CN110041269A - A kind of preparation method of the chloro- 5- hydroxy pyrimidine of 2- - Google Patents
A kind of preparation method of the chloro- 5- hydroxy pyrimidine of 2- Download PDFInfo
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- CN110041269A CN110041269A CN201910408684.1A CN201910408684A CN110041269A CN 110041269 A CN110041269 A CN 110041269A CN 201910408684 A CN201910408684 A CN 201910408684A CN 110041269 A CN110041269 A CN 110041269A
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- pyrimidine
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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 present invention relates to a kind of preparation methods of the chloro- 5- hydroxy pyrimidine of 2-, characterized by the following steps: 2- chloro-5-methoxyl pyrimidine and organic acid solvent step a, are added in reaction vessel, it is stirring evenly and then adding into hydrobromic acid and methionine, stirring is warming up to back flow reaction 3-8h；Step b, it is cooled to room temperature after reaction, adds water, merge organic phase afterwards for several times with solvent extraction；Step c, organic phase is washed and is dried, then carried out concentration and purification obtains faint yellow solid target product.The invention has the benefit that the proportion of raw material is optimized, so that product impurity content is substantially reduced；Demethylating reaction is carried out instead of Boron tribromide with hydrobromic acid-methionine system, so that the cost-effective reduction of raw material, the purity of product and the yield of reaction greatly improve.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to the preparation method of the chloro- 5- hydroxy pyrimidine of 2-.
Background technique
Pyrimidines are a kind of important nitrogen-containing heterocycle compounds, since its structure is special, so that miazines chemical combination
Object has very high bioactivity, such compound has the function of antimycotic, promotion plant growth regulating.In recent years, as
The pyrimidines of pesticide emerge one after another, including Insecticides (tech) & Herbicides (tech) and fungicide.The chloro- 5- hydroxy pyrimidine of 2- is synthesis 2-
The important source material of (substituent phenoxy) -5- hydroxyl pyridine compound is widely used in antimycotic equal organic chemistry and drug
Field.Currently, the method for the synthesis chloro- 5- hydroxy pyrimidine of 2- reported in the literature is used using 2- chloro-5-methoxyl pyrimidine as raw material
Boron tribromide carries out demethylating reaction, this route is low with reaction temperature, expensive reagents and dosage are big, at high cost, and yield is low,
And Boron tribromide easily decomposes and is not easy the disadvantages of depositing long.Add sulfuric acid reaction, gained as another route 5- amino -2- chlorine pyrimidine
For the yield of product between 25%-33%, yield is very low.
Therefore, it is badly in need of a kind of improved technology to solve problems of the prior art.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the disadvantages mentioned above of the prior art, provide a kind of chloro- 5- hydroxyl of 2-
The preparation method of pyrimidine, the raw material which uses is cheap and readily available, can greatly reduce production cost, reaction condition temperature
With, securely and reliably, particularly suitable industrialized production.
In order to solve the above technical problems, a kind of preparation method of the chloro- 5- hydroxy pyrimidine of 2- provided by the invention, feature
Be the following steps are included:
Step a, 2- chloro-5-methoxyl pyrimidine and organic acid solvent are added in reaction vessel, be stirring evenly and then adding into hydrobromic acid and
Methionine, stirring are warming up to back flow reaction 3-8h；
Step b, it is cooled to room temperature after reaction, adds water, merge organic phase afterwards for several times with solvent extraction；
Step c, organic phase is washed and is dried, then carried out concentration and purification obtains the production of faint yellow solid target
Object.
Chemical equation are as follows:
Further, the present invention also has the feature that
1, in step a, hydrobromic acid adds 0.5-8 times, preferably 1.2-2 times that quality is 2- chloro-5-methoxyl pyrimidine quality.
2, in step a, the addition quality of methionine is 0.001-0.5 times of 2- chloro-5-methoxyl pyrimidine quality, preferably
0.01-0.12 times.
3, in step c, it is described using saturation sodium bicarbonate solution to organic phase wash, then using anhydrous sodium sulfate into
Row dries, filters, and crude product is concentrated under reduced pressure to obtain in organic phase, and faint yellow solid target product is obtained after purification.
4, the method for purification is that methanol, ethyl alcohol, isopropanol, acetone, dioxane, chlorine are added into resulting crude product
One of imitative or several mixing carries out recrystallization purification.
The invention has the benefit that (1) this method optimizes the proportion of raw material, so that product impurity content obviously drops
It is low；(2) this method carries out demethylating reaction instead of Boron tribromide with hydrobromic acid-methionine system, so that the cost of raw material has
The reduction of effect, the purity of product and the yield of reaction greatly improve.
Specific embodiment
In order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below in conjunction with the embodiment of the present invention
In technical solution of the present invention is clearly and completely described.
