CN102675125B - Simple, convenient and high-efficiency synthesis method of 4-chloro-2-trifluoroacetylaniline and analogs thereof - Google Patents
Simple, convenient and high-efficiency synthesis method of 4-chloro-2-trifluoroacetylaniline and analogs thereof Download PDFInfo
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- 0 *c(c(C(C(F)(F)F)(O)O)c1)ccc1Cl Chemical compound *c(c(C(C(F)(F)F)(O)O)c1)ccc1Cl 0.000 description 1
- IZISMXMXCLUHGI-UHFFFAOYSA-N CC(C)(C)C(Nc(cc1)ccc1Cl)=O Chemical compound CC(C)(C)C(Nc(cc1)ccc1Cl)=O IZISMXMXCLUHGI-UHFFFAOYSA-N 0.000 description 1
- PPPQKMYILLVLDD-UHFFFAOYSA-N CC(C)(C)C(Nc(ccc(Cl)c1)c1C(C(F)(F)F)=O)=O Chemical compound CC(C)(C)C(Nc(ccc(Cl)c1)c1C(C(F)(F)F)=O)=O PPPQKMYILLVLDD-UHFFFAOYSA-N 0.000 description 1
- DMBLTSODFHHZMS-UHFFFAOYSA-N CC(C)C(C)(C)C(Cl)=O Chemical compound CC(C)C(C)(C)C(Cl)=O DMBLTSODFHHZMS-UHFFFAOYSA-N 0.000 description 1
- NOKSRMDODJGCPZ-UHFFFAOYSA-N Nc(c(C(C(F)(F)F)=O)c1)ccc1Cl Chemical compound Nc(c(C(C(F)(F)F)=O)c1)ccc1Cl NOKSRMDODJGCPZ-UHFFFAOYSA-N 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N Nc(cc1)ccc1Cl Chemical compound Nc(cc1)ccc1Cl QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a simple, convenient and high-efficiency synthesis method of 4-chloro-2-trifluoroacetylaniline and analogs thereof. The 4-chloro-2-trifluoroacetylaniline can be used as a key midbody for synthesizing the anti-AIDS (Acquired Immune Deficiency Syndrome) drug efavirenz.
Description
Technical field:
The present invention relates to the synthetic method of the new simple and effective of 4-chloro-2-trifluoroacetyl aniline (formula I) and analogue thereof, wherein the chloro-2-trifluoroacetyl aniline of 4-can be used as the key intermediate of synthesis hiv reverse transcriptase inhibitor efavirenz (formula II).For the chloro-2-trifluoroacetyl aniline of 4-; the method becomes 3-hydroxyl-3-trifluoro methyl indole-2-ketone mainly through the aniline of cheapness with the methyl esters of trifluoropropyl ketone acid or the symphysis of ethyl ester Efficient Ring; obtain 5-chloro-3-hydroxyl-3-trifluoro methyl indole-2-ketone with N-chlorosuccinimide reaction preference chloro again, what be finally oxidized open loop height yield in the basic conditions obtains the chloro-2-trifluoroacetyl aniline of 4-.
Background technology:
Reverse transcription is specific to retrovirus copies.Virus replication requires that the reversed transcriptive enzyme of encoding viral produces the DNA copy of virus sequence by the reverse transcription of viral RNA genes group.Because the suppression of the reversed transcriptive enzyme to encoding viral can interrupt virus replication, therefore, for the chemotherapy of retroviral infection, reversed transcriptive enzyme is a clinical related target.
Chemical compound lot is effective in treatment HIV (human immunodeficiency virus) (HIV), and this virus can cause human immune system's Progressive symmetric erythrokeratodermia to destroy and the retrovirus causing AIDS to fall ill.To the inhibitor based on nucleosides, such as Zidovodine and the inhibitor based on non-nucleosides, by being known effective methods for the treatment of for the inhibitor of hiv reverse transcriptase, have been found that benzoxazine ketone is the useful hiv reverse transcriptase inhibitor based on non-nucleosides at present.In addition, HIV (human immunodeficiency virus) (HIV) is easily suddenlyd change, this can cause resistance, Efavirenz, DPC961 and DPC083 of being researched and developed by E.I.Du Pont Company have highly active HIV non-nucleoside reverse transcriptase inhibitor (NNRTIs), but because it is easy to produce resistance, also consider important medical value and the social effect of reverse transcriptase inhibitors compounds simultaneously, be badly in need of developing for the preparation of the economy of Efavirenz (formula II) efficient asymmetric synthesis technique.
