CN106083734A - A kind of method preparing 2 chloropyrimide 4 formic acid - Google Patents
A kind of method preparing 2 chloropyrimide 4 formic acid Download PDFInfo
- Publication number
- CN106083734A CN106083734A CN201610605863.0A CN201610605863A CN106083734A CN 106083734 A CN106083734 A CN 106083734A CN 201610605863 A CN201610605863 A CN 201610605863A CN 106083734 A CN106083734 A CN 106083734A
- Authority
- CN
- China
- Prior art keywords
- reaction
- methylpyrimidine
- chloro
- preparing
- chloropyrimide
- 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.)
- Pending
Links
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
- C07D239/30—Halogen atoms or nitro radicals
Abstract
The present invention relates to a kind of method preparing 2 chloropyrimide 4 formic acid, including operating as follows: 2 chlorine 4 methylpyrimidine hydrochlorates and phosphorus oxychloride are carried out desalination acid reaction, isolated 2 chlorine 4 methylpyrimidine；2 chlorine 4 methylpyrimidines and methyl oxidation agent are carried out methyl oxidation reaction, isolated 2 chloropyrimide 4 formic acid.The process route of above-mentioned offer, the synthetic ratio of its target product is high, and process route can be amplified, and raw material is easy to get and inexpensively, can carry out industrialized production.
Description
Technical field
The present invention relates to compou nd synthesis field, be specifically related to a kind of method preparing 2-chloropyrimide-4 formic acid.
Background technology
2-chloropyrimide-4-formic acid may be used for treating hyperphosphatemia and the key of synthesis benzsulfamide pyrazole kinase inhibitors
Intermediate.But there is presently no the report about the synthesis of 2-chloropyrimide-4 formic acid, it is therefore necessary to provide one to prepare 2-chlorine
The method of pyrimidine-4 formic acid.
Summary of the invention
It is an object of the invention to provide a kind of method preparing 2-chloropyrimide-4 formic acid, it is phonetic that it can effectively produce 2-chlorine
Pyridine-4 formic acid, provides foundation for industrialized production.
For achieving the above object, present invention employs techniques below scheme:
A kind of method preparing 2-chloropyrimide-4 formic acid, including operating as follows:
S1: chloro-for 2-4-methylpyrimidine hydrochlorate and phosphorus oxychloride are carried out desalination acid reaction, isolated 2-chloro-4-first
Yl pyrimidines；
S2: chloro-for 2-4-methylpyrimidine and methyl oxidation agent are carried out methyl oxidation reaction, isolated 2-chloropyrimide-4 first
Acid.
2, the method for preparing 1,2,3-thiadiazoles-4-carboxylic acids according to claim 1, it is characterised in that step
In rapid S2, methyl oxidation agent is potassium permanganate or selenium dioxide.
Further scheme is:
The concrete operations of step S1 are: chloro-to Phosphorous chloride. and 2-4-methylpyrimidine hydrochlorate is mixed and heated to 80 DEG C, drip
Adding triethylamine and carry out desalination acid reaction, reaction is lowered the temperature after terminating, and reactant is poured into after cooling decomposition phosphorus oxychloride in trash ice, with
Rear addition dichloroethanes disperses reaction system and is 6～7 with sodium hydroxide solution regulation PH, is subsequently adding ethyl acetate extraction point
From reclaim organic facies, to reclaim organic facies decolour successively, sucking filtration, evaporation and concentration process obtain 2-chloro-4-methylpyrimidine.
The concrete operations of step S2 are: by chloro-for 2-4-methylpyrimidine and potassium permanganate hot water dissolving, the solution after dissolving
Dropping to carry out in potassium hydroxide solution methyl oxidation reaction, it is colourless that reaction adds sodium sulfite to reactant liquor after terminating,
Being subsequently adding dichloromethane extract and separate and reclaim unreacted raw material, be subsequently added suction filtered through kieselguhr, the filtrate after sucking filtration is with dense
Hydrochloric acid regulation PH to 2～3, is then concentrated to dryness, and uses methanol that the product after concentrating is carried out reflux, extract, and methanol is concentrated into half
After dry, cold filtration obtains 2-chloropyrimide-4 formic acid.
