CN110396065A - A kind of synthetic method of the chloro- 5- pyrimidine formyl chloride of 2,4- bis- - Google Patents
A kind of synthetic method of the chloro- 5- pyrimidine formyl chloride of 2,4- bis- Download PDFInfo
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- CN110396065A CN110396065A CN201910556183.8A CN201910556183A CN110396065A CN 110396065 A CN110396065 A CN 110396065A CN 201910556183 A CN201910556183 A CN 201910556183A CN 110396065 A CN110396065 A CN 110396065A
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- pyrimidine
- chloro
- bis
- formyl chloride
- synthetic method
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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
- C07D239/30—Halogen atoms or nitro radicals
Abstract
The present invention provides the synthetic method of chloro- 5- pyrimidine formyl chloride of 2,4- of one kind bis-, and synthesis step is as follows: taking urea pyrimidine -5- formic acid, phosphorus oxychloride and phosphorus pentachloride and mixes, is warming up to back flow reaction；After the completion of back flow reaction, cooling boils off excessive phosphorus oxychloride；Vacuum distillation obtains sterling.The present invention generates the chloro- 5- pyrimidine formyl chloride of 2,4- bis- using commercially available urea pyrimidine -5- formic acid as raw material, through superchlorination single step reaction；The starting material of reaction has a large amount of commercialization supplies, cheap and easy to get, and auxiliary material is recyclable to be applied, hence it is evident that while reducing cost, is avoided pollution of the noxious material to environment in production process, is improved the safety in operating process；Yield greatly improves, and effectively shortens the time, and easy to operate, postprocessing working procedures are simplified.
Description
Technical field
The invention belongs to medicine intermediate fields, and in particular to the synthetic method of the chloro- 5- pyrimidine formyl chloride of 2,4- of one kind bis-.
Background technique
Pyrimidine ring is drug, one of most common heterocycle in natural products.Pyrimidine heterocyclic compounds are such as synthesizing
The intermediate of drug has important application in field of medicaments, is widely used in anticancer drug, the research and development of anti-AIDS drug etc.
Clinically.That there are synthetic routes is long for the synthetic method of the chloro- 5- pyrimidine formyl chloride of existing 2,4- bis-, yield is low, material toxicity is big
And the shortcomings that environmental pollution.
Therefore, a kind of synthetic thread section, high income, and the synthetic method with high security are developed in view of the above problems
It is those skilled in the art institute urgent need to solve the problem.
Summary of the invention
To solve the above problems, the invention discloses the synthetic methods of the chloro- 5- pyrimidine formyl chloride of 2,4- of one kind bis-.
In order to achieve the above object, the invention provides the following technical scheme:
The synthetic method of the chloro- 5- pyrimidine formyl chloride of 2,4- of one kind bis-, synthesis step are as follows:
(1) urea pyrimidine -5- formic acid, phosphorus oxychloride and phosphorus pentachloride are taken and is mixed, back flow reaction is warming up to；
(2) after the completion of back flow reaction, cooling boils off excessive phosphorus oxychloride；
(3) vacuum distillation obtains sterling；
The above reaction equation are as follows:
Further, the weight ratio of urea pyrimidine -5- formic acid, phosphorus oxychloride and phosphorus pentachloride is 1:4-6 in step (1):
3-6。
Further, the mixed method of urea pyrimidine -5- formic acid, phosphorus oxychloride and phosphorus pentachloride is as follows: first that urea is phonetic
Pyridine -5- formic acid is scattered in phosphorus oxychloride, is cooled to 5-10 DEG C, is added phosphorus pentachloride and is completed mixing.
Further, the temperature of back flow reaction is 100-120 DEG C in step (1), when reaction a length of 4-8h.
Further, phosphorus oxychloride is removed by distillation under vacuum in step (2).
Compared with prior art, the present invention 2 are generated through superchlorination single step reaction using commercially available urea pyrimidine -5- formic acid as raw material,
The chloro- 5- pyrimidine formyl chloride of 4- bis-；The starting material of reaction has a large amount of commercialization supplies, cheap and easy to get, and auxiliary material is recyclable to be applied, bright
It is aobvious while reduce cost, pollution of the noxious material to environment in production process is avoided, the safety in operating process is improved
Property；Yield greatly improves, and effectively shortens the time, and easy to operate, postprocessing working procedures are simplified.
Specific embodiment
Technical solution provided by the invention is described in detail below with reference to specific embodiment, it should be understood that following specific
Embodiment is only illustrative of the invention and is not intended to limit the scope of the invention.
Embodiment 1:
The present embodiment provides the synthetic method of the chloro- 5- pyrimidine formyl chloride of 2,4- of one kind bis-, synthesis step is as follows:
(1) it first disperses 125g urea pyrimidine -5- formic acid in 445ml phosphorus oxychloride, is cooled to 5-10 DEG C, adds
600g phosphorus pentachloride completes mixing, is warming up to 105 DEG C of progress back flow reactions, reacts duration 5h；
(2) after the completion of back flow reaction, cooling removes excessive phosphorus oxychloride by distillation under vacuum；
(3) vacuum distillation obtains sterling 168g, and purity is greater than 97%, yield 92%.
