CN114591250A - One-step synthesis method of 5-bromo-2-chloropyrimidine - Google Patents
One-step synthesis method of 5-bromo-2-chloropyrimidine Download PDFInfo
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- XPGIBDJXEVAVTO-UHFFFAOYSA-N 5-bromo-2-chloropyrimidine Chemical compound ClC1=NC=C(Br)C=N1 XPGIBDJXEVAVTO-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000001308 synthesis method Methods 0.000 title claims abstract description 16
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 82
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical group ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 45
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims abstract description 34
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000010438 heat treatment Methods 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 21
- 150000001412 amines Chemical class 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 10
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims abstract description 8
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000000746 purification Methods 0.000 claims abstract description 8
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 claims abstract description 4
- PEAOEIWYQVXZMB-UHFFFAOYSA-N 5-bromo-2-chloropyridine Chemical compound ClC1=CC=C(Br)C=N1 PEAOEIWYQVXZMB-UHFFFAOYSA-N 0.000 claims abstract description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 38
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 19
- 238000001035 drying Methods 0.000 claims description 9
- 102000016938 Catalase Human genes 0.000 claims description 6
- 108010053835 Catalase Proteins 0.000 claims description 6
- 238000007664 blowing Methods 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 29
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 28
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 28
- 229910052794 bromium Inorganic materials 0.000 abstract description 28
- 238000009776 industrial production Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 38
- 238000002360 preparation method Methods 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000000779 smoke Substances 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000012362 glacial acetic acid Substances 0.000 description 9
- 230000000391 smoking effect Effects 0.000 description 7
- 238000004364 calculation method Methods 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- 238000004321 preservation Methods 0.000 description 6
- VTUDATOSQGYWML-UHFFFAOYSA-N 5-bromo-1h-pyrimidin-2-one Chemical compound OC1=NC=C(Br)C=N1 VTUDATOSQGYWML-UHFFFAOYSA-N 0.000 description 5
- 238000005660 chlorination reaction Methods 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000004973 liquid crystal related substance Substances 0.000 description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000012320 chlorinating reagent Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003344 environmental pollutant Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000009533 lab test Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 231100000719 pollutant Toxicity 0.000 description 2
- 208000002815 pulmonary hypertension Diseases 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960003065 bosentan Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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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
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a one-step synthesis method of 5-bromo-2-chloropyrimidine. The method comprises the following steps: taking 2-hydroxypyrimidine and hydrobromic acid as raw materials, carrying out heating reaction under the catalysis of hydrogen peroxide, then carrying out purification treatment to obtain an intermediate, taking the intermediate and chloride as raw materials, carrying out heating reaction under the catalysis of organic amine, and then purifying to obtain 5-bromo-2-chloropyridine; the chloride is phosphorus oxychloride; the organic amine is triethylamine and/or diisopropylethylamine and/or N, N-dimethylaniline and/or N, N-dimethylbenzylamine. The invention greatly simplifies the production flow of the 5-bromo-2-chloropyrimidine, optimizes the synthetic route, greatly improves the production efficiency, and can improve the production efficiency by more than 4 times in the actual industrial production flow; by optimizing and improving the synthesis route, the effective utilization rate of the bromine can be improved by more than 100 percent compared with the traditional reaction system.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a one-step synthesis method of 5-bromo-2-chloropyrimidine.
Background
Marxitemtan is a small molecule drug developed by Actelion Pharmaceuticals Ltd, and is an ETAR antagonist and an ETBR antagonist. At present, the highest research and development stage of the medicine is approved to be on the market and is used for treating pulmonary hypertension and pulmonary hypertension.
In the preparation process of the McStriptan, 5-bromo-2-chloropyrimidine is an important intermediate. At present, the bromine addition of the 2-hydroxypyrimidine is realized by the reaction of a glacial acetic acid/bromine system, but the utilization rate of bromine element in the actual industrial production of the reaction system is low, and meanwhile, because bromine vapor has strong irritation, corrosivity and harmfulness, and glacial acetic acid has strong volatility, the volatilization of bromine is simultaneously caused by the volatilization of the glacial acetic acid in the traditional reaction system, the harm to human bodies is generated, and the environment is polluted.
Meanwhile, the existing preparation system needs to carry out multiple times of reflux heat treatment, the whole reaction process is slow, and the efficiency is low.