The concrete operations of step S2 are: by chloro-for 2-4-methylpyrimidine, dichloro six ring, selenium dioxide mixing back flow reaction, instead
Less than 80 DEG C should be heated up to after terminating and cross kieselguhr filtration while hot, the filtrate after filtering is concentrated and use cold sodium hydroxide
Solution regulation PH to more than 8, then adds ethyl acetate extract and separate and reclaims aqueous phase, regulate aqueous phase PH to less than 2 with concentrated hydrochloric acid, with
Reclaim aqueous phase by dichloromethane extract and separate afterwards and be concentrated to dryness, using methanol that the product after concentrating is carried out reflux, extract, first
Alcohol is concentrated into half-dried rear cold filtration and obtains 2-chloropyrimide-4 formic acid.
2-chloropyrimide-4 formic acid production technology of above-mentioned offer, it is workable, and raw material is easy to get, and process conditions are prone to control
System, can be used for industrialized production.
Accompanying drawing explanation
Fig. 1 is the collection of illustrative plates of 2-chloropyrimide-4 formic acid.
Detailed description of the invention
In order to make objects and advantages of the present invention clearer, below in conjunction with embodiment, the present invention is carried out specifically
Bright.Should be appreciated that following word only in order to describe one or more specific embodiments of the present invention, not to the present invention
The protection domain of concrete request carries out considered critical.
Embodiment 1
In 10L reaction bulb, add the raw material A of the phosphorus oxychloride of 4.09kg, 1.6Kg, be heated to 80 degree；Dropping 2.22kg
Triethylamine (dropping easily slow stifled), close heating, maintain temperature by exothermic heat of reaction；After dripping off, 100-105 DEG C of reaction 4h, TLC
Monitoring.Reaction is cooled to 30 DEG C after terminating and carries out post processing.
Post processing is: be poured slowly into by reactant liquor in 40L trash ice, decomposes phosphorus oxychloride；Add the dispersion of 2L dichloroethanes anti-
Answer system, it is simple to pour out material, adjust PH=6-7 with 30% sodium hydroxide subsequently；Add 4L ethyl acetate to extract 3 times, merge extraction
Take the organic facies of separation, and with obtaining 970g red brown solid product with dried active carbon decoloring, sucking filtration, Rotary drying successively.Inspection
Survey result: fusing point about 45 degree, HPLC:220nm, 60:40,97.6% theory: 1403g, yield: 69.1%.
In 20L reaction bulb, add the potassium hydroxide aqueous solution of 100g/3L, be subsequently adding the compound B of 250g, 650g's
Drop to after potassium permanganate hot water dissolving in bottle, with about water 15L.During dropping, temperature controls at 5-15 DEG C, drip off rear 20 DEG C anti-
24h, TLC is answered to monitor (raw material reaction is the completeest).
Reaction terminates to add in backward reactant the sodium sulfite of 120g, stirs 15min, and reactant liquor stands a period of time
For colourless, if not adding sodium sulfite again.Add the extraction of 4L dichloromethane to separate and recover unreacted raw material for 3 times and (reclaim former
Material 40g).Then adding suction filtered through kieselguhr in aqueous phase, filtrate regulates pH=2-3 with concentrated hydrochloric acid, stirs 30min, is concentrated to dryness.
Said synthesis route is:
Embodiment 2
In 10L reaction bulb, add the raw material A of the phosphorus oxychloride of 4.09kg, 1.6Kg, be heated to 80 degree；Dropping 2.22kg
Triethylamine (dropping easily slow stifled), close heating, maintain temperature by exothermic heat of reaction；After dripping off, 100-105 DEG C of reaction 4h, TLC
Monitoring.Reaction is cooled to 30 DEG C after terminating and carries out post processing.
