane, o-dichlorohenzene, nitrobenzene, methylene chloride, chloroform or chlorine
Benzene.
For mostly reacting, we only need through simple solvent extraction, washing, drying, select dry can be obtained
Purity is not less than 95% product, and for higher purity, our product can be dissolved in organic solvent by we, be passed through
Silica gel column chromatography obtains the product that purity is not less than 99%, can also pass through distillation under pressure and other common organic compounds
Purification process obtain purity be not less than 99% product.
It advantages of the present invention and has the beneficial effect that：
1, the present invention passes through control chlorination reagent, alkaline matter, the charging sequence of 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and anti-
It answers temperature, realizes that 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine is steady, efficient chloro, it is suppressed that 2- methoxyl group -4- hydroxyl-5-fluorine is phonetic
Pyridine easily removes the side reaction of methyl in acid condition, so that entire reaction yield is close to theoretical yield 97-98.5%.
2, the selection of present invention process condition rationally, by using phosgene, surpalite or triphosgene as chlorination reagent, avoids
The use of hypertoxic phosphorus oxychloride or phosphorus pentachloride to reduce the generation of phosphorus-containing wastewater, and post-processes and simplifies, thermal discharge
Small, energy saving, by-product is few, it is easy to accomplish industrialized production.
Detailed description of the invention
Fig. 1 is the synthesis route figure of the chloro- 5-FU of 2- methoxyl group -4-；
Fig. 2 is the nuclear magnetic resonance spectroscopy of the chloro- 5-FU of 2- methoxyl group -4-；
Fig. 3 is the carbon-13 nmr spectra of the chloro- 5-FU of 2- methoxyl group -4-；
Fig. 4 is the mass spectrogram of the chloro- 5-FU of 2- methoxyl group -4-（EI）.
Specific embodiment
In order to make the objectives, technical solutions and advantages of the present invention clearer, With reference to embodiment and join
According to attached drawing, the present invention is described in more detail.It should be understood that these descriptions are merely illustrative, and it is not intended to limit this hair
Bright range.In addition, in the following description, descriptions of well-known structures and technologies are omitted, to avoid this is unnecessarily obscured
The concept of invention.
The present invention provides a kind of 2- methoxyl group -4- preparation method of chloro- 5-FU, and synthetic route such as attached drawing 1 is specific to walk
It is rapid as follows：
Embodiment 1：
By N,N-dimethylformamide 89g（120mol%）One is put into equipped with thermometer, reflux with Isosorbide-5-Nitrae-dioxane 200ml
In condenser, dropping funel and churned mechanically 1000ml three-necked bottle flask, it is small to 0 DEG C of stirring 1 to reduce temperature of reaction system
When, keep phosgene be passed through speed be 2 gram/minutes, keep 5 DEG C of reaction temperature, it is common enter 2mol phosgene.Then 2- is added portionwise
Methoxyl group -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and reaction temperature is controlled no more than 20 DEG C.After reaction, it is passed through
Nitrogen removes system remnants phosgene, and 200ml water is added portionwise into reaction solution and stirs 50 minutes, then liquid separation removes water phase, water
200ml methylene chloride extraction merging organic phase twice is mutually used, solvent is recovered under reduced pressure, is isolated and purified to obtain yellow oily liquid
159g, yield 98%.