Disclosure of Invention
In order to solve the problems of low raw material utilization rate, low efficiency, easy large pollution, obvious harm to human bodies and the like of the existing 5-bromo-2-chloropyrimidine preparation system, the invention provides a one-step synthesis method of 5-bromo-2-chloropyrimidine.
The main purposes of the invention are as follows:
firstly, the preparation of 5-bromo-2-chloropyrimidine can be realized rapidly and efficiently;
secondly, pollution and harm generated in the preparation process are reduced;
and thirdly, the effective utilization rate of the raw materials is improved.
In order to achieve the purpose, the invention adopts the following technical scheme.
A one-step synthesis method of 5-bromo-2-chloropyrimidine,
the method comprises the following steps:
taking 2-hydroxypyrimidine and hydrobromic acid as raw materials, carrying out heating reaction under the catalysis of hydrogen peroxide, then carrying out purification treatment to obtain an intermediate, taking the intermediate and chloride as raw materials, carrying out heating reaction under the catalysis of organic amine, and then purifying to obtain 5-bromo-2-chloropyridine; the chloride is phosphorus oxychloride;
the organic amine is triethylamine and/or diisopropylethylamine and/or N, N-dimethylaniline and/or N, N-dimethylbenzylamine.
In the technical scheme of the invention, a hydrogen peroxide and hydrobromic acid system is adopted to replace the traditional glacial acetic acid and bromine system, and hydrogen peroxide and hydrogen bromide do not have too strong volatility as bromine and glacial acetic acid. Therefore, a great amount of corrosive and hazardous gas generated in the traditional glacial acetic acid/bromine system is not generated, and the pollution and the harm to human bodies in the production process are reduced.
On the other hand, compared with the long-time reflux heating required by the traditional scheme, the reaction time can be remarkably shortened to within 24 hours, the reaction time of a traditional reaction system is usually as long as 48-72 hours, and effective gas purification is required in the actual industrial production process, so that the actual production efficiency needs 3-4 days to complete the preparation of one batch of products. The method of the invention does not need gas purification, the whole reaction process can be integrated and finished in one step, the actual production efficiency can be controlled within 24h to finish the preparation of one batch of products, and the production efficiency is improved by more than 4 times in the actual industrial production process.
In addition, in the two-stage reaction process, the selection of the chloride and the organic amine can also influence the product yield and the preparation efficiency more obviously. The phosphorus oxychloride which is a single chloride is specially selected in the invention, mainly because the volatilization needs to be strictly controlled, the utilization rate of raw materials is improved, and the pollution and the harm of volatile gas are reduced, while conventional chlorinating agents such as phosphorus pentachloride and the like have the test results that the phosphorus pentachloride cannot realize the effective chlorination of an intermediate, namely cannot realize the reaction to obtain a target product, and has extremely serious fuming phenomenon.
As a preference, the first and second liquid crystal compositions are,
the molar ratio of the 2-hydroxypyrimidine to the hydrogen bromide in the hydrobromic acid is 1: (1-3);
the concentration of the hydrobromic acid is 20-50 wt%.
When the molar ratio of the 2-hydroxypyrimidine to the hydrogen bromide in the hydrobromic acid is controlled to be lower, the effective utilization rate of bromine in the hydrobromic acid can be effectively improved. Tests show that when the consumption of the hydrogen bromide is lower than the range, the utilization rate of the bromine cannot be further improved, but the yield of the product is influenced and remarkably reduced, and when the consumption of the hydrogen bromide is further increased, the improvement of the yield of the product is not remarkable, but the utilization rate of the bromine is remarkably reduced.
Meanwhile, since high-concentration hydrobromic acid has a certain fuming phenomenon like high-concentration hydrochloric acid, i.e. has strong volatility, it is necessary to control the concentration within the above range in order to ensure the product yield, the utilization rate of bromine and reduce volatilization pollution.
