CN112574095A - Novel method for nitrifying isatin derivative - Google Patents

Novel method for nitrifying isatin derivative Download PDF

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Publication number
CN112574095A
CN112574095A CN202011516497.4A CN202011516497A CN112574095A CN 112574095 A CN112574095 A CN 112574095A CN 202011516497 A CN202011516497 A CN 202011516497A CN 112574095 A CN112574095 A CN 112574095A
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isatin
nmr
trifluoroacetic acid
nitrate
nitration
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殷子健
赵帅
陈湘香
陈新
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Changzhou University
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Changzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention belongs to the technical field of chemical pharmacy and fine chemical preparation, and particularly discloses a novel method for nitrifying an isatin derivative. Trifluoroacetic acid is adopted to replace the traditional sulfuric acid, and under the action of nitrate, nitro can be efficiently introduced into the 5-position or the 7-position of the isatin derivative. The invention provides a practical synthesis method for preparing nitroisatin compounds, and has wide application in the technical fields of chemical pharmacy and fine chemical preparation.

Description

Novel method for nitrifying isatin derivative
Technical Field
The invention belongs to the technical field of chemical pharmacy and fine chemical preparation, and particularly discloses a novel method for nitrifying an isatin derivative.
Background
Isatin derivatives are important synthetic intermediates, widely used for the synthesis of molecules with antitumor, antiviral and antitubercular biological activities (bioorg. med. chem. lett.2006,16,2158-2162. DOI: 10.1016/j.bmcl.2006.01.063; bioorg. med. chem.lett.2006,16,2109-2112. DOI: 10.1016/j.bmcl.2006.01.066; bioorg. med. chem.lett.2005,15,4451-4455. DOI: 10.1016/j.bmcl.2005.07.046).
The nitration of aromatic hydrocarbons is widely used in the modern chemical industry. The development of the nitration reaction of the isatin derivative has important theoretical significance and practical value. The nitration of isatin derivatives in the literature currently uses mainly nitrate or nitric acid as the nitro source, and typically sulfuric acid as the catalyst and solvent (bioorg. med. chem. lett.2012,22,7578-7581. DOI:10.1016/j.bmcl.2012.10.005), see the following formula.
Figure BDA0002847593190000011
The method adopts sulfuric acid with very high acidity and oxidability as a catalyst and a solvent, has the problems of high reaction speed and low cost, but still has the problems of poor nitration selectivity, more side reactions (such as sulfonation) and the like, particularly has poor reaction effect on raw materials containing reducing groups, and the sulfuric acid is easy to perform addition reaction on unsaturated bonds to generate corresponding esters. These have limited the use of concentrated sulfuric acid in complex molecular nitration.
Disclosure of Invention
The invention aims to provide a novel method for nitrifying isatin derivatives, aiming at overcoming the defects in the prior art. The 5-position or 7-position nitration of the isatin compounds can be realized by using relatively mild trifluoroacetic acid to replace sulfuric acid in the traditional method, and a series of various substituted nitroisatin compounds can be synthesized with high yield.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a novel method for nitrating isatin derivative has a reaction formula shown as the following formula:
Figure BDA0002847593190000021
the molecular general formula 1 is substituted isatin, the molecular general formula 2 is isatin substituted by 5-bit nitro, and the molecular general formula 3 is isatin substituted by 7-bit nitro; r in the general molecular formulas 1, 2 and 31And various substituents at various positions (specifically, 4-position, 5-position, 6-position and 7-position) on the benzene ring, including but not limited to alkyl, alkoxy, alkenyl, aryl, halogen, trifluoromethyl and the like. R in the general molecular formulas 1, 2 and 32Is a substituent on the N atom, including but not limited to various alkyl, alkenyl, aryl, acyl groups, and the like;
the specific synthesis method comprises the following steps:
adding isatin derivative and nitric acid reagent into a certain amount of trifluoroacetic acid according to a certain proportion, reacting for a certain time at a certain reaction temperature, removing the trifluoroacetic acid, and separating the residue by column chromatography to obtain the final product.
Wherein the nitrating reagent is nitrate such as potassium nitrate, sodium nitrate, silver nitrate, calcium nitrate, ammonium nitrate and the like.
The amount of the nitrating agent is 1-3 equivalents.