The spectral characterization of the prepared chloro- 5-FU of 2- methoxyl group -4- is as shown in attached drawing 2,3：1H NMR (400
MHz, CDCl3) δ 8.38 (s, 1H), 4.04 (s, 3H)；13C NMR (100 MHz, CDCl3) δ 160.0,
159.9, 150.5, 148.5, 148.3, 148.0, 146.1, 145.9, 55.3. GC-MS(EI)(M+): 162.1。
Embodiment 2：
By N,N-dimethylformamide 89g（120mol%）One is put into equipped with thermometer, reflux with Isosorbide-5-Nitrae-dioxane 200ml
In condenser, dropping funel and churned mechanically 1000ml three-necked bottle flask, it is small to 0 DEG C of stirring 1 to reduce temperature of reaction system
When, keep phosgene be passed through speed be 2 gram/minutes, keep 5 DEG C of reaction temperature, it is common enter 1mol phosgene.Then 2- is added portionwise
Methoxyl group -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and reaction temperature is controlled no more than 25 DEG C.After reaction, it is passed through
Nitrogen removes system remnants phosgene, and 200ml water is added portionwise into reaction solution and stirs 50 minutes, then liquid separation removes water phase, water
200ml methylene chloride extraction merging organic phase twice is mutually used, solvent is recovered under reduced pressure, is isolated and purified to obtain yellow oily liquid
157g, yield 97%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
Embodiment 3：
By N,N-dimethylformamide 89g（120mol%）One is put into equipped with thermometer, reflux with Isosorbide-5-Nitrae-dioxane 200ml
In condenser, dropping funel and churned mechanically 1000ml three-necked bottle flask, it is small to 0 DEG C of stirring 1 to reduce temperature of reaction system
When, keep phosgene be passed through speed be 2 gram/minutes, keep 5 DEG C of reaction temperature, it is common enter 3.3mol phosgene.Then it is added portionwise
2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and reaction temperature is controlled no more than 20 DEG C.After reaction, lead to
Enter nitrogen and remove system remnants phosgene, 200ml water is added portionwise into reaction solution and stirs 50 minutes, then liquid separation removes water phase,
Water phase 200ml methylene chloride extraction merging organic phase twice, is recovered under reduced pressure solvent, is isolated and purified to obtain yellow oily liquid
157g, yield 97%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
Embodiment 4：
By N,N-dimethylformamide 89g（120mol%）One is put into tetrahydrofuran 200ml, and thermometer, reflux condensation mode are housed
In device, dropping funel and churned mechanically 1000ml three-necked bottle flask, reduce temperature of reaction system to 0 DEG C stir 1 hour, protect
Hold surpalite be passed through speed be 1.5 gram/minutes, keep 5 DEG C of reaction temperature, it is common enter 0.5mol surpalite.Then it is added portionwise
2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and reaction temperature is controlled no more than 20 DEG C.After reaction, lead to
Enter nitrogen and remove system remnants surpalite, 200ml water is added portionwise into reaction solution and stirs 50 minutes, then liquid separation removes water
Phase, water phase 200ml methylene chloride extraction merging organic phase twice, is recovered under reduced pressure solvent, is isolated and purified to obtain yellow oily liquid
Body 158g, yield 97.5%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
Embodiment 5：
By N,N-dimethylformamide 89g（120mol%）One is put into equipped with thermometer, reflux with Isosorbide-5-Nitrae-dioxane 200ml
In condenser, dropping funel and churned mechanically 1000ml three-necked bottle flask, it is small to 0 DEG C of stirring 1 to reduce temperature of reaction system
When, keep surpalite be passed through speed be 2 gram/minutes, keep 5 DEG C of reaction temperature, it is common enter 1mol surpalite.Then it is added portionwise
2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and reaction temperature is controlled no more than 20 DEG C.After reaction, lead to
Enter nitrogen and remove system remnants surpalite, 200ml water is added portionwise into reaction solution and stirs 50 minutes, then liquid separation removes water
Phase, water phase 200ml methylene chloride extraction merging organic phase twice, is recovered under reduced pressure solvent, is isolated and purified to obtain yellow oily liquid
Body 159g, yield 98%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
Embodiment 6：
By N,N-dimethylformamide 89g（120mol%）One is put into equipped with thermometer, reflux with Isosorbide-5-Nitrae-dioxane 200ml
In condenser, dropping funel and churned mechanically 1000ml three-necked bottle flask, it is small to 0 DEG C of stirring 1 to reduce temperature of reaction system
When, keep surpalite be passed through speed be 2 gram/minutes, keep reaction temperature be no more than 5 DEG C, it is common enter 1.5mol surpalite.Then
2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol) is added portionwise, and controls reaction temperature no more than 25 DEG C.Reaction
After, it is passed through nitrogen and removes system remnants surpalite, 200ml water is added portionwise into reaction solution and stirs 50 minutes, then divides
Liquid removes water phase, and water phase 200ml methylene chloride extraction merging organic phase twice is recovered under reduced pressure solvent, is isolated and purified yellow