Formula (I)
Formula (II)
People (the J.Org.Chem. such as Michael E.Pierce, 1998, 63, 8536-8543) describe the synthetic method of the chloro-2-trifluoroacetyl aniline (formula I) of a kind of 4-, as shown below, it is first protected by p-Chlorobenzoic acid amide, (-20 DEG C) react with Trifluoroacetic Acid Ethyl Ester after taking out proton with n-Butyl Lithium more at low temperatures, introduce trifluoroacetyl group, the chloro-2-trifluoroacetyl aniline of 4-is obtained after deprotection base under strong acidic condition, generally four-step reaction will be experienced, which use highly basic n-Butyl Lithium and the strong acid of equivalent, and require low temperature and anhydrous and oxygen-free reaction, complex operation and high to the requirement of equipment, be unfavorable for large-scale commercial production.
In addition; people (the J.Med.Chem. such as Jeffrey W.Corbett; 2000; 43; 2019-2030); people (the Tetrahedron Letters such as Andrew S.Thompson; 1995,36,8937-8940); with people (Bioorganic Medicinal Chemistry letters such as Mona Patel; 1999,9,2805-2810) and European patent 582455A1 also all apply similar method to prepare the chloro-2-trifluoroacetyl aniline of 4-or its analogue; not only still there is above-mentioned defect, and combined coefficient is often very low.
In sum, the method of more than synthesizing the chloro-2-trifluoroacetyl aniline (formula I) of 4-or its analogue all employs a large amount of dangerous reagent, as highly basic n-Butyl Lithium or tert-butyl lithium and strong acid, and require low temperature and anhydrous and oxygen-free reaction, complex operation and high to the requirement of equipment, be unfavorable for large-scale commercial production, therefore, be badly in need of the synthesis technique seeking the chloro-2-trifluoroacetyl aniline of the new 4-that can adapt to large-scale industrialized production, above-mentioned restricted condition be avoided or be improved to such synthesis technique can not only, and the required chloro-2-trifluoroacetyl aniline of 4-can also be provided efficiently.
For this reason; the invention provides the technique of the chloro-2-trifluoroacetyl aniline (formula I) of a kind of synthesis 4-newly and analogue thereof, wherein the chloro-2-trifluoroacetyl aniline of 4-can be used as the key intermediate of the reverse transcriptase inhibitors efavirenz synthesizing human immunodeficiency virus (HIV).The method mild condition, easy and simple to handle, reaction yield is high and avoid and a large amount of use dangerous reagent, as highly basic n-Butyl Lithium or tert-butyl lithium and strong acid, is conducive to large-scale commercial production.
One section is not had to describe the method for the present invention in order to the key intermediate 4-chloro-2-trifluoroacetyl aniline of synthesis as hiv reverse transcriptase inhibitor efavirenz in above citing document.
Summary of the invention
The invention provides the method for the new simple and effective of a kind of synthesis 4-chloro-2-trifluoroacetyl aniline (formula I) and analogue (formula III) thereof, wherein the chloro-2-trifluoroacetyl aniline of 4-can be used as the key intermediate of synthesis hiv reverse transcriptase inhibitor efavirenz (formula II).For the chloro-2-trifluoroacetyl aniline of 4-, the method becomes 3-hydroxyl-3-trifluoro methyl indole-2-ketone mainly through the aniline of cheapness with the methyl esters of trifluoropropyl ketone acid or the symphysis of ethyl ester Efficient Ring, 5-chloro-3-hydroxyl-3-trifluoro methyl indole-2-ketone is obtained again with N-chlorosuccinimide reaction preference chloro, what be finally oxidized open loop height yield in the basic conditions obtains the chloro-2-trifluoroacetyl aniline of 4-, reaction conditions is gentle, easy and simple to handle, yield is high and avoid and a large amount of use dangerous reagent, as highly basic n-Butyl Lithium or tert-butyl lithium and strong acid, be conducive to large-scale commercial production.