The concentration of the isatin derivative in trifluoroacetic acid is 0.05-0.2 moL/mL.
The reaction temperature is 20-100 ℃.
The reaction time is 10 minutes to 12 hours.
The invention has the beneficial effects that:
(1) according to the invention, trifluoroacetic acid is used as a catalyst and a solvent of the nitration reaction instead of sulfuric acid, so that the reaction condition is milder, and the application range of the nitration reaction is expanded;
(2) the reaction of the invention can simultaneously realize 5-site or 7-site nitration reaction of the isatin compounds, and the isatin compounds can be easily separated and purified by column chromatography.
Detailed Description
The following non-limiting examples 1-19 are intended to illustrate the present invention, but not to limit the present invention, and any modifications and variations of the present invention within the spirit of the present invention and the scope of the claims are included in the scope of the present invention.
The reagents, catalysts and solvents used in the present invention are commercially available or synthesized according to literature reports, and the solvents are purified and purified before use.
Example 1
At room temperature, 16.1mg
Figure BDA0002847593190000031
And 25.5mg of silver nitrate were added to 1mL of trifluoroacetic acid, heated to 60 ℃, reacted at this temperature for 30 minutes, the trifluoroacetic acid was removed, and the residue was separated by column chromatography to give compound 2a having a molecular structure:
Figure BDA0002847593190000032
it was a red solid, 87% yield.1H NMR(300MHz,DMSO-d6):δ8.56-8.53(dd,J＝2.4Hz,J＝8.7Hz,1H),8.24-8.23(d,J＝3.0Hz,1H),7.37-7.34(d,J＝9.0Hz,1H),3.22(s,3H)；13C NMR(75MHz,DMSO-d6):δ181.3,158.9,155.7,142.9,133.0,119.0,117.8,110.9,26.5ppm.HRMS(ESI):C9H6N2NaO4[M+Na]+Theoretical 229.0220, found 229.0164.
Examples 2-10 below were all carried out using the procedure of example 1, with only the specific starting materials being changed.
Example 2
To be provided with
Figure BDA0002847593190000041
As a starting material, compound 2b was prepared, the molecular structure of which was:
Figure BDA0002847593190000042
it was a red solid, 29% yield.1H NMR(400MHz,DMSO-d6):δ9.51(s,1H),8.44-8.42(dd,J＝1.0Hz,J＝8.5Hz,1H),8.00-7.98(d,J＝7.3Hz,1H),7.36-7.32(dd,J＝7.5Hz,J＝8.4Hz,1H).；13C NMR(100MHz,DMSO-d6):δ181.5,159.9,145.2,131.9,131.4,130.5,122.5,121.4ppm.HRMS(ESI):C8H4N2NaO4[M+Na]+Theoretical 215.0069, found 215.0036.
Example 3
To be provided with
Figure BDA0002847593190000043
As a starting material, compound 2c was prepared, having the molecular structure:
Figure BDA0002847593190000044
it was a red solid, 72% yield.1H NMR(400MHz,DMSO-d6):δ7.86-7.86(d,J＝2.1Hz,1H),7.73-7.73(d,J＝2.1Hz,1H),3.32(s,3H).13C NMR(100MHz,DMSO-d6):δ179.4,158.0,144.0,142.2,125.6,122.1,121.3,121.2,119.1,30.2ppm.HRMS(ESI)C10H4F3N2O5[M-H]-Theoretical 289.0073, found 289.0093.
Example 4
To be provided with
Figure BDA0002847593190000045
As a starting material, compound 2d was prepared, the molecular structure of which was:
Figure BDA0002847593190000046
it was a red solid, 94% yield.1H NMR(400MHz,DMSO-d6):δ8.28(s,2H),3.60(s,3H),2.70(s,3H).13C NMR(100MHz,DMSO-d6):δ181.7,158.9,153.5,136.5,123.1,118.8,118.1,30.0,19.2ppm.HRMS(ESI)C10H8N2NaO4[M+Na]+Theoretical 243.0382, found 243.0380.
Example 5
To be provided with
Figure BDA0002847593190000051
As a starting material, compound 2e was prepared, having the molecular structure:
Figure BDA0002847593190000052
it was a red solid, 82% yield.1H NMR(400MHz,CDCl3):δ7.96-7.95(d,J＝2.2Hz,1H),7.80-7.79(d,J＝2.2Hz,1H),3.30(s,3H)；13C NMR(100MHz,CDCl3):δ179.5,157.9,142.1,136.3,132.2,129.5,129.0,121.3,30.1ppm.HRMS(ESI):C9H4ClN2O4[M-H]-Theoretical 238.9865, found 238.9880.
Example 6
To be provided with
Figure BDA0002847593190000053
As a starting material, compound 2f is prepared, having the molecular structure：
Figure BDA0002847593190000054
It was a red solid, 66% yield.1H NMR(400MHz,CDCl3):δ8.23(s,1H),7.09(s,1H),3.33(s,3H)；13C NMR(100MHz,CDCl3):δ179.5,157.9,142.1,136.3,132.2,129.5,129.0,121.3,30.1ppm.HRMS(ESI)C9H5ClN2NaO4[M+Na]+Theoretical 262.9836, found 262.9826.
Example 7
To be provided with
Figure BDA0002847593190000055
As starting material, 2g of compound was prepared, the molecular structure of which was:
Figure BDA0002847593190000056
it was a red solid, 78% yield.1H NMR(400MHz,DMSO-d6):δ8.49-8.48(d,J＝2.2Hz,1H),8.35-8.35(d,J＝2.2Hz,1H),3.71(s,3H)；13C NMR(100MHz,CDCl3):180.4,158.2,151.3,143.9,135.4,119.3,119.1,118.1,30.0ppm.HRMS(ESI)C9H5ClN2NaO4[M+Na]+Theoretical 262.9836, found 262.9787.
Example 8
To be provided with
Figure BDA0002847593190000061
As a starting material, compound 2h was prepared, having the molecular structure:
Figure BDA0002847593190000062
it was a red solid, 92% yield.1H NMR(400MHz,DMSO-d6):8.31-8.29(m,2H),3.55-3.54(d,J＝3.1Hz,3H)；13C NMR(100MHz,CDCl3):δ180.1,180.1,157.6,148.2,146.2,143.9,143.0,142.9,121.9,121.7,119.1,119.1,116.8,116.8,29.4,29.4ppm.HRMS(ESI):C9H4FN2O4[M-H]-Theoretical value 223.0160, measuredValue 222.9148.