Preferably, the concentration of the hydrogen peroxide is 10-50 wt%, and the molar ratio of the hydrogen peroxide to the 2-hydroxypyrimidine in the hydrogen peroxide is controlled to be (1-5): 1.
the relative molar ratio of the hydrogen peroxide to the hydrogen bromide is actually required to be controlled to be at least more than or equal to 1 so as to ensure the effective utilization rate of bromine in the hydrogen bromide, and therefore, the practical control of the molar ratio has relatively good use effect. In addition, the concentration of hydrogen peroxide can also affect the catalytic effect of the actual hydrogen peroxide, the low concentration can cause low catalytic efficiency and reduce the overall reaction efficiency, and the high concentration can easily cause side reaction and reduce the utilization rate of the actual bromine element.
In addition, in order to ensure that the subsequent chlorination reaction is carried out more smoothly and improve the product yield, the molar ratio of the hydrogen peroxide to the 2-hydroxypyrimidine is preferably (1.5-5): 1, so as to ensure that the hydrogen peroxide is relatively excessive, greatly improve the utilization rate of the hydrogen bromide and reduce the residual hydrogen peroxide as much as possible.
As a preference, the first and second liquid crystal compositions are,
in the process of heating reaction under the catalysis of hydrogen peroxide, the reaction temperature is 30-100 ℃.
The invention adopts relatively low reaction temperature to carry out direct heating reaction, does not need complex and high-temperature reaction equipment, actually reduces the production and reaction cost and improves the production safety. And the lower reaction temperature is controlled, so that the method plays an important role in maintaining the high utilization rate of bromine and reducing the volatilization of raw materials.
Meanwhile, the reaction temperature is related to the concentration of hydrobromic acid, the concentration of hydrogen peroxide and the like, and a relatively low reaction temperature can be selected when the relative concentration of hydrogen peroxide is higher. In order to avoid volatilization, the reaction temperature is optimally controlled within the range of 30-60 ℃, and the reaction is carried out by heating in a warm water bath.
As a preference, the first and second liquid crystal compositions are,
the purification treatment comprises the following steps:
adding catalase, reacting for at least 30min, cooling to be less than or equal to 10 ℃, filtering under reduced pressure, and drying by blowing air for 4-6 h at the temperature of 70-85 ℃.
In the technical scheme of the invention, only a small amount of hydrogen bromide remains in the hydrogen bromide reaction, so that the components such as catalase and hydrogen bromide can be more effectively removed by matching a blowing drying mode with reduced-pressure filtration.
As a preference, the first and second liquid crystal compositions are,
the molar ratio of the phosphorus oxychloride to the 2-hydroxypyrimidine is (1-5): 1.
the yield of the product can be ensured to be higher by controlling the component molar ratio of the intermediate to the chloride. And the actual chloride can be recycled after the reaction is completed.
Preferably, the molar ratio of the organic amine to the 2-hydroxypyrimidine is (0.6-2): 1, carrying out heating reaction at 50-120 ℃ under the catalysis of organic amine.
The organic amine is catalyzed to react at a relatively low temperature, and the method has the advantages of safety, high efficiency, energy conservation and the like.
The invention has the beneficial effects that:
1) the production process of the 5-bromo-2-chloropyrimidine is greatly simplified, the synthetic route is optimized, the production efficiency is greatly improved, and the production efficiency in the actual industrial production process can be improved by more than 4 times;
2) by optimizing and improving the synthesis route, the effective utilization rate of the bromine element can be improved by more than 100 percent compared with the traditional reaction system, and can reach more than 300 percent of the traditional reaction system at most;
3) the reaction process is clean and pollution-free, the energy consumption is low, and the economic benefit of industrial production is greatly improved.
Drawings
FIG. 1 is a schematic diagram of the reaction process of the present invention.
Detailed Description
The invention is described in further detail below with reference to specific embodiments and the attached drawing figures. Those skilled in the art will be able to implement the invention based on these teachings. Moreover, the embodiments of the present invention described in the following description are generally only some embodiments of the present invention, and not all embodiments. Therefore, all other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present invention without any creative effort shall fall within the protection scope of the present invention.
Unless otherwise specified, the raw materials used in the examples of the present invention are all commercially available or available to those skilled in the art; unless otherwise specified, the methods used in the examples of the present invention are all those known to those skilled in the art.
Specifically, the reaction process from 2-hydroxypyrimidine to intermediate 5-bromo-2-hydroxypyrimidine and then to target product 5-bromo-2-chloropyrimidine according to the technical scheme of the present invention is schematically shown in fig. 1.