Formula (III)
In formula, Y is hydrogen, F, Cl or Br;
When Y is Cl, formula (III) compound is exactly the chloro-2-trifluoroacetyl aniline (formula I) of 4-;
The synthetic method of the chloro-2-trifluoroacetyl aniline (formula I) of 4-provided by the invention and analogue thereof, specifically describes as follows:
Take aniline as raw material (formula IV), refluxing in organic solvent with trifluoropropyl ketone acid methyl esters or ethyl ester (formula V) obtains 3-hydroxyl-3-trifluoro methyl indole-2-ketone (formula VI);
The compound of formula (IV), formula (V) and formula (VI) has following structural formula:
Formula (IV),
Formula (V),
Wherein R
1for methyl or ethyl;
Formula (VI),
Y in formula
1for hydrogen, F, Cl or Br;
Work as Y
1during for hydrogen, the compound of formula VI is the 3-hydroxyl-3-trifluoro methyl indole-2-ketone of following formula VII:
Formula (VII).
The preferred reaction conditions of this step is:
The methyl esters of aniline described in above-mentioned steps and trifluoropropyl ketone acid or the mol ratio of ethyl ester are 1: (1-10); The mol ratio of the methyl esters or ethyl ester that are recommended as aniline and trifluoropropyl ketone acid is 1: (1-5);
The temperature of reacting described in above-mentioned steps is between 100-200 DEG C; Be recommended as between 100-150 DEG C;
The time of reacting described in above-mentioned steps is 10-20 hour;
In above-mentioned steps, preferred organic solvent is benzene, toluene, chlorobenzene, 1,2-dichlorobenzene, Isosorbide-5-Nitrae-dioxane; More preferably toluene, chlorobenzene or 1,2-dichlorobenzene.
Work as Y
1during for hydrogen, the compound of formula VI is the 3-hydroxyl-3-trifluoro methyl indole-2-ketone of formula VII.At 0-120 DEG C, in organic solvent, the 3-hydroxyl-3-trifluoro methyl indole-2-ketone of formula VII and halide reagent react, and add zirconium tetrachloride catalysis, obtain formula (VIII) compound;
Formula (VIII)
Wherein Y
2for Cl or Br;
In above-mentioned steps, halide reagent is NCS (N-chlorosuccinimide) or NBS (N-bromo-succinimide);
The preferred reaction conditions of this step is:
The molar ratio of above-mentioned steps Chinese style (VI) compound and NCS or NBS is 1: (1-3);
The mol ratio of formula VI compound and zirconium tetrachloride is 1: (0.02-0.2);
The temperature of reacting described in above-mentioned steps between 0-120 DEG C, preferred 40-80 DEG C;
The time of reacting described in above-mentioned steps is 24-72 hour;
Organic solvent used in this step is preferably tetrahydrofuran (THF), methyltetrahydrofuran, 1,4-dioxane, t-butyl methyl ether, diethylene glycol dimethyl ether, acetonitrile, ethyl acetate, n-butyl acetate, N, dinethylformamide or N,N-dimethylacetamide; More preferably tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, DMF, t-butyl methyl ether or acetonitrile.
In the mixed solvent of organic solvent and water, formula (VI) or formula (VIII) compound in the basic conditions, add oxidizing open loop and obtain formula (III) compound;
The preferred reaction conditions of this step is:
Alkali used in above-mentioned steps is LiOH, NaOH or KOH; Be recommended as KOH;
Oxygenant used in above-mentioned steps is K
3[Fe (CN)
6], peroxy tert-butyl alcohol or H
2o
2; Be recommended as K
3[Fe (CN)
6];
Organic solvent used in above-mentioned steps is preferably tetrahydrofuran (THF), methyltetrahydrofuran, 1,4-dioxane, t-butyl methyl ether, diethylene glycol dimethyl ether, acetonitrile, ethyl acetate, n-butyl acetate, N, dinethylformamide or N,N-dimethylacetamide; More preferably tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, DMF, t-butyl methyl ether or acetonitrile;
In above-mentioned steps, the volume ratio of organic solvent and water is (1-5): 1;
The molar ratio of above-mentioned steps Chinese style (VI) or formula (VIII) compound and alkali and oxygenant is 1: (1-10): (1-6); Be recommended as 1: (1-5): (1-3);
The temperature of reacting described in above-mentioned steps is between 0-100 DEG C;
The time of reacting described in above-mentioned steps is 0.5-24 hour.
