CN112939922A - Synthesis method of 1-cyano-6-methylsulfonyl-7-nitro-9H-xanthene-9-ketone - Google Patents
Synthesis method of 1-cyano-6-methylsulfonyl-7-nitro-9H-xanthene-9-ketone Download PDFInfo
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- CN112939922A CN112939922A CN202110084532.8A CN202110084532A CN112939922A CN 112939922 A CN112939922 A CN 112939922A CN 202110084532 A CN202110084532 A CN 202110084532A CN 112939922 A CN112939922 A CN 112939922A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
- C07D311/86—Oxygen atoms, e.g. xanthones
Abstract
The invention discloses a method for synthesizing 1-cyano-6-methylsulfonyl-7-nitro-9H-xanthene-9-ketone, which comprises the following steps of using cheap 2-chloro-4-fluoro-5-nitrobenzoic acid, namely compound 1 is used as a starting material, the nucleophilic substitution of sodium methyl mercaptide is carried out on the fluorine atom in the compound 1 to obtain compound 2, esterifying carboxyl of the compound 2 to obtain a compound 3, substituting chlorine atoms of the compound 3 with m-cyanophenol to obtain a compound 4, oxidizing methyl sulfide in the compound 4 into sulfonyl by using m-chloroperoxybenzoic acid to obtain a compound 5, and cyclizing the compound 5 by using sulfuric acid to obtain 1-cyano-6-methylsulfonyl-7-nitro-9H-xanthen-9-one. The whole reaction route is simple and economic, and has strong practical value.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a method for synthesizing 1-cyano-6-methylsulfonyl-7-nitro-9H-xanthene-9-ketone.
Background
Mesotrione, also known as mitoxantrone, mesotrione, is an effective herbicide for corn fields developed by Zhenda crop protection, Inc. 1-cyano-6-methylsulfonyl-7-nitro-9H-xanthen-9-one, an impurity introduced during mesotrione production, is considered toxic and is required by European standards to be less than 0.0002% (w/w) of the parent drug.
In recent years, the importance of impurity components in raw pesticides is also paid to China, and in the registration of raw pesticides, registration enterprises are required to provide more than 0.1% of impurity conditions including impurity names, contents, structures, necessary qualitative spectrograms and the like. Therefore, extensive studies on the impurity components, such as the structure and properties of 1-cyano-6-methylsulfonyl-7-nitro-9H-xanthen-9-one, have been carried out.
Because the content of 1-cyano-6-methylsulfonyl-7-nitro-9H-xanthen-9-one in the production process of mesotrione is low, the extraction method is not feasible, and therefore the mesotrione needs to be synthesized.
In conclusion, it is an important research direction to provide a synthesis method of 1-cyano-6-methylsulfonyl-7-nitro-9H-xanthen-9-one.
Disclosure of Invention
The present invention has been made to solve the above-mentioned problems occurring in the prior art.
The invention provides a method for synthesizing 1-cyano-6-methylsulfonyl-7-nitro-9H-xanthene-9-ketone, which comprises the following steps:
s1: dissolving 2-chloro-4-fluoro-5-nitrobenzoic acid in methanol, adding sodium methyl mercaptide in batches for a first reaction, adjusting the pH value after the first reaction is finished, filtering and drying to obtain a compound 2;
s2: dissolving the compound 2 in methanol, sequentially adding DCC and DMAP for a second reaction, performing spin drying after the second reaction is finished, and performing column chromatography separation to obtain a compound 3;
s3: the compound 3, K2CO3Sequentially adding CUI, CU powder and 3-hydroxybenzonitrile into a container to carry out a third reaction, and after the third reaction is finished, carrying out column chromatography separation to obtain a compound 4;
s4: dissolving the compound 4 in DCM, dropwise adding m-chloroperoxybenzoic acid at the temperature of below 0 ℃ to carry out a fourth reaction, obtaining a first reaction solution after the fourth reaction is finished, washing with liquid, drying, and carrying out column chromatography separation to obtain a compound 5;
s5: the compound 5 is soluble in H2SO4And continuously stirring at a high temperature for a period of time to obtain a second reaction solution, pouring the second reaction solution into a saturated potassium bicarbonate aqueous solution, concentrating and extracting by using dichloromethane, and performing column chromatography separation to obtain the compound 6.
Preferably, in step S1, the molar ratio of the 2-chloro-4-fluoro-5-nitrobenzoic acid to the sodium methyl mercaptide is: 1: 3-3.5.
Preferably, in step S1, the reaction temperature of the first reaction is room temperature, and the reaction time is 2-4 h.
Preferably, in step S1, the pH is adjusted to 1.5-2.5 by adding 1mol/L HCl.
Preferably, in step S2, the molar ratio of compound 2, DCC and DMAP is: 10: 8-10: 1.
preferably, in step S2, the mass-to-volume ratio of the compound 2 to the methanol is 0.8-1: 10.