Example 1
A one-step synthesis method of 5-bromo-2-chloropyrimidine comprises the following steps:
112.1g (1mol) of 2-hydroxypyrimidine are taken and the 2-hydroxypyrimidine is mixed with 404.6g of 20% strength by weight hydrobromic acid in a molar ratio of hydrogen bromide to 2-hydroxypyrimidine of 1: 1, adding 340g of hydrogen peroxide with the concentration of 10 wt%, wherein the molar ratio of the hydrogen peroxide to the 2-hydroxypyrimidine in the hydrogen peroxide is 1: 1; heating to 100 ℃ in a reaction vessel, and carrying out heat preservation reaction for 8h to obtain 5-bromo-2-hydroxypyrimidine;
adding catalase according to the proportion of 150IU/mL of reaction solution, reacting for 30min, cooling to be less than or equal to 10 ℃, filtering under reduced pressure to remove filtrate, and drying by blowing at 75 ℃ for 5 h;
153.3g (1mol) of phosphorus oxychloride and 60.7g (0.6mol) of triethylamine are added into a reaction vessel, and the reaction vessel is heated to 120 ℃ for reaction for 8 hours under the condition of heat preservation, thus completing the preparation of 5-bromo-2-chloropyrimidine.
Almost no smoke phenomenon exists in the whole reaction process.
And (4) extracting by adopting methane, crystallizing and drying, calculating the yield of the 5-bromo-2-chloropyrimidine, and detecting the purity by HPLC. Through calculation and detection, the molar weight of the obtained 5-bromo-2-chloropyrimidine product is 182.02g (about 0.941mol), the yield is about 94.1% (the yield is calculated according to the theoretical yield of the 2-hydroxypyrimidine), and the analysis result shows that the purity of the product reaches 98.2%. The effective utilization rate of bromine in hydrobromic acid is calculated to be 98 percent, and the utilization rate calculation method comprises the following steps:
the calculation formula of the effective rate of the subsequent bromine is the same as that described above.
Example 2
A one-step synthesis method of 5-bromo-2-chloropyrimidine comprises the following steps:
112.1g (1mol) of 2-hydroxypyrimidine are taken and the 2-hydroxypyrimidine is mixed with 462.3g of 35% strength by weight hydrobromic acid, the molar ratio of hydrogen bromide to 2-hydroxypyrimidine in the hydrobromic acid being 2: 1, adding 226.7g of 30 wt% hydrogen peroxide, wherein the molar ratio of hydrogen peroxide to 2-hydroxypyrimidine in the hydrogen peroxide is 2: 1; heating the mixture to 40 ℃ in a reaction vessel, and carrying out heat preservation reaction for 12 hours to obtain 5-bromo-2-hydroxypyrimidine;
adding catalase according to the proportion of 150IU/mL of reaction solution, reacting for 30min, cooling to be less than or equal to 10 ℃, filtering under reduced pressure to remove filtrate, and drying by blowing air at 85 ℃ for 4 h;
191.7g (1.25mol) of phosphorus oxychloride and 65.8g (0.65mol) of triethylamine are added into the reaction vessel, and the reaction vessel is heated to 80 ℃ for reaction for 6 hours under the condition of heat preservation, thus completing the preparation of 5-bromo-2-chloropyrimidine.
Almost no smoke phenomenon exists in the whole reaction process.
And (4) extracting by adopting methane, crystallizing and drying, calculating the yield of the 5-bromo-2-chloropyrimidine, and detecting the purity by HPLC. The molar weight of the obtained 5-bromo-2-chloropyrimidine product is 186.08g (about 0.962mol) through calculation and detection, the yield is about 96.2%, and the analysis result shows that the purity reaches 98.4%. The effective utilization of bromine in hydrobromic acid was 96%.