Post processing is: be poured slowly into by reactant liquor in 40L trash ice, decomposes phosphorus oxychloride；Add the dispersion of 2L dichloroethanes anti-
Answer system, it is simple to pour out material, adjust PH=6-7 with 30% sodium hydroxide subsequently；Add 4L ethyl acetate to extract 3 times, merge extraction
Take the organic facies of separation, and with obtaining 970g red brown solid product with dried active carbon decoloring, sucking filtration, Rotary drying successively.Inspection
Survey result: fusing point about 45 degree, HPLC:220nm, 60:40,97.6% theory: 1403g, yield: 69.1%.
1,4-dichloro six ring and the titanium dioxide of 109.66g of compound B, 1035mL of 69g is added in 2L four-hole boiling flask
Selenium.Finishing, system back flow reaction, reaction: EA:PE=1:1 followed the tracks of by some plate.
After reaction terminates, reaction system is cooled to less than 80 DEG C and twice of the silicon bath soil of warming up, with cold after filtrate concentration
Sodium hydrate aqueous solution adjust after PH>8, be extracted with ethyl acetate 3 times, the aqueous phase of recovery adjusts PH<after 2, with two with concentrated hydrochloric acid again
Chloromethanes repeatedly extracts, and reclaims and merge aqueous phase and concentrate dry after extraction.
Said synthesis route is:
Embodiment 3
Merging concentrating dry product in embodiment 1 and embodiment 2, add 3L*2 methanol eddy and extract product, methanol is dense
It is reduced to half-dried, cold filtration, obtain product 250g, mother liquor concentrations does to obtain crude product 60g, yield 44%, records collection of illustrative plates such as Fig. 1 of product
Shown in.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For Yuan, after knowing content described in the present invention, under the premise without departing from the principles of the invention, it is also possible to it is made some
Equal conversion and replacement, these convert on an equal basis and substitute and also should be regarded as belonging to protection scope of the present invention.
Claims (8)
1. the method preparing 2-chloropyrimide-4 formic acid, including operating as follows:
S1: chloro-for 2-4-methylpyrimidine hydrochlorate and phosphorus oxychloride are carried out desalination acid reaction, and isolated 2-chloro-4-methyl is phonetic
Pyridine；
S2: chloro-for 2-4-methylpyrimidine and methyl oxidation agent are carried out methyl oxidation reaction, isolated 2-chloropyrimide-4 formic acid.
Method for preparing 1,2,3-thiadiazoles-4-carboxylic acids the most according to claim 1, it is characterised in that step S2
Middle methyl oxidation agent is potassium permanganate or selenium dioxide.
Method for preparing 1,2,3-thiadiazoles-4-carboxylic acids the most according to claim 1, it is characterised in that step S1
Concrete operations be: chloro-to Phosphorous chloride. and 2-4-methylpyrimidine hydrochlorate is mixed and heated to 80 DEG C, dropping triethylamine take off
Hydrochloric acid reaction, reaction is lowered the temperature after terminating, and reactant is poured into after cooling decomposition phosphorus oxychloride in trash ice, is subsequently added dichloroethanes
Dispersion reaction system and with sodium hydroxide solution regulation PH be 6～7, be subsequently adding ethyl acetate extract and separate reclaim organic facies,
Decolour the organic facies reclaimed successively, sucking filtration, evaporation and concentration process and obtain 2-chloro-4-methylpyrimidine.
Method for preparing 1,2,3-thiadiazoles-4-carboxylic acids the most according to claim 1 and 2, it is characterised in that step
The concrete operations of S2 are: by chloro-for 2-4-methylpyrimidine and potassium permanganate hot water dissolving, the solution after dissolving drops to hydroxide
Carrying out methyl oxidation reaction in potassium solution, it is colourless that reaction adds sodium sulfite to reactant liquor after terminating, and is subsequently adding dichloro
Methane extract and separate reclaims unreacted raw material, is subsequently added suction filtered through kieselguhr, and the filtrate after sucking filtration regulates PH to 2 with concentrated hydrochloric acid
～3, then it being concentrated to dryness, use methanol that the product after concentrating is carried out reflux, extract, methanol is concentrated into half-dried rear cold filtration
Obtain 2-chloropyrimide-4 formic acid.