Preferably, in step S2, the reaction temperature of the second reaction is room temperature, and the reaction time is 2-4 h.
Preferably, in step S3, the molar ratio of the compound 3 to the 3-hydroxybenzonitrile is 1:1.4 to 2.
Preferably, in the step S3, the reaction temperature of the third reaction is 120 to 130 ℃, and the reaction time is 1 to 3 hours.
Preferably, in step S4, the molar ratio of the compound 4 to the m-chloroperoxybenzoic acid is 1: 4-6.
Preferably, in step S4, the reaction temperature of the 4 th reaction is room temperature, and the reaction time is 1-3 h.
Preferably, in step S4, the liquid washing sequentially includes alkali washing with a saturated aqueous sodium bicarbonate solution, liquid washing with an aqueous sodium hydrosulfite solution, alkali washing with an aqueous sodium carbonate solution twice, and water washing twice.
Preferably, in step S5, the reaction temperature is 50-70 ℃ and the reaction time is 5-7 h.
By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:
the method takes cheap 2-chloro-4-fluoro-5-nitrobenzoic acid as an initial raw material, carries out nucleophilic substitution on fluorine atoms in molecules by sodium methyl mercaptide, esterifies carboxylic acid, substitutes chlorine atoms by m-cyanophenol, oxidizes methyl sulfide into sulfone, and carries out ring closure by sulfuric acid to obtain a final target product. The whole reaction route is simple and economic, and has strong practical value.
Detailed Description
The present invention will be described in detail and specifically with reference to the following examples to facilitate better understanding of the present invention, but the following examples do not limit the scope of the present invention.
Example 1
This example provides a method for the preparation of compound 2:
2-chloro-4-fluoro-5-nitrobenzoic acid (Compound 1) (2.5g, 11.3mmol) was added to 25ml of methanol, sodium thiomethoxide (2.4g, 34.1mmol) was added in portions, and then reacted at room temperature for 3 hours, after the reaction was completed, pH was adjusted to about 2 with 1mol/L HCl solution, and a solid was filtered off, and dried to give Compound 2(2.0g, yield: 72%).
The compound 2 was subjected to the nmr hydrogen spectrum test, and the test results were as follows:
1H NMR(300MHz,DMSO)δ13.86(s,1H),8.61(s,1H),7.60(s,1H),2.60(s,3H).
example 2
This example provides a method for the preparation of compound 3:
compound 2(9g, 36.3mmol) was added to 100ml of methanol, DCC (9g, 30.2mmol) and DMAP (0.43g, 3.63mmol) were sequentially added to the above reaction solution, followed by reaction at room temperature for 2 hours, spin-drying, and column chromatography to isolate Compound 3(5.1g, yield: 50%).
The compound 3 was subjected to the nmr hydrogen spectroscopy test, and the test results were as follows:
1H NMR(300MHz,DMSO)δ8.64(s,1H),7.64(s,1H),3.88(s,3H),2.61(s,3H).
example 3
This example provides a method for the preparation of compound 4:
compound 3(3g, 11.4mmol), K2CO3(4.8g, 34.2mmol), CUI (0.9g, 3.4mmol), CU powder (0.9g, 3.4mmol) and 3-hydroxybenzonitrile (1.9g, 16mmol) were sequentially added to a 100ml single-neck flask, followed by reaction at 120 ℃ for 1 hour and column chromatography to isolate compound 4(3g, yield: 70%).
The compound 4 was subjected to the nmr hydrogen spectroscopy test, and the test results were as follows:
1H NMR(300MHz,CDCl3)δ8.96(s,1H),7.56-7.42(m,2H),7.25{(d,J＝7.7Hz,2H},6.84(s,1H),3.85(s,3H),2.43(s,3H)
example 4
This example provides a method for the preparation of compound 5:
dissolving the compound 4(2.04g, 5.9mmol) in DCM, cooling to below 0 ℃, dropwise adding m-chloroperoxybenzoic acid (4.09g, 23.6mmol), reacting at room temperature for 1h, pouring the reaction solution into saturated aqueous sodium bicarbonate solution, separating an organic phase, washing once with sodium hydrosulfite aqueous solution, washing twice with sodium carbonate aqueous solution, washing twice with water, drying, and separating by column chromatography to obtain the compound 5(1.4g, yield: 80%).
The compound 5 was subjected to the nmr hydrogen spectrum test, and the test results were as follows: 44
1H NMR(300MHz,DMSO)δ8.75(s,1H),7.73–7.54(m,3H),7.52–7.37(m,1H),7.14(s,1H),3.74(s,3H),2.44(s,3H).
Example 5
This example provides a method for the preparation of compound 6:
compound 5(1.4g, 3.8mmol) is dissolved in H2SO4(14ml), and the mixture was stirred at 60 ℃ for 5 hours. The reaction solution was poured into a saturated aqueous solution of potassium hydrogencarbonate, extracted with dichloromethane, concentrated, and separated by column chromatography to give the product 6(810mg, yield: 62%).