Embodiment 1
Prepare the four-hole boiling flask that 1L has agitating device and thermometer, 2- chloro-5-methoxyl pyrimidine 100g, 300mL acetic acid is added
It is added in reaction flask, stirs evenly, 48% hydrobromic acid of 800g and 1g methionine is then added, is warming up to back flow reaction 5h, sample
It is controlled in HPLC, until reaction terminates, product content 80%, dihydroxy by-product 15%；It is down to room temperature, 300mL is added in reaction solution
Water three times with the extraction of 300mL methylene chloride merges organic phase, is washed using the sodium bicarbonate solution of saturation, then with anhydrous sulphur
Sour sodium is dried, and after filtering, crude product is concentrated under reduced pressure to obtain in organic phase；Ethyl alcohol recrystallization is added in crude product and obtains faint yellow solid
64g, yield 70%, purity 98%.
Embodiment 2
Prepare the four-hole boiling flask that 1L has agitating device and thermometer, 2- chloro-5-methoxyl pyrimidine 100g, 300mL acetic acid is added
It is added in reaction flask, stirs evenly, 48% hydrobromic acid of 300g and 1g methionine is then added, is warming up to back flow reaction 5h, sample
It is controlled in HPLC, until reaction terminates, product content 92%, dihydroxy by-product 5%；It is down to room temperature, 300mL is added in reaction solution
Water three times with the extraction of 300mL methylene chloride merges organic phase, is washed using the sodium bicarbonate solution of saturation, then with anhydrous sulphur
Sour sodium is dried, and after filtering, crude product is concentrated under reduced pressure to obtain in organic phase；Ethyl alcohol recrystallization is added in crude product and obtains faint yellow solid
74g, yield 80%, purity 98%.
Embodiment 3
Prepare the four-hole boiling flask that 1L has agitating device and thermometer, 2- chloro-5-methoxyl pyrimidine 100g, 300mL acetic acid is added
It is added in reaction flask, stirs evenly, 48% hydrobromic acid of 153g and 1g methionine is then added, is warming up to back flow reaction 5h, sample
It is controlled in HPLC, until reaction terminates, product content 96%, dihydroxy by-product 0.5%；It is down to room temperature, 300mL is added in reaction solution
Water three times with the extraction of 300mL methylene chloride merges organic phase, is washed using the sodium bicarbonate solution of saturation, then with anhydrous sulphur
Sour sodium is dried, and after filtering, crude product is concentrated under reduced pressure to obtain in organic phase；Ethyl alcohol recrystallization is added in crude product and obtains faint yellow solid
82g, yield 91%, purity 98%.
Embodiment 4
Prepare the four-hole boiling flask that 1L has agitating device and thermometer, 2- chloro-5-methoxyl pyrimidine 100g, 300mL acetic acid is added
It is added in reaction flask, stirs evenly, 48% hydrobromic acid of 153g and 0.5g methionine is then added, is warming up to back flow reaction 5h, takes
It is controlled in sample HPLC, until reaction terminates, product content 70%, dihydroxy by-product 23%；It is down to room temperature, is added in reaction solution
300mL water three times with the extraction of 300mL ethyl acetate merges organic phase, is washed using the sodium bicarbonate solution of saturation, is then used
After anhydrous sodium sulfate dries, filters, crude product is concentrated under reduced pressure to obtain in organic phase；Ethyl alcohol recrystallization is added in crude product and obtains faint yellow solid
57.3g, yield 61%, purity 98%.
It is compared by test data, hydrobromic acid adds 0.5-8 times that quality is 2- chloro-5-methoxyl pyrimidine quality, egg ammonia
The addition quality of acid is 0.001-0.5 times of 2- chloro-5-methoxyl pyrimidine quality, can industrially realize the method for the present invention.
Preferably, hydrobromic acid addition quality is 1.2-2 times of 2- chloro-5-methoxyl pyrimidine quality, the addition quality of methionine is 2-
0.01-0.12 times of chloro-5-methoxyl pyrimidine quality, can obtain preferable yield.
In addition to the implementation, the present invention can also have other embodiments.It is all to use equivalent substitution or equivalent transformation shape
At technical solution, fall within the scope of protection required by the present invention.
Claims (9)
1. a kind of preparation method of the chloro- 5- hydroxy pyrimidine of 2-, it is characterised in that the following steps are included:
Step a, 2- chloro-5-methoxyl pyrimidine and organic acid solvent are added in reaction vessel, be stirring evenly and then adding into hydrobromic acid and
Methionine, stirring are warming up to back flow reaction 3-8h；
Step b, it is cooled to room temperature after reaction, adds water, merge organic phase afterwards for several times with solvent extraction；
Step c, organic phase is washed and is dried, then carried out concentration and purification obtains the production of faint yellow solid target
Object.