Example 3
A one-step synthesis method of 5-bromo-2-chloropyrimidine comprises the following steps:
112.1g (1mol) of 2-hydroxypyrimidine are taken and the 2-hydroxypyrimidine is mixed with 485.5g of 50% strength by weight hydrobromic acid, the molar ratio of hydrogen bromide to 2-hydroxypyrimidine in the hydrobromic acid being 3: 1, adding 340g of 50 wt% hydrogen peroxide, wherein the molar ratio of hydrogen peroxide to 2-hydroxypyrimidine in hydrogen peroxide is 5: 1; heating to 30 ℃ in a reaction vessel, and carrying out heat preservation reaction for 14h to obtain 5-bromo-2-hydroxypyrimidine;
adding catalase according to the proportion of 150IU/mL of reaction solution, reacting for 30min, cooling to be less than or equal to 10 ℃, filtering under reduced pressure to remove filtrate, and drying by air blast at 70 ℃ for 6 h;
766.7g (5mol) of phosphorus oxychloride and 202.4g (2mol) of triethylamine are added into the reaction vessel, and the reaction vessel is heated to 50 ℃ for 5 hours of heat preservation reaction, thus completing the preparation of 5-bromo-2-chloropyrimidine.
Almost no smoke phenomenon exists in the whole reaction process.
And (4) extracting by adopting methane, crystallizing and drying, calculating the yield of the 5-bromo-2-chloropyrimidine, and detecting the purity by HPLC. Through calculation and detection, the molar weight of the obtained 5-bromo-2-chloropyrimidine product is 192.27g (about 0.994mol), the yield is about 99.4%, and the analysis result shows that the purity of the product reaches 98.9%. The effective utilization rate of bromine in hydrobromic acid is 95%.
Example 4
Based on the technical scheme of the embodiment 2, the types of the chlorinating agents are selectively replaced, the following equal doses (calculated by the molar weight of chlorine element, for example, the equal dose of 1.25mol of phosphorus oxychloride and the like is 0.75mol of phosphorus pentachloride) are selected, and the other preparation parameters are kept unchanged. The yield, purity, and macroscopic white smoke phenomenon were recorded as shown in the table below.
In the table: in the smoking phenomenon symbols, "-" indicates almost no smoking phenomenon, "+" indicates the presence of significant smoking phenomenon, and "+" indicates the presence of intense smoking phenomenon.
The product yield calculation process comprises the following steps:
it can be found from the table that most of the chlorinating agents for chlorination substitution can not be realized, and meanwhile, the phosphorus oxychloride has irreplaceable specificity in the aspect of fuming phenomenon. Phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride and the like are easy to smoke, but in the unique preparation system of the invention, the smoke inhibition on the phosphorus oxychloride is not recorded before, and in order to improve the efficiency of preparation and production and reduce the harm to the environment, the phosphorus oxychloride has irreplaceable uniqueness on the technical scheme of the invention from all aspects.
Example 5
Based on the technical scheme of the embodiment 2, the hydrobromic acid concentration (concentration a), the molar ratio of hydrogen bromide to 2-hydroxypyrimidine (denoted as molar ratio a), the hydrogen peroxide concentration (concentration B), and the molar ratio of hydrogen peroxide to 2-hydroxypyrimidine (denoted as molar ratio B) were subjected to adjustment tests, and the optimal selection range of the scheme system of the present invention was examined, and the other preparation parameters were kept unchanged. The yield, purity, and macroscopic white smoke phenomenon were recorded as shown in the table below.
In the table: in the smoking phenomenon symbols, "-" indicates no smoking phenomenon, and "+" indicates the presence of significant smoking phenomenon.
It can be seen that the two experimental examples in which the fuming phenomenon was present, compared to example 2, were mainly changed in two significant points by increasing the hydrobromic acid concentration to 60 wt% and decreasing the molar ratio of hydrogen peroxide to 2-hydroxypyrimidine to 0.5: 1. it has thus been found that fuming is primarily a result of heated hydrobromic acid during the reaction, and that the hydrogen bromide produced by volatilization is toxic and harmful, hazardous, polluting to humans and to the environment and therefore needs to be suppressed. Hydrogen peroxide is used as a catalyst, and when the concentration of hydrogen peroxide is too high, fuming is not generated, but hydrogen peroxide is easy to generate impurities due to strong chemical activity, so that the yield and the purity of the product are reduced, when the amount of hydrogen peroxide is too small, the reaction process is slow, and under the heating condition, hydrobromic acid finally generates a certain fuming phenomenon. According to the test record, the fuming phenomenon is generated within the time range of about 20-120 min after the reaction starts, the expectation is relatively met, and the reaction process is promoted under the condition of sufficient hydrogen peroxide, so that the fuming phenomenon cannot be generated. However, under the conditions of low hydrogen peroxide content and heating, white smoke was gradually generated in the transparent glass container after about 20 minutes as the temperature was kept, and white smoke was gradually disappeared as the hydrogen bromide concentration decreased with the progress of the reaction.