With following typical reaction formula, method of the present invention also can represent that route synthesizes:
In formula, Y can be Y
1or Y
2; Wherein Y, Y
1, Y
2or R
1definition as previously mentioned.
The invention provides the method for the new simple and effective of a kind of synthesis 4-chloro-2-trifluoroacetyl aniline (formula I) and analogue (formula III) thereof, wherein the chloro-2-trifluoroacetyl aniline of 4-can be used as the key intermediate of synthesis hiv reverse transcriptase inhibitor efavirenz (formula II).The method becomes 3-hydroxyl-3-trifluoro methyl indole-2-ketone mainly through the aniline of cheapness with the methyl esters of trifluoropropyl ketone acid or the symphysis of ethyl ester Efficient Ring; 5-chloro-3-hydroxyl-3-trifluoro methyl indole-2-ketone is obtained again with N-chlorosuccinimide reaction preference chloro; what be finally oxidized open loop height yield in the basic conditions obtains the chloro-2-trifluoroacetyl aniline of 4-; reaction conditions is gentle, easy and simple to handle, yield is high and avoid and a large amount of use dangerous reagent; as highly basic n-Butyl Lithium or tert-butyl lithium and strong acid, be conducive to large-scale commercial production.
Embodiment
Following examples contribute to understanding this patent but are not limited thereto scope.
Embodiment 1
the preparation of 3-hydroxyl-3-trifluoro methyl indole-2-ketone:
Aniline (1.4g, 15mmol) is dissolved in benzene (20mL), drips trifluoropropyl ketone acid methyl esters (23.4g, 150mmol), after dropwising, is warming up to oil bath about 130 DEG C.After reaction carries out 18 hours, remove oil bath, naturally cool to room temperature, visible a large amount of white solid is separated out, leach white solid, then petroleum ether, dry, obtain product (2.6g, yield 78%), do not need to be further purified and can carry out next step reaction.
1HNMR(Acetone-d
6,400MHz)δ6.51(s,1H),7.03(d,J=5.7Hz,1H),7.13(t,J=11.4Hz,5.7Hz,1H),7.42(t,J=11.4Hz,5.7Hz,1H),7.52(d,J=5.7Hz,1H),9.76(s,1H).
HRMS. calculated value C
9h
6f
3nO
2: 217.0351. measured value: 217.0353.
Embodiment 2
the preparation of 5-chloro-3-hydroxyl-3-trifluoro methyl indole-2-ketone:
3-hydroxyl-3-trifluoro methyl indole-2-ketone (3.3g, 15.2mmol) with NCS (2.5g, 18.7mmol) be dissolved in DMF (50mL), add zirconium tetrachloride (180mg, 5%eq) as catalyzer, oil bath is warming up to 50 DEG C, reacts after 48 hours and terminates.After question response is complete, add extraction into ethyl acetate, saturated sodium bicarbonate washs, then uses water successively, and saturated common salt is washed, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, crude product can use toluene/ethanol (20: 1) recrystallization, obtains product (3.7g, yield 98%).
1H NMR(500MHz,acetone-d
6)δ6.77(s,1H),7.08(d,1H,J=8.0Hz),7.47(dd,1H,J=1.5Hz,J=8.5Hz),9.96(s,1H);
19F NMR(acetone-d6)δ79.99;
MS(GC)m/z 251(M
+).
Embodiment 3
the preparation of the chloro-2-trifluoroacetyl aniline of 4-:
Under room temperature, get 5-chloro-3-hydroxyl-3-trifluoro methyl indole-2-ketone (251mg, 1mmol) and be dissolved in acetonitrile (10mL), add water (3mL), then add KOH (280mg, 5mmol), dissolve fully, disposablely add K
3[Fe (CN)
6] (990mg, 3mmol), treat that raw material reaction is complete, add extraction into ethyl acetate, organic phase washed with water, saturated common salt is washed, and anhydrous sodium sulfate drying, removes solvent under reduced pressure, obtains product (211.9mg, yield 95%).