Method for preparing 1,2,3-thiadiazoles-4-carboxylic acids the most according to claim 1 and 2, it is characterised in that step
The concrete operations of S2 are: by chloro-for 2-4-methylpyrimidine, dichloro six ring, selenium dioxide mixing back flow reaction, reaction is heated after terminating
To less than 80 DEG C and add while hot kieselguhr filter, to filter after filtrate concentrate and use cold sodium hydroxide solution regulate PH extremely
More than 8, then add ethyl acetate extract and separate and reclaim aqueous phase, regulate aqueous phase PH to less than 2 with concentrated hydrochloric acid, use dichloromethane subsequently
Extract and separate reclaims aqueous phase and is concentrated to dryness, and uses methanol that the product after concentrating is carried out reflux, extract, and methanol is concentrated into half-dried
Rear cold filtration obtains 2-chloropyrimide-4 formic acid.
Method for preparing 1,2,3-thiadiazoles-4-carboxylic acids the most according to claim 3, it is characterised in that step S1
In: the Phosphorous chloride. of 4.09g and the 2-of 1.6Kg chloro-4-methylpyrimidine hydrochlorate are mixed and heated to 80 DEG C, the three of dropping 2.22Kg
Ethamine, 100～105 DEG C of reaction 4h after dripping off.
Method for preparing 1,2,3-thiadiazoles-4-carboxylic acids the most according to claim 4, it is characterised in that step S2
In: by chloro-for the 2-of 250g 4-methylpyrimidine and the potassium permanganate hot water dissolving of 650g, the solution after dissolving drops to hydroxide
In potassium solution, potassium hydroxide solution be 100g potassium hydroxide and 3L water configuration obtain, drip rear 20 DEG C reaction 24h.
Method for preparing 1,2,3-thiadiazoles-4-carboxylic acids the most according to claim 5, it is characterised in that step S2
In: the selenium dioxide of chloro-for the 2-of 69g 4-methylpyrimidine, 1,4-dichloro six ring of 1035mL and 109.66g is mixed and refluxes
Reaction.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610605863.0A CN106083734A (en) | 2016-07-28 | 2016-07-28 | A kind of method preparing 2 chloropyrimide 4 formic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610605863.0A CN106083734A (en) | 2016-07-28 | 2016-07-28 | A kind of method preparing 2 chloropyrimide 4 formic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106083734A true CN106083734A (en) | 2016-11-09 |
Family
ID=57479271
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610605863.0A Pending CN106083734A (en) | 2016-07-28 | 2016-07-28 | A kind of method preparing 2 chloropyrimide 4 formic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106083734A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110642789A (en) * | 2019-11-25 | 2020-01-03 | 天津凯莱英制药有限公司 | Continuous synthesis method of 2-chloropyrimidine-4-formic acid compound |
| CN111393376A (en) * | 2020-05-11 | 2020-07-10 | 安徽赛迪生物科技有限公司 | Synthetic method of 2-chloropyrimidine-4-formic acid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5591853A (en) * | 1992-01-24 | 1997-01-07 | Lonza Ltd. | Products of a microbiological process for the production of 2-halo-pyrimidine-4-carboxylic acids |
-
2016
- 2016-07-28 CN CN201610605863.0A patent/CN106083734A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5591853A (en) * | 1992-01-24 | 1997-01-07 | Lonza Ltd. | Products of a microbiological process for the production of 2-halo-pyrimidine-4-carboxylic acids |