Therefore, reasonable control of the concentration of hydrobromic acid, the molar ratio of hydrogen bromide, the concentration of hydrogen peroxide and the molar ratio of hydrogen peroxide plays an important role in controlling the yield and the purity of products and inhibiting fuming in the production process.
Example 6
Based on the technical scheme of the embodiment 2, the purification treatment mode is adjusted.
Specifically, the comparison is performed by an extraction crystallization method, a recrystallization method, or the like. Wherein, the extraction crystallization method adopts a proper solvent to extract 5-bromo-2-hydroxypyrimidine and then crystallize, and the recrystallization method is carried out by firstly crystallizing, then washing, dissolving and recrystallizing. The yield, purity and fuming (heating of the chlorination) of the target product were recorded and are shown in the following table.
| Method | Yield of product | Purity of the product | Phenomenon of smoke formation |
| Example 2 | 96.2％ | 98.4％ | - |
| Extractive crystallization process | 95.4％ | 97.9％ | ++ |
| Recrystallization process | 91.3％ | 97.2％ | + |
Compared with the method, the technical scheme of the invention has very obvious effect on controlling and reducing pollution in the whole industrial production.
Example 7
Based on the technical scheme of the embodiment 2, the phosphorus oxychloride, the triethylamine and the relative dosage of the phosphorus oxychloride and the triethylamine are adjusted. The yield, purity and fuming (heating of the chlorination) of the target product were recorded and are shown in the following table.
| Phosphorus oxychloride dosage | Amount of triethylamine | Yield of the product | Purity of the product | Phenomenon of smoke formation |
| 1.25mol | 0.65mol | 96.2％ | 98.4％ | - |
| 0.5mol | 0.65mol | 46.9％ | 94.3％ | - |
| 1.0mol | 0.65mol | 96.9％ | 95.2％ | - |
| 1.25mol | 0.8mol | 97.0％ | 94.3％ | - |
| 5.5mol | 0.65mol | 98.4％ | 98.7％ | ++ |
| 5.5mol | 2.05mol | 98.6％ | 99.1％ | + |
| 5.5mol | 2.2mol | 98.3％ | 96.6％ | + |
As can be seen from the above table, the phosphorus oxychloride must not be below the theoretical minimum amount (i.e., 1: 1 molar ratio) otherwise it will have a dramatic effect on the product yield. The triethylamine can be seen to have a certain effect of inhibiting fuming (accelerating reaction consumption), but under the condition of excessive phosphorus oxychloride consumption, the fuming phenomenon cannot be effectively inhibited by adopting more triethylamine, which indicates that the fuming phenomenon is inhibited by the combined action of the triethylamine and the residual solvent system of the pre-reaction, and cannot be simply inhibited by accelerating reaction adjustment. In addition, the dosage of triethylamine is not suitable to be too large, and the purity of the product is relatively reduced if the dosage of triethylamine is too large.
And after a large number of laboratory tests, any one or more organic amine catalysts selected by the invention, including triethylamine and/or diisopropylethylamine and/or N, N-dimethylaniline and/or N, N-dimethylbenzylamine, have similar phenomena. In addition, for the relative dosage of organic amine and phosphorus oxychloride, in order to ensure that the product purity can reach higher 98% or more, research and development personnel summarize the following rule.
The optimal molar amount of the organic amine catalyst is controlled to accord with the rule formula, so that the purity of the target product can be ensured to reach more than 98% in a plurality of laboratory tests which are carried out at present, and the preparation method has relatively excellent preparation effect.
Record of the specific industrialized production process
Through tests, the optimal production parameters should refer to the parameters of example 2 in consideration of the utilization rate of raw materials, the recovery rate, the use cost performance of various auxiliaries, the production cycle and the like.