Color oily liquids 160g, yield 98.5%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
Embodiment 7：
By triethylamine 121.44g（120mol%）One is put into methylene chloride 200ml, and thermometer, reflux condenser, drop are housed
In liquid funnel and churned mechanically 1000ml three-necked bottle flask, reduce temperature of reaction system to 0 DEG C stir 1 hour, keep three
Phosgene be passed through speed be 2 gram/minutes, keep reaction temperature be no more than 5 DEG C, it is common enter 0.4mol triphosgene.Then it is added portionwise
2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and reaction temperature is controlled no more than 25 DEG C.After reaction, lead to
Enter nitrogen and remove system remnants triphosgene, 200ml water is added portionwise into reaction solution and stirs 50 minutes, then liquid separation removes water
Phase, water phase 200ml methylene chloride extraction merging organic phase twice, is recovered under reduced pressure solvent, is isolated and purified to obtain yellow oily liquid
Body 160g, yield 98.5%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
Embodiment 8：
By N,N-dimethylformamide 89g（120mol%）With chlorobenzene 200ml put into one equipped with thermometer, reflux condenser,
In dropping funel and churned mechanically 1000ml three-necked bottle flask, reduce temperature of reaction system to 0 DEG C stir 1 hour, keep
Triphosgene be passed through speed be 2 gram/minutes, keep reaction temperature be no more than 4 DEG C, it is common enter 1.5mol triphosgene.Then add in batches
Enter 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and controls reaction temperature no more than 25 DEG C.After reaction,
It is passed through nitrogen and removes system remnants triphosgene, 120mL 40wt%NaOH aqueous solution quenching reaction is added portionwise into reaction solution, stirs
Mix 50 minutes, then liquid separation removes water phase, and solvent is recovered under reduced pressure in water phase 200ml methylene chloride extraction merging organic phase twice,
Isolated and purified to obtain yellow oily liquid 160g, yield 98.5%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
Embodiment 9：
By 4-dimethylaminopyridine 6.1g（5mol%）One is put into chlorobenzene 200ml, and thermometer, reflux condenser, dropping liquid are housed
In funnel and churned mechanically 1000ml three-necked bottle flask, reduce temperature of reaction system to 0 DEG C stir 1 hour, keep phosgene
Be passed through speed be 2 gram/minutes, keep reaction temperature be no more than 5 DEG C, it is common enter 10.0mol phosgene.Then 2- first is added portionwise
Oxygroup -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and reaction temperature is controlled no more than 25 DEG C.After reaction, it is passed through nitrogen
Gas removes system remnants surpalite, and 200ml water is added portionwise into reaction solution and stirs 50 minutes, then liquid separation removes water phase, water
200ml methylene chloride extraction merging organic phase twice is mutually used, solvent is recovered under reduced pressure, is isolated and purified to obtain yellow oily liquid
157g, yield 97%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
Embodiment 10：
By 4-dimethylaminopyridine 6.1g（5mol%）With dichloroethanes 200ml put into one equipped with thermometer, reflux condenser,
In dropping funel and churned mechanically 1000ml three-necked bottle flask, reduce temperature of reaction system to 0 DEG C stir 1 hour, keep
Phosgene be passed through speed be 2 gram/minutes, keep reaction temperature be no more than 5 DEG C, it is common enter 20.0mol phosgene.Then it is added portionwise
2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and reaction temperature is controlled no more than 25 DEG C.After reaction, lead to
Enter nitrogen and remove system remnants surpalite, 200ml water is added portionwise into reaction solution and stirs 50 minutes, then liquid separation removes water
Phase, water phase 200ml methylene chloride extraction merging organic phase twice, is recovered under reduced pressure solvent, is isolated and purified to obtain yellow oily liquid
Body 157g, yield 97%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
Embodiment 11：
By 4-dimethylaminopyridine 24.4g（20mol%）One is put into chlorobenzene 200ml, and thermometer, reflux condenser, drop are housed
In liquid funnel and churned mechanically 1000ml three-necked bottle flask, reduce temperature of reaction system to 0 DEG C stir 1 hour, keep light
Gas be passed through speed be 2 gram/minutes, keep reaction temperature be no more than 5 DEG C, it is common enter 1.2mol phosgene.Then 2- first is added portionwise
Oxygroup -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and reaction temperature is controlled no more than 25 DEG C.After reaction, it is passed through nitrogen
Gas removes system remnants surpalite, and 200ml water is added portionwise into reaction solution and stirs 50 minutes, then liquid separation removes water phase, water
200ml methylene chloride extraction merging organic phase twice is mutually used, solvent is recovered under reduced pressure, is isolated and purified to obtain yellow oily liquid
158g, yield 97.5%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
Embodiment 12：
By tetrahydrofuran 360g（500mol%）One is put into chlorobenzene 200ml, and thermometer, reflux condenser, dropping funel are housed