2. the preparation method of the chloro- 5- hydroxy pyrimidine of 2- according to claim 1, it is characterised in that: in step a, the hydrogen
Bromic acid mass percent concentration is 48%, and hydrobromic acid adds 0.5-8 times that quality is 2- chloro-5-methoxyl pyrimidine quality.
3. the preparation method of the chloro- 5- hydroxy pyrimidine of 2- according to claim 2, it is characterised in that: hydrobromic acid adds quality
It is 1.2-2 times of 2- chloro-5-methoxyl pyrimidine quality.
4. the preparation method of the chloro- 5- hydroxy pyrimidine of 2- according to claim 1, it is characterised in that: described to have in step a
Machine sour solvent is one of acetic acid, propionic acid, butyric acid.
5. the preparation method of the chloro- 5- hydroxy pyrimidine of 2- according to claim 1, it is characterised in that: in step a, methionine
Addition quality be 0.001-0.5 times of 2- chloro-5-methoxyl pyrimidine quality.
6. the preparation method of the chloro- 5- hydroxy pyrimidine of 2- according to claim 5, it is characterised in that: in step a, methionine
Addition quality be 0.01-0.12 times of 2- chloro-5-methoxyl pyrimidine quality.
7. the preparation method of the chloro- 5- hydroxy pyrimidine of 2- according to claim 1, it is characterised in that: in step b, extract institute
It is one of methylene chloride, ethyl acetate, tetrahydrofuran, methanol with solvent.
8. the preparation method of the chloro- 5- hydroxy pyrimidine of 2- according to claim 1, it is characterised in that: described to make in step c
Organic phase is washed with the sodium bicarbonate solution of saturation, is then dried using anhydrous sodium sulfate, is filtered, organic phase decompression is dense
Contract to obtain crude product, and faint yellow solid target product is obtained after purification.
9. the preparation method of the chloro- 5- hydroxy pyrimidine of 2- according to claim 8, it is characterised in that: the method for purification
For one of methanol, ethyl alcohol, isopropanol, acetone, dioxane, chloroform or several mixing are added into resulting crude product
Carry out recrystallization purification.
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Citations (7)
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| CN101679235A (en) * | 2007-05-10 | 2010-03-24 | 辉瑞有限公司 | Azetidine derivatives and their use as prostaglandin E2 antagonists |
| CN102209710A (en) * | 2008-11-10 | 2011-10-05 | 辉瑞股份有限公司 | Pyrrolidines |
| CN102639495A (en) * | 2009-10-06 | 2012-08-15 | 百时美施贵宝公司 | Pyrrolidine GPR40 Modulators |
| CN102898397A (en) * | 2012-09-26 | 2013-01-30 | 江苏华益科技有限公司 | Synthesis method of (4aR,10bR)-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazine-9-ol substance and hydrochloride thereof |
| CN103113378A (en) * | 2013-02-20 | 2013-05-22 | 北京华素制药股份有限公司 | Synthesis method of oxymorphone hydrochloride |
| CN104628582A (en) * | 2015-01-29 | 2015-05-20 | 济南爱思医药科技有限公司 | Preparation method of desvenlafaxine hydrochloride |
| CN105829321A (en) * | 2013-12-31 | 2016-08-03 | 靳博涵 | Novel compounds for the treatment of cancer and inflammatory diseases |
-
2019
- 2019-05-16 CN CN201910408684.1A patent/CN110041269A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101679235A (en) * | 2007-05-10 | 2010-03-24 | 辉瑞有限公司 | Azetidine derivatives and their use as prostaglandin E2 antagonists |
| CN102209710A (en) * | 2008-11-10 | 2011-10-05 | 辉瑞股份有限公司 | Pyrrolidines |
| CN102639495A (en) * | 2009-10-06 | 2012-08-15 | 百时美施贵宝公司 | Pyrrolidine GPR40 Modulators |
| CN102898397A (en) * | 2012-09-26 | 2013-01-30 | 江苏华益科技有限公司 | Synthesis method of (4aR,10bR)-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazine-9-ol substance and hydrochloride thereof |
| CN103113378A (en) * | 2013-02-20 | 2013-05-22 | 北京华素制药股份有限公司 | Synthesis method of oxymorphone hydrochloride |
| CN105829321A (en) * | 2013-12-31 | 2016-08-03 | 靳博涵 | Novel compounds for the treatment of cancer and inflammatory diseases |
| CN104628582A (en) * | 2015-01-29 | 2015-05-20 | 济南爱思医药科技有限公司 | Preparation method of desvenlafaxine hydrochloride |
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Application publication date: 20190723 |