Example 9
To be provided with
Figure BDA0002847593190000063
As a starting material, compound 2i was prepared, the molecular structure of which was:
Figure BDA0002847593190000064
it was a red solid, 39% yield.1H NMR(500MHz,DMSO-d6):δ8.11(s,1H),7.06(s,1H),4.11(s,3H),3.22(s,3H)；13C NMR(125MHz,CDCl3):δ180.5,161.6,159.8,156.8,134.5,123.1,109.8,96.9,58.7,27.0ppm.HRMS(ESI)C10H8N2NaO5[M+Na]+Theoretical 259.0331, found 259.0328.
Example 10
To be provided with
Figure BDA0002847593190000071
As a starting material, compound 2j was prepared, the molecular structure of which was:
Figure BDA0002847593190000072
it was a red solid, 24% yield.1H NMR(400MHz,DMSO-d6):δ8.38-8.36(d,J＝8.7Hz,1H),7.92-7.88(d,J＝16.1Hz,1H),7.03-7.00(d,J＝8.7Hz,1H),6.33-6.29(d,J＝16.2Hz,1H),3.85(s,3H),3.35(s,3H)；13C NMR(100MHz,CDCl3):δ180.1,165.5,157.1,155.2,144.2,134.5,133.6,132.9,127.7,114.5,109.7,52.2,26.7ppm.HRMS(ESI)C13H10N2NaO6[M+Na]+Theoretical 313.0437, found 313.0435.
Example 11
Referring to the experimental procedure of example 1, silver nitrate was changed to 12.75mg sodium nitrate, and the reaction was carried out for 2 hours to obtain compound 2a in 97% yield.
Example 12
Referring to the experimental procedure of example 1, the silver nitrate was changed to 15.17mg of potassium nitrate and reacted for 2 hours to obtain compound 2a with a yield of 81%.
Example 13
At room temperature, 24.0mg
Figure BDA0002847593190000073
And 25.5mg of silver nitrate were added to 1mL of trifluoroacetic acid, heated to 60 ℃ and reacted at this temperature for 12 hours, the trifluoroacetic acid was removed, and the residue was separated by column chromatography to give compounds 2k and 2l, respectively, 2k having the molecular structures:
Figure BDA0002847593190000081
it was a red solid, 35% yield.1H NMR(400MHz,CDCl3):δ8.21-8.19(d,J＝8.5Hz,1H),6.99-6.97(d,J＝8.5Hz,1H),3.34(s,3H)；13C NMR(100MHz,DMSO-d6):δ179.5,158.0,155.1,145.0,134.1,117.4,112.3,109.8,26.4ppm.HRMS(ESI):C9H5BrN2NaO4[M+Na]+Theoretical 306.9325, found 306.9321.
2l has the molecular structure:
Figure BDA0002847593190000082
it was a red solid, 31% yield.1H NMR(400MHz,CDCl3):δ7.79-7.76(d,J＝8.8Hz,1H),7.39-7.36(d,J＝8.8Hz,1H),3.30(s,3H)；13C NMR(100MHz,DMSO-d6):δ177.8,158.8,145.3,134.5,132.3,127.3,123.6,119.6,29.3ppm.HRMS(ESI):C9H5BrN2NaO4[M+Na]+Theoretical 306.9325, found 306.9329.
Example 14
The same procedures and steps as in example 13 were referenced to
Figure BDA0002847593190000083
As starting material, compounds 2m and 2n were obtained. 2m has a molecular structure of:
Figure BDA0002847593190000084
it is red solid, 22%Yield.1H NMR(400MHz,CDCl3):δ8.30-8.28(d,J＝8.6Hz,1H),6.95-6.93(d,J＝8.6Hz,1H),3.35(s,3H)；13C NMR(100MHz,DMSO-d6):δ179.2,158.6,155.5,143.0,135.2,124.8,116.1,109.8,27.0ppm.HRMS(ESI)C9H5ClN2NaO4[M+Na]+Theoretical 262.9836, found 262.9834.
2n has a molecular structure of:
Figure BDA0002847593190000091
it was a red solid, 24% yield.1H NMR(400MHz,CDCl3):δ7.89-7.87(d,J＝8.9Hz,1H),7.19-7.17(d,J＝8.9Hz,1H),3.30(s,3H)；13C NMR(100MHz,DMSO-d6):δ177.2,158.8,145.0,134.8,134.0,132.6,124.2,118.0,29.4ppm.HRMS(ESI)C9H5ClN2NaO4[M+Na]+Theoretical 262.9836, found 262.9834.
Example 15
At room temperature, 16.1mg
Figure BDA0002847593190000092
And 25.5mg of silver nitrate were added to 1mL of trifluoroacetic acid, and reacted at room temperature (20 ℃ C.) for 30 minutes, the trifluoroacetic acid was removed, and the residue was separated by column chromatography to give Compound 2a in 5% yield.
Example 16
At room temperature, 16.1mg
Figure BDA0002847593190000093
And 25.5mg of silver nitrate were added to 1mL of trifluoroacetic acid, reacted at 40 ℃ for 30 minutes, the trifluoroacetic acid was removed, and the residue was separated by column chromatography to give compound 2a in 40% yield.
Example 17
At room temperature, 16.1mg
Figure BDA0002847593190000094
And 25.5mg of silver nitrate were added to 1mL of trifluoroacetic acid, reacted at 100 ℃ for 10 minutes,trifluoroacetic acid was removed and the residue was isolated by column chromatography to give compound 2a in 80% yield.
Example 18
At room temperature, 16.1mg
Figure BDA0002847593190000101
And 17.0mg of silver nitrate were added to 1mL of trifluoroacetic acid, reacted at 60 ℃ for 30 minutes, the trifluoroacetic acid was removed, and the residue was separated by column chromatography to give Compound 2a in 60% yield.
Example 19
At room temperature, 16.1mg
Figure BDA0002847593190000102
And 25.5mg of silver nitrate were added to 2mL of trifluoroacetic acid, reacted at 60 ℃ for 30 minutes, the trifluoroacetic acid was removed, and the residue was separated by column chromatography to give compound 2a in 40% yield.
The present invention is not limited to the above-described embodiments, and any obvious improvements, substitutions or modifications can be made by those skilled in the art without departing from the spirit of the present invention.