And in churned mechanically 1000ml three-necked bottle flask, reduce temperature of reaction system to 0 DEG C stir 1 hour, keep phosgene be passed through
Speed be 2 gram/minutes, keep reaction temperature be no more than 10 DEG C, it is common enter 3.0mol phosgene.Then 2- methoxyl group-is added portionwise
4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and reaction temperature is controlled no more than 25 DEG C.After reaction, it is passed through nitrogen removing
200ml water is added portionwise into reaction solution and stirs 50 minutes for system remnants surpalite, and then liquid separation removes water phase, and water phase is used
200ml methylene chloride extraction merging organic phase twice, is recovered under reduced pressure solvent, is isolated and purified to obtain yellow oily liquid 159g, produces
Rate 98.0%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
Embodiment 13：
By N,N-dimethylformamide 1460g（2000mol%）One is put into chlorobenzene 200ml, and thermometer, reflux condensation mode are housed
In device, dropping funel and churned mechanically 1000ml three-necked bottle flask, reduce temperature of reaction system to 0 DEG C stir 1 hour, protect
Hold phosgene be passed through speed be 2 gram/minutes, keep reaction temperature be no more than 15 DEG C, it is common enter 5.0mol phosgene.Then it is added portionwise
2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and reaction temperature is controlled no more than 25 DEG C.After reaction, lead to
Enter nitrogen and remove system remnants surpalite, 200ml water is added portionwise into reaction solution and stirs 50 minutes, then liquid separation removes water
Phase, water phase 200ml methylene chloride extraction merging organic phase twice, is recovered under reduced pressure solvent, is isolated and purified to obtain yellow oily liquid
Body 160g, yield 98.5%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
Embodiment 14：
By N,N-dimethylformamide 730g（1000mol%）With toluene 200ml put into one equipped with thermometer, reflux condenser,
In dropping funel and churned mechanically 1000ml three-necked bottle flask, reduce temperature of reaction system to 0 DEG C stir 1 hour, keep
Phosgene be passed through speed be 2 gram/minutes, keep reaction temperature be no more than 20 DEG C, it is common enter 10.0mol phosgene.Then it is added portionwise
2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and reaction temperature is controlled no more than 25 DEG C.After reaction, lead to
Enter nitrogen and remove system remnants surpalite, 200ml water is added portionwise into reaction solution and stirs 50 minutes, then liquid separation removes water
Phase, water phase 200ml methylene chloride extraction merging organic phase twice, is recovered under reduced pressure solvent, is isolated and purified to obtain yellow oily liquid
Body 159g, yield 98.0%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
Embodiment 15：
By n,N-Dimethylaniline 1815g（1500mol%）One is put into nitrobenzene 200ml, and thermometer, reflux condensation mode are housed
In device, dropping funel and churned mechanically 1000ml three-necked bottle flask, reduce temperature of reaction system to 0 DEG C stir 1 hour, protect
Hold phosgene be passed through speed be 2 gram/minutes, keep reaction temperature be no more than 5 DEG C, it is common enter 15.0mol phosgene.Then it is added portionwise
2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine 144g (1.0mol), and reaction temperature is controlled no more than 25 DEG C.After reaction, lead to
Enter nitrogen and remove system remnants surpalite, 200ml water is added portionwise into reaction solution and stirs 50 minutes, then liquid separation removes water
Phase, water phase 200ml methylene chloride extraction merging organic phase twice, is recovered under reduced pressure solvent, is isolated and purified to obtain yellow oily liquid
Body 160g, yield 98.5%.
Spectrogram of the spectrogram of prepared product with product in embodiment 1.
It should be understood that above-mentioned specific embodiment of the invention is used only for exemplary illustration or explains of the invention
Principle, but not to limit the present invention.Therefore, that is done without departing from the spirit and scope of the present invention is any
Modification, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.In addition, appended claims purport of the present invention
Covering the whole variations fallen into attached claim scope and boundary or this range and the equivalent form on boundary and is repairing
Change example.
Claims (10)
1. a kind of preparation method of the chloro- 5-FU of 2- methoxyl group -4-, which is characterized in that the method includes：First to basic species
Chlorination reagent is added in matter, adds 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and carries out chlorination reaction, obtain 2- methoxyl group -4-
Chloro- 5-FU, the chlorination reagent are selected from phosgene, surpalite, triphosgene.
2. the preparation method of the chloro- 5-FU of 2- methoxyl group -4- according to claim 1, it is characterised in that：This method
Include the following steps：Alkaline matter is dissolved in solvent, chlorination reagent is added at 0 ~ 30 DEG C, adds 2- methoxyl group -4- hydroxyl
Base -5-FU obtains the chloro- 5-FU of 2- methoxyl group -4-.