Using the manufacturing preparation parameters of example 2, randomly selected 4d records from 28d before the production line and an average of 28d records were recorded as follows.
| Number of days marked | Production cycle | Yield of product | Purity of the product | Utilization ratio of bromine |
| Week 1, day 6 | 20h | 97.3％ | 98.1％ | 96％ |
| Week 2, day 4 | 20h | 97.9％ | 98.2％ | 97％ |
| Week 3, day 1 | 20h | 97.2％ | 98.0％ | 96％ |
| Week 4, day 4 | 20h | 98.0％ | 97.8％ | 96％ |
| Mean of 28 days | 20h | 97.81％ | 98.06％ | 96.69％ |
According to the production records, the product yield can be basically maintained between 97 and 98 percent, the product yield is extremely high, the product purity can be basically and stably maintained above 98 percent, the integral product quality is ensured to meet the expectation, and the extremely excellent industrial preparation effect can be realized.
On the other hand, compared with the traditional bromine/glacial acetic acid system, the feedback from the workshop shows that the white smoke phenomenon does not occur again in the workshop after the novel process is adopted, and the emission of gas-liquid pollutants can be obviously reduced according to the pollutant emission detection, so that the process has great significance for environmental protection.
Comparative example
Compared with the original bromine/glacial acetic acid system production record.
The average values in the original production records are shown in the table below.
| Production cycle | Yield of product | Purity of the product | Bromine utilization rate |
| 4.36 days | 97.69％ | 98.12％ | 43.11％ |
Through the comparison, the invention can be found that the product yield is improved, the product purity is slightly reduced, but in other aspects, especially in the production period and the bromine utilization rate, the production period can be obviously shortened by more than four times, the bromine utilization rate is improved by more than 120 percent, and the improvement effect is very obvious. And a large amount of volatile harmful substances generated by a bromine and glacial acetic acid system are inhibited, and are not obviously discharged, so that the method has the instant technical effect.
In terms of the benefit and cost performance of industrial production, the net yield of the single-day production value can be improved by more than 9 times compared with the original traditional reaction system, the treatment cost of tail gas and waste liquid is greatly reduced, the process cost performance can be greatly improved, and the method has great significance for the benign development of industry and environment.
Claims (7)
1. A one-step synthesis method of 5-bromo-2-chloropyrimidine, which is characterized in that,
the method comprises the following steps:
taking 2-hydroxypyrimidine and hydrobromic acid as raw materials, carrying out heating reaction under the catalysis of hydrogen peroxide, then carrying out purification treatment to obtain an intermediate, taking the intermediate and chloride as raw materials, carrying out heating reaction under the catalysis of organic amine, and then purifying to obtain 5-bromo-2-chloropyridine; the chloride is phosphorus oxychloride;
the organic amine is triethylamine and/or diisopropylethylamine and/or N, N-dimethylaniline and/or N, N-dimethylbenzylamine.
2. The one-step synthesis method of 5-bromo-2-chloropyrimidine according to claim 1,
the molar ratio of the 2-hydroxypyrimidine to the hydrogen bromide in the hydrobromic acid is 1: (1-3);
the concentration of the hydrobromic acid is 20-50 wt%.
3. The one-step synthesis method of 5-bromo-2-chloropyrimidine according to claim 1 or 2,
the concentration of hydrogen peroxide is 10-50 wt%, and the molar ratio of hydrogen peroxide to 2-hydroxypyrimidine in the hydrogen peroxide is controlled to be (1-5): 1.
4. the one-step synthesis method of 5-bromo-2-chloropyrimidine according to claim 1,
in the process of heating reaction under the catalysis of hydrogen peroxide, the reaction temperature is 30-100 ℃.
5. The one-step synthesis method of 5-bromo-2-chloropyrimidine according to claim 1,
the purification treatment comprises the following steps:
adding catalase, reacting for at least 30min, cooling to be less than or equal to 10 ℃, filtering under reduced pressure, and drying by blowing air for 4-6 h at the temperature of 70-85 ℃.
6. The one-step synthesis method of 5-bromo-2-chloropyrimidine according to claim 1,
the molar ratio of the phosphorus oxychloride to the 2-hydroxypyrimidine is (1-5): 1.
7. the one-step synthesis method of 5-bromo-2-chloropyrimidine according to claim 1 or 6,
the molar ratio of the organic amine to the 2-hydroxypyrimidine is (0.6-2): 1, carrying out heating reaction at 50-120 ℃ under the catalysis of organic amine.
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