Embodiment 2:
The present embodiment provides the synthetic method of the chloro- 5- pyrimidine formyl chloride of 2,4- of one kind bis-, synthesis step is as follows:
(1) it first disperses 125g urea pyrimidine -5- formic acid in 300ml phosphorus oxychloride, is cooled to 5-10 DEG C, adds
400g phosphorus pentachloride completes mixing, is warming up to 100 DEG C of progress back flow reactions, reacts duration 6h；
(2) after the completion of back flow reaction, cooling removes excessive phosphorus oxychloride by distillation under vacuum；
(3) vacuum distillation obtains sterling 170g, and purity is greater than 97%, yield 93%.
Embodiment 3:
The present embodiment provides the synthetic method of the chloro- 5- pyrimidine formyl chloride of 2,4- of one kind bis-, synthesis step is as follows:
(1) it first disperses 125g urea pyrimidine -5- formic acid in 400ml phosphorus oxychloride, is cooled to 5-10 DEG C, adds
500g phosphorus pentachloride completes mixing, is warming up to 100 DEG C of progress back flow reactions, reacts duration 7h；
(2) after the completion of back flow reaction, cooling removes excessive phosphorus oxychloride by distillation under vacuum；
(3) vacuum distillation obtains sterling 177g, and purity is greater than 97%, yield 96.8%.
Finally, it should be noted that property technical side the above examples are only used to illustrate the technical scheme of the present invention and are not limiting
Case, those skilled in the art should understand that, modification or equivalent replacement of the technical solution of the present invention are made for those, and
The objective and range for not departing from the technical program, are intended to be within the scope of the claims of the invention.
Claims (5)
1. one kind 2, the synthetic method of the chloro- 5- pyrimidine formyl chloride of 4- bis-, it is characterised in that: synthesis step is as follows:
(1) urea pyrimidine -5- formic acid, phosphorus oxychloride and phosphorus pentachloride are taken and is mixed, back flow reaction is warming up to；
(2) after the completion of back flow reaction, cooling boils off excessive phosphorus oxychloride；
(3) vacuum distillation obtains sterling；
The above reaction equation are as follows:
2. a kind of synthetic method of the chloro- 5- pyrimidine formyl chloride of 2,4- bis- according to claim 1, it is characterised in that: described
The weight ratio of urea pyrimidine -5- formic acid, phosphorus oxychloride and phosphorus pentachloride is 1:4-6:3-6 in step (1).
3. a kind of synthetic method of the chloro- 5- pyrimidine formyl chloride of 2,4- bis- according to claim 2, it is characterised in that: described
The mixed method of urea pyrimidine -5- formic acid, phosphorus oxychloride and phosphorus pentachloride is as follows: dispersing three for urea pyrimidine -5- formic acid first
In chlorethoxyfos, it is cooled to 5-10 DEG C, phosphorus pentachloride is added and completes mixing.
4. a kind of synthetic method of the chloro- 5- pyrimidine formyl chloride of 2,4- bis- according to claim 1, it is characterised in that: described
The temperature of back flow reaction is 100-120 DEG C in step (1), when reaction a length of 4-8h.
5. a kind of synthetic method of the chloro- 5- pyrimidine formyl chloride of 2,4- bis- according to claim 1, it is characterised in that: described
Phosphorus oxychloride is removed by distillation under vacuum in step (2).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1675225A (en) * | 2002-08-21 | 2005-09-28 | 舍林股份公司 | Macrocyclic pyrimidines, their production and use as pharmaceutical agents |
| CN101808996A (en) * | 2007-09-28 | 2010-08-18 | 赛诺菲-安万特 | Nicotinamide derivatives, preparation thereof and therapeutic use thereof |
| CN104341388A (en) * | 2013-10-16 | 2015-02-11 | 上海润诺生物科技有限公司 | Aromatic amide derivative as well as preparation method and medicinal application thereof |
| CN105592850A (en) * | 2013-08-06 | 2016-05-18 | H·李·莫菲特癌症中心研究所公司 | Inhibitors of ACK1/TNK2 tyrosine kinase |
-
2019
- 2019-06-25 CN CN201910556183.8A patent/CN110396065A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1675225A (en) * | 2002-08-21 | 2005-09-28 | 舍林股份公司 | Macrocyclic pyrimidines, their production and use as pharmaceutical agents |
| CN101808996A (en) * | 2007-09-28 | 2010-08-18 | 赛诺菲-安万特 | Nicotinamide derivatives, preparation thereof and therapeutic use thereof |
| CN105592850A (en) * | 2013-08-06 | 2016-05-18 | H·李·莫菲特癌症中心研究所公司 | Inhibitors of ACK1/TNK2 tyrosine kinase |
| CN104341388A (en) * | 2013-10-16 | 2015-02-11 | 上海润诺生物科技有限公司 | Aromatic amide derivative as well as preparation method and medicinal application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 唐除痴等: "磷氯化物(PCl_3,PCl_5,POCl_3)作为氯化试剂在有机合成中应用的研究进展", 《化学研究》 * |
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