The compound 6 was subjected to the nmr hydrogen spectrum test, and the test results were as follows:
1H NMR(300MHz,DMSO)δ8.79(s,1H),8.36(s,1H),8.11(m,3H),3.64(s,3H).
the embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
Claims (10)
1. A method for synthesizing 1-cyano-6-methylsulfonyl-7-nitro-9H-xanthen-9-one is characterized by comprising the following steps:
s1: dissolving 2-chloro-4-fluoro-5-nitrobenzoic acid in methanol, adding sodium methyl mercaptide in batches for a first reaction, adjusting the pH value after the first reaction is finished, filtering and drying to obtain a compound 2;
s2: dissolving the compound 2 in methanol, sequentially adding DCC and DMAP for a second reaction, performing spin drying after the second reaction is finished, and performing column chromatography separation to obtain a compound 3;
s3: the compound 3, K2CO3Sequentially adding CUI, CU powder and 3-hydroxybenzonitrile into a container to carry out a third reaction, and after the third reaction is finished, carrying out column chromatography separation to obtain a compound 4;
s4: dissolving the compound 4 in DCM, dropwise adding m-chloroperoxybenzoic acid at the temperature of below 0 ℃ to carry out a fourth reaction, obtaining a first reaction solution after the fourth reaction is finished, washing with liquid, drying, and carrying out column chromatography separation to obtain a compound 5;
s5: the compound 5 is soluble in H2SO4And continuously stirring at a high temperature for a period of time to obtain a second reaction solution, pouring the second reaction solution into a saturated potassium bicarbonate aqueous solution, concentrating and extracting by using dichloromethane, and performing column chromatography separation to obtain the compound 6.
2. The synthesis method according to claim 1, wherein in step S1, the molar ratio of the 2-chloro-4-fluoro-5-nitrobenzoic acid to the sodium thiomethoxide is: 1: 3-3.5.
3. The method of claim 1, wherein in step S1, the pH is adjusted to 1.5-2.5 by adding 1mol/L HCl.
4. The method of claim 1, wherein in step S2, the molar ratio of compound 2, DCC, and DMAP is: 10: 8-10: 1.
5. the synthesis method according to claim 1, wherein in step S2, the mass-to-volume ratio of compound 2 to methanol is 0.8-1: 10.
6. The method according to claim 1, wherein in step S3, the molar ratio of the compound 3 to the 3-hydroxybenzonitrile is 1: 1.4-2.
7. The synthesis method according to claim 1, wherein in step S3, the reaction temperature of the third reaction is 120-130 ℃ and the reaction time is 1-3 h.
8. The method according to claim 1, wherein in step S4, the molar ratio of the compound 4 to the m-chloroperoxybenzoic acid is 1:4 to 6.
9. The synthesis method according to claim 1, wherein in step S4, the liquid washing sequentially comprises alkali washing with saturated aqueous sodium bicarbonate solution, liquid washing with sodium hydrosulfite solution, alkali washing with aqueous sodium carbonate solution twice, and water washing twice.
10. The synthesis method according to claim 1, wherein in step S5, the reaction temperature is 50-70 ℃ and the reaction time is 5-7 h.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114813999A (en) * | 2022-03-29 | 2022-07-29 | 北京安胜瑞力科技有限公司 | HPLC analysis method and application of xanthenone related substances |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584650A (en) * | 2011-01-05 | 2012-07-18 | 中国中化股份有限公司 | Preparation method of 2-nitro-4-methylsulphonylbenzoic acid |
| WO2015054887A1 (en) * | 2013-10-18 | 2015-04-23 | 浙江省诸暨合力化学对外贸易有限公司 | Triketone ammonium salt compound, and preparation method and application thereof |
| CN112225698A (en) * | 2020-11-05 | 2021-01-15 | 河北临港化工有限公司 | Mesotrione impurity, salt thereof, tautomer thereof or salt of tautomer thereof and preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584650A (en) * | 2011-01-05 | 2012-07-18 | 中国中化股份有限公司 | Preparation method of 2-nitro-4-methylsulphonylbenzoic acid |
| WO2015054887A1 (en) * | 2013-10-18 | 2015-04-23 | 浙江省诸暨合力化学对外贸易有限公司 | Triketone ammonium salt compound, and preparation method and application thereof |
| CN112225698A (en) * | 2020-11-05 | 2021-01-15 | 河北临港化工有限公司 | Mesotrione impurity, salt thereof, tautomer thereof or salt of tautomer thereof and preparation method |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114813999A (en) * | 2022-03-29 | 2022-07-29 | 北京安胜瑞力科技有限公司 | HPLC analysis method and application of xanthenone related substances |
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