3. the preparation method of the chloro- 5-FU of 2- methoxyl group -4- according to claim 1, it is characterised in that：The alkalinity
Substance is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, ammonium carbonate, ammonium hydrogen carbonate, triethylamine, diethylamine, trimethylamine, pyridine, three
Ethamine, N, N- diisopropylethylamine, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, 4-dimethylaminopyridine or N, N-
One of dimethylaniline is a variety of.
4. the preparation method of the chloro- 5-FU of 2- methoxyl group -4- according to claim 3, it is characterised in that：The alkalinity
Substance is selected from triethylamine, N, N- diisopropylethylamine, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, pyridine, 4- diformazan
Aminopyridine or N, one of accelerine or a variety of.
5. the preparation method of the chloro- 5-FU of 2- methoxyl group -4- according to claim 2, it is characterised in that：The solvent
Selected from one of nitrile, glycol, halogenated alkane, aromatic hydrocarbons, halogenated aryl hydrocarbon, nitro-aromatic or a variety of.
6. the preparation method of the chloro- 5-FU of 2- methoxyl group -4- as claimed in claim 5, it is characterised in that：Solvent is selected from second
Nitrile, glycol dimethyl ether, 1,4- dioxane, 1,2- dichloroethanes, 1,1,2,2- tetrachloroethanes, toluene, tetrahydrofuran, 1,4-
One of dioxane, o-dichlorohenzene, methylene chloride, nitrobenzene, chloroform or chlorobenzene are a variety of.
7. the preparation method of the chloro- 5-FU of 2- methoxyl group -4- according to claim 1 to 2, it is characterised in that：The 2-
Methoxyl group -4- hydroxyl-5-fluorine pyrimidine, alkaline matter the mass ratio of the material example be 1：0. 05 ~ 20, the 2- methoxyl group -4- hydroxyl
The concentration of base -5-FU in a solvent is 1.0-30.0mol/L.
8. the preparation method of the chloro- 5-FU of 2- methoxyl group -4- according to claim 1 to 2, it is characterised in that：The 2-
Methoxyl group -4- hydroxyl-5-fluorine pyrimidine, alkaline matter the mass ratio of the material example be 1：0.05-2.5, the 2- methoxyl group -4- hydroxyl
The concentration of base -5-FU in a solvent is 3 ~ 10mol/L.
9. the preparation method of the chloro- 5-FU of 2- methoxyl group -4- according to claim 1 to 2, it is characterised in that：Phosgene is made
When for chlorination reagent, the molar ratio of 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and phosgene is 1:0.9~20；Surpalite is as chlorination
When reagent, the molar ratio of 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and surpalite is 1:0.45~10；Triphosgene is as chlorination reagent
When, the molar ratio of 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and triphosgene is 1:0.3~6.
10. the preparation method of the chloro- 5-FU of 2- methoxyl group -4- according to claim 1 to 2, it is characterised in that：Work as light
When gas is as chlorination reagent, the molar ratio of 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and phosgene is 1:1~3；When surpalite is as chlorine
When changing reagent, the molar ratio of 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and surpalite is 1:0.5~1.5；When triphosgene is as chlorination
When reagent, the molar ratio of 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidine and triphosgene is 1:0.33~1.
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| CN111548314A (en) * | 2020-05-22 | 2020-08-18 | 上海万巷制药有限公司 | Production method of N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitro-4-quinazolinamine |
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| CN102432547A (en) * | 2011-11-22 | 2012-05-02 | 太仓市运通化工厂 | Method for synthetizing 4,6-dichloro-2-methyl pyridine |
| 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 |
| CN105646368A (en) * | 2016-03-03 | 2016-06-08 | 深圳诺普信农化股份有限公司 | Preparation method of 2, 4-dichloro-5-methoxy pyrimidine |
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| CN102432547A (en) * | 2011-11-22 | 2012-05-02 | 太仓市运通化工厂 | Method for synthetizing 4,6-dichloro-2-methyl pyridine |
| 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 |
| CN105646368A (en) * | 2016-03-03 | 2016-06-08 | 深圳诺普信农化股份有限公司 | Preparation method of 2, 4-dichloro-5-methoxy pyrimidine |
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| CN111548314A (en) * | 2020-05-22 | 2020-08-18 | 上海万巷制药有限公司 | Production method of N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitro-4-quinazolinamine |
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