Non-Patent Citations (3)
| Title |
|---|
| CHRISTER B. AAKERÖY，ET AL.: "Robust building blocks for inorganic crystal engineering", 《INORGANICA CHIMICA ACTA》 * |
| DONGSHENG DENG，ET AL.: "Syntheses, Photoluminescent Properties, and Structural Investigation of Five Complexes based on a NewT-Shaped 2-(Pyridin-3-yl)-4,6-Pyrimidine Dicarboxylic Acid Ligand: Structure Evolution from One-dimensional Chains to Three-dimensional Architectures", 《AUST.J.CHEM.》 * |
| 马养民等: "杂环氨基酸酯的合成与表征", 《食品工业科技》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110642789A (en) * | 2019-11-25 | 2020-01-03 | 天津凯莱英制药有限公司 | Continuous synthesis method of 2-chloropyrimidine-4-formic acid compound |
| CN110642789B (en) * | 2019-11-25 | 2020-05-26 | 天津凯莱英制药有限公司 | Continuous synthesis method of 2-chloropyrimidine-4-formic acid compound |
| WO2021103256A1 (en) * | 2019-11-25 | 2021-06-03 | 天津凯莱英制药有限公司 | Continuous synthesis method for 2-chloropyrimidine-4-formic acid compound |
| CN111393376A (en) * | 2020-05-11 | 2020-07-10 | 安徽赛迪生物科技有限公司 | Synthetic method of 2-chloropyrimidine-4-formic acid |
| CN111393376B (en) * | 2020-05-11 | 2022-05-13 | 安徽赛迪生物科技有限公司 | Synthetic method of 2-chloropyrimidine-4-formic acid |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104496983B (en) | A kind of preparation method of Pa Boxini | |
| ES2564204T3 (en) | Pyrrolopyridinyl-pyrimidin-2-yl-amine derivatives | |
| NO814454L (en) | PROCEDURE FOR THE PREPARATION OF NEW PIPERAZINOKINAZOLINE DERIVATIVES | |
| TW200404786A (en) | Chemical process | |
| CN106083734A (en) | A kind of method preparing 2 chloropyrimide 4 formic acid | |
| CN105524045A (en) | Tetracyclic anaplastic lymphoma kinase inhibitor | |
| CN105566215A (en) | Preparation method of Stivarga | |
| CN106146560B (en) | A kind of refining methd of high-purity phosphoric acid specially azoles amine | |
| CN104130307B (en) | Close O-(Pyrrolidine base) ethyl derivative, the preparation method and its usage of flowers and trees ketone Cleistanone | |
| CN107879986A (en) | A kind of synthetic method of avanaphil impurity | |
| CN110981816A (en) | Synthesis method of 4-amino-2, 6-dimethoxypyrimidine | |
| CN106632081A (en) | 5-chloro-6-(chloromethyl) uracil and preparation method thereof | |
| CN107522742A (en) | A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediates | |
| CN106008362A (en) | Preparation method of novel pyrimidine derivative | |
| CN103664885A (en) | Preparation method of benzimidazole proton pump inhibitor intermediate | |
| CN109232579B (en) | Method for synthesizing pemetrexed intermediate pemetrexed benzoic acid | |
| CN105669539B (en) | A kind of preparation process of 2- amino -3- fluorine pyridines | |
| CN106831733B (en) | Preparation method and application of afatinib cis-isomer | |
| CN105061327A (en) | Synthetic method of long-acting sulfonamide | |
| CN114874232B (en) | Preparation method and application of thienopyrimidinone compound containing ethyl naphthalene structure | |
| CN108997350A (en) | A kind of 8 inhibitor of cyclin-dependent kinase | |
| CN109996800B (en) | Crystal of pyrido [3,4-d ] pyrimidine derivative or solvate thereof | |
| CN107652230A (en) | A kind of EEDQ 6 of 2 methoxyl group 7,8（5H）The synthetic method of ketone | |
| CN109705119B (en) | Preparation method of risperidone chloride | |
| CN112778215B (en) | 2-methoxyphenoxypyrimidine antitumor compound and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20161109 |