1H NMR(300MHz,CDCl
3)δ6.46(brs,2H),6.70(d,1H,J=9.0Hz),7.32(dd,1H,J=2.1Hz,9.0Hz),7.71(d,1H,J=2.1Hz);
MS(ESI)m/z 222(M-H);
Embodiment 4
the preparation of the bromo-3-hydroxyl of 5--3-trifluoro methyl indole-2-ketone:
3-hydroxyl-3-trifluoro methyl indole-2-ketone (4.5g, 20.7mmol) with NBS (2.5g, 18.7mmol) be dissolved in 1, in 2-ethylene dichloride (60mL), add zirconium tetrachloride (180mg) as catalyzer, then the operation with reference to embodiment 2 obtains product, yield 96%.
1H NMR(500MHz,acetone-d
6)δ6.75(s,1H),7.02(d,1H,J=8.5Hz),7.59-7.62(m,2H),9.95(s,1H);
MS(GC)m/z 295(M
+).
Embodiment 5
the preparation of the bromo-2-trifluoroacetyl aniline of 4-:
Get the bromo-3-hydroxyl of 5--3-trifluoro methyl indole-2-ketone (295mg, 1mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (15mL), add water (3mL), add KOH (560mg again, 10mmol), dissolve fully, disposablely add peroxy tert-butyl alcohol (540.7mg, 6mmol, 70%), then product is obtained, yield 93% with reference to the operation of embodiment 3.
1HNMR(CDCl
3,300MHz)δ6.49(brs,2H),6.64(d,J=9.0Hz,1H),7.42(d,J=9.0Hz,1H),7.82(s,1H).
19FNMR(CDCl
3,300MHz)δ70.13
Embodiment 6
the preparation of 2-trifluoroacetyl aniline:
Get 3-hydroxyl-3-trifluoro methyl indole-2-ketone (217mg, 1mmol) be dissolved in tetrahydrofuran (THF) (12mL), add water (6mL), then add KOH (224mg, 10mmol), dissolve fully, disposablely add hydrogen peroxide (204mg, 6mmol, 30%), then the operation with reference to embodiment 3 obtains product, yield 90%.
1H NMR(300MHz,CDCl
3)δ6.24(brs,2H),6.67(d,1H,J=1.2Hz),6.73(dd,1H,J=1.8Hz,3.9Hz),7.38(dd,1H,J=1.2Hz,J
1/
43.9Hz),6.67(d,1H,J=1.8Hz);MS(ESI):188(M-H);
Embodiment 7
the preparation of the fluoro-2-trifluoroacetyl aniline of 4-:
Under room temperature, get 5-fluoro-3-hydroxyl-3-trifluoro methyl indole-2-ketone (235mg, 1mmol) and be dissolved in N, in dinethylformamide (10mL), add water (3mL), then add NaOH (400mg, 10mmol), dissolve fully, disposablely add K
3[Fe (CN)
6] (990mg, 3mmol), treat that raw material reaction is complete, add extraction into ethyl acetate, organic phase washed with water, saturated common salt is washed, and anhydrous sodium sulfate drying, removes solvent under reduced pressure, obtains product (196.7mg, yield 95%).
1H NMR(300MHz,CDCl
3)δ
1H NMR(300MHz,CDCl
3)δ7.43(d,J=9.6Hz,1H),7.19(m,1H),6.71(dd,J=9.2,4.5Hz,1H),6.36(s,2H).
Embodiment 8
the preparation of 5-chloro-3-hydroxyl-3-trifluoro methyl indole-2-ketone:
In p-Chlorobenzoic acid amide (3.8g, 30mmol), drip trifluoroacetone acetoacetic ester (51.3g, 300mmol), after dropwising, be warming up to oil bath about 150 DEG C.After reaction carries out 15 hours, remove oil bath, naturally cool to room temperature, visible a large amount of white solid is separated out, leach white solid, then petroleum ether, dry, obtain product (4.9g, yield 75%), do not need to be further purified and can carry out next step