Claims (5)

1. A novel method for nitrifying isatin derivatives is characterized by comprising the following steps: adding the isatin derivative and the nitrating reagent into trifluoroacetic acid according to a certain proportion for reaction, then removing the trifluoroacetic acid, and separating the residue by column chromatography to obtain the final product.
2. The novel process for the nitration of isatin derivatives according to claim 1, wherein the nitrating agent is potassium nitrate, sodium nitrate, silver nitrate, calcium nitrate, ammonium nitrate.
3. The novel process for the nitration of isatin derivatives according to claim 1, wherein the nitrating agent is used in an amount of 1 to 3 equivalents.
4. The novel process for the nitration of isatin derivatives according to claim 1, wherein the reaction concentration of the isatin derivative is 0.05-0.2 moL/mL.
5. The novel process for the nitration of isatin derivatives according to claim 1, wherein the reaction temperature is 20-100 ℃ and the reaction time is 10 minutes to 12 hours.
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CN104870422A (en) * 2012-10-31 2015-08-26 富山化学工业株式会社 Novel amine derivative or salt thereof
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CN102603740A (en) * 2012-03-01 2012-07-25 南京药石药物研发有限公司 Synthetic method of 4-nitro-7-azaindole
CN104870422A (en) * 2012-10-31 2015-08-26 富山化学工业株式会社 Novel amine derivative or salt thereof
CN104496885A (en) * 2015-01-12 2015-04-08 中国药科大学 N-methyl-4-amino-5-nitroisatin preparation method
CN106674116A (en) * 2016-12-20 2017-05-17 苏州汉德创宏生化科技有限公司 4-amino-1,3-dimethyl pyrazol and compound method for pharmaceutical acceptable salt thereof

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Application publication date: 20210330