CN110372605B - Synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine - Google Patents
Synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine Download PDFInfo
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- CN110372605B CN110372605B CN201910551597.1A CN201910551597A CN110372605B CN 110372605 B CN110372605 B CN 110372605B CN 201910551597 A CN201910551597 A CN 201910551597A CN 110372605 B CN110372605 B CN 110372605B
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- GHAWBARMICSLQS-UHFFFAOYSA-N 4,6-dichloro-2-methylsulfanyl-5-nitropyrimidine Chemical compound CSC1=NC(Cl)=C([N+]([O-])=O)C(Cl)=N1 GHAWBARMICSLQS-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000001308 synthesis method Methods 0.000 title description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 14
- 238000005406 washing Methods 0.000 claims abstract description 14
- 238000001816 cooling Methods 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 13
- 238000010438 heat treatment Methods 0.000 claims abstract description 12
- 239000012065 filter cake Substances 0.000 claims abstract description 11
- 230000007935 neutral effect Effects 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 10
- AEXCUJUYEZIWJV-UHFFFAOYSA-N 4-hydroxy-2-methylsulfanyl-1h-pyrimidin-6-one Chemical compound CSC1=NC(O)=CC(=O)N1 AEXCUJUYEZIWJV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000047 product Substances 0.000 claims abstract description 9
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000005457 ice water Substances 0.000 claims abstract description 6
- 238000010189 synthetic method Methods 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 239000003960 organic solvent Substances 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 238000010791 quenching Methods 0.000 claims abstract description 3
- 230000000171 quenching effect Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- 239000002274 desiccant Substances 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- QIPRLPVLUZXMQX-UHFFFAOYSA-N CCCCCC=NCCCN Chemical compound CCCCCC=NCCCN QIPRLPVLUZXMQX-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 claims description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 238000006396 nitration reaction Methods 0.000 abstract description 2
- 231100000614 poison Toxicity 0.000 abstract description 2
- 239000003440 toxic substance Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- -1 pyrimidine heterocyclic compound Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
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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
- C07D239/38—One sulfur atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a synthetic method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine, which comprises the following synthetic steps: adding 2-methylthio-4, 6-dihydroxypyrimidine into fuming nitric acid in batches, stirring at room temperature for 1h, and heating for reaction; after the reaction is finished, cooling to room temperature, slowly pouring into ice water, stirring for 1h, filtering, washing a filter cake to be neutral, digging out and drying to obtain a compound B; mixing the compound B, phosphorus oxychloride and organic alkali, and carrying out chlorination reaction; and after the reaction is finished, cooling the mixture, concentrating under reduced pressure to remove redundant phosphorus oxychloride, adding water for quenching, extracting with an organic solvent, drying, and concentrating to obtain a pure product. The invention uses the commercial raw materials to generate a pure product through nitration and chlorination reaction; the raw materials are commercially supplied in a large quantity, are cheap and easily available, and the auxiliary materials can be recycled, so that the cost is obviously reduced, the pollution of toxic substances to the environment in the production process is avoided, and the safety in the operation process is improved; the yield is greatly improved, the time is effectively shortened, the operation is simple, and the post-treatment process is simplified.
Description
Technical Field
The invention belongs to the field of medical intermediates, and particularly relates to a synthetic method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine.
Background
The pyrimidine ring is one of the most common heterocyclic rings in drugs and natural products. The pyrimidine heterocyclic compound is used as an intermediate for synthesizing the medicaments, has important application in the field of medicines, and is widely applied to research, development and clinic of anti-cancer medicaments, anti-AIDS medicaments and the like. The existing synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine has the defects of long synthesis route, low yield, high raw material toxicity and environmental pollution.
Therefore, the development of a synthetic method with high yield and high safety for the synthetic route section aiming at the above problems is a problem to be solved urgently by those skilled in the art.
Disclosure of Invention
In order to solve the problems, the invention discloses a method for synthesizing 2-methylthio-4, 6-dichloro-5-nitropyrimidine.
In order to achieve the purpose, the invention provides the following technical scheme:
a synthetic method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine comprises the following synthetic steps: (1) adding 2-methylthio-4, 6-dihydroxypyrimidine into fuming nitric acid in batches, stirring at room temperature for 1h, and adding
Carrying out a reaction by heat; (2) after the heating reaction is finished, cooling to room temperature, slowly pouring into ice water, stirring for 1h, filtering, washing a filter cake to be neutral, digging out the filter cake, and drying to obtain a compound B;
(3) mixing the compound B, phosphorus oxychloride and organic alkali, and carrying out chlorination reaction;
(4) after the chlorination reaction is finished, cooling the obtained mixture, reducing the pressure, concentrating to remove redundant phosphorus oxychloride, adding water for quenching, extracting by using an organic solvent, drying, and concentrating to obtain a pure product;
the above reaction formula is:
further, the volume ratio of the 2-methylthio-4, 6-dihydroxypyrimidine to fuming nitric acid in the step (1) is 1: 3.
Further, in the step (1), the reaction is carried out for 4 hours by heating to 50 ℃.
Further, the compound B, the phosphorus oxychloride and the organic base in the step (3) are mixed according to the mass ratio of 1:5-10: 0.3-0.7.
Furthermore, the temperature of the chlorination reaction is 25-100 ℃, and the reaction time is 2-5 h.
Further, the organic solvent in the step (4) is any one of triethylamine, diisopropylethylamine, triisopropylamine, N-dimethylaniline, N-diethylaniline, N-dimethylpyridinylamine, pyridine, 1, 8-diaza-bicyclo (5, 4, 0) undecene-7, bicyclo [ 4.3.0 ] 1, 5-diaza-5-undecene, or a mixture thereof.
Further, the specific method of the step (4) is as follows: after chlorination reaction is finished, cooling the obtained mixture, reducing pressure, concentrating to remove excessive phosphorus oxychloride, slowly pouring the residue into 1kg of crushed ice, stirring for 1h, extracting for 2-3 times by using 200ml of ethyl acetate, combining organic phases, washing with saturated sodium bicarbonate aqueous solution until the pH is neutral, washing with saturated sodium chloride aqueous solution once, drying with anhydrous sodium sulfate, filtering to remove a drying agent, concentrating to obtain a crude product, and recrystallizing with n-hexane to obtain a pure product.
Compared with the prior art, the method takes commercially available 2-methylthio-4, 6-dihydroxypyrimidine as a raw material, and 2-methylthio-4, 6-dichloro-5-nitropyrimidine is generated through nitration and chlorination reaction; the raw materials are commercially supplied in a large quantity, are cheap and easily available, and the auxiliary materials can be recycled, so that the cost is obviously reduced, the pollution of toxic substances to the environment in the production process is avoided, and the safety in the operation process is improved; the yield is greatly improved, the time is effectively shortened, the operation is simple, and the post-treatment process is simplified.
Detailed Description
The technical solutions provided by the present invention will be described in detail below with reference to specific examples, and it should be understood that the following specific embodiments are only illustrative of the present invention and are not intended to limit the scope of the present invention.
Example 1:
this example is a method for synthesizing 2-methylthio-4, 6-dichloro-5-nitropyrimidine, comprising the following steps:
(1) adding 100g of 2-methylthio-4, 6-dihydroxypyrimidine into 300ml of fuming nitric acid in batches, stirring at room temperature for 1h, and heating to 50 ℃ for reaction for 4 h;
(2) after the heating reaction is finished, cooling to room temperature, slowly pouring into ice water, stirring for 1h, filtering, washing a filter cake with water to be neutral, digging out the filter cake, and drying to obtain 110 g of a compound B, wherein the purity is more than 95%, and the yield is 81.3%;
(3) dispersing 100g of compound B in 375ml of phosphorus oxychloride, dropwise adding 50ml of triethylamine at room temperature, and raising the temperature to the reflux temperature for chlorination reaction for 2-5h after the triethylamine is dropwise added;
(4) after chlorination reaction is finished, the obtained mixture is cooled, decompressed, concentrated and removed of redundant phosphorus oxychloride, the residue is slowly poured into 1kg of crushed ice and stirred for 1 hour, extracted for 2-3 times by 200ml of ethyl acetate, organic phases are combined, washed by saturated sodium bicarbonate aqueous solution until the pH is neutral, washed by saturated sodium chloride aqueous solution for one time, dried by anhydrous sodium sulfate, filtered to remove a drying agent and concentrated to obtain a crude product, and normal hexane is recrystallized to obtain 113g of a pure product with the purity of more than 98 percent and the yield of 93.7 percent.
Example 2:
this example is a method for synthesizing 2-methylthio-4, 6-dichloro-5-nitropyrimidine, comprising the following steps:
(1) 200g of 2-methylthio-4, 6-dihydroxypyrimidine are added in portions to 600ml of fuming nitric acid and stirred at room temperature
After 1h, heating to 50 ℃ for reaction for 4 h;
(2) after the heating reaction is finished, cooling to room temperature, slowly pouring into ice water, stirring for 1h, filtering, washing a filter cake with water to be neutral, digging out the filter cake, and drying to obtain 240 g of a compound B, wherein the purity is higher than 95%, and the yield is 88.75%;
(3) dispersing 100g of compound B in 450ml of phosphorus oxychloride, dropwise adding 60ml of diisopropylethylamine at room temperature, and raising the temperature to the reflux temperature for chlorination reaction for 2-5h after the dropwise addition of the diisopropylethylamine is finished;
(4) after chlorination reaction is finished, cooling the obtained mixture, reducing pressure, concentrating to remove excessive phosphorus oxychloride, slowly pouring the residue into 1kg of crushed ice, stirring for 1h, extracting for 2-3 times by using 200ml of ethyl acetate, combining organic phases, washing with saturated sodium bicarbonate aqueous solution until the pH is neutral, washing with saturated sodium chloride aqueous solution once, drying with anhydrous sodium sulfate, filtering to remove a drying agent, concentrating to obtain a crude product, recrystallizing with n-hexane to obtain 118g of a pure product with the purity of more than 98% and the yield of 97.87%.
Example 3:
this example is a method for synthesizing 2-methylthio-4, 6-dichloro-5-nitropyrimidine, comprising the following steps:
(1) 300g of 2-methylthio-4, 6-dihydroxypyrimidine are added in portions to 900ml of fuming nitric acid and stirred at room temperature
After 1h, heating to 50 ℃ for reaction for 4 h;
(2) after the heating reaction is finished, cooling to room temperature, slowly pouring into ice water, stirring for 1h, filtering, washing a filter cake with water to be neutral, digging out the filter cake, and drying to obtain 340 g of a compound B, wherein the purity is more than 95%, and the yield is 91.12%;
(3) dispersing 100g of the compound B in 590ml of phosphorus oxychloride, dropwise adding 70ml of N, N-dimethylaniline at room temperature, and raising the temperature to the reflux temperature for chlorination reaction for 2-5h after the N, N-dimethylaniline is dropwise added;
(4) after chlorination reaction is finished, cooling the obtained mixture, reducing pressure, concentrating to remove excessive phosphorus oxychloride, slowly pouring the residue into 1kg of crushed ice, stirring for 1h, extracting for 2-3 times by using 200ml of ethyl acetate, combining organic phases, washing with saturated sodium bicarbonate aqueous solution until the pH is neutral, washing with saturated sodium chloride aqueous solution once, drying with anhydrous sodium sulfate, filtering to remove a drying agent, concentrating to obtain a crude product, recrystallizing with n-hexane to obtain a pure product of 109g, wherein the purity is more than 98%, and the yield is 90.41%.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the technical solutions, and those skilled in the art should understand that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions, and all the modifications and equivalent substitutions should be covered by the claims of the present invention.
Claims (5)
1. A synthetic method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine is characterized by comprising the following steps: the synthesis steps are as follows: (1) adding 2-methylthio-4, 6-dihydroxypyrimidine into fuming nitric acid in batches, stirring for 1h at room temperature, and heating for reaction; wherein the volume ratio of the 2-methylthio-4, 6-dihydroxypyrimidine to fuming nitric acid is 1:3, and the reaction is carried out for 4 hours by heating to 50 ℃;
(2) after the heating reaction is finished, cooling to room temperature, slowly pouring into ice water, stirring for 1h, filtering, washing a filter cake with water to be neutral, digging out the filter cake, and drying to obtain a compound B;
(3) mixing the compound B, phosphorus oxychloride and organic alkali, and carrying out chlorination reaction;
(4) after the chlorination reaction is finished, cooling the obtained mixture, reducing the pressure, concentrating to remove redundant phosphorus oxychloride, adding water for quenching, extracting by using an organic solvent, drying, and concentrating to obtain a pure product;
the reaction formula is as follows:
2. the method for synthesizing 2-methylthio-4, 6-dichloro-5-nitropyrimidine according to claim 1, wherein: the compound B, the phosphorus oxychloride and the organic alkali in the step (3) are mixed according to a mass ratio of 1:5-10: 0.3-0.7.
3. The method for synthesizing 2-methylthio-4, 6-dichloro-5-nitropyrimidine according to claim 1, wherein: the temperature of the chlorination reaction is 25-100 ℃, and the reaction time is 2-5 h.
4. The method for synthesizing 2-methylthio-4, 6-dichloro-5-nitropyrimidine according to claim 1, wherein: the organic base in the step (3) is any one of triethylamine, diisopropylethylamine, triisopropylamine, N, N-dimethylaniline, N, N-diethylaniline, N, N-dimethylpyridinylamine, pyridine, 1, 8-diaza-bicyclo (5, 4, 0) undecene-7, bicyclo [ 4.3.0 ] 1, 5-diaza-5-undecene or a mixture thereof.
5. The method for synthesizing 2-methylthio-4, 6-dichloro-5-nitropyrimidine according to claim 1, wherein: the specific method of the step (4) comprises the following steps: after chlorination reaction is finished, cooling the obtained mixture, reducing pressure, concentrating to remove excessive phosphorus oxychloride, slowly pouring the residue into 1kg of crushed ice, stirring for 1h, extracting for 2-3 times by using 200ml of ethyl acetate, combining organic phases, washing with saturated sodium bicarbonate aqueous solution until the pH is neutral, washing with saturated sodium chloride aqueous solution once, drying with anhydrous sodium sulfate, filtering to remove a drying agent, concentrating to obtain a crude product, and recrystallizing with n-hexane to obtain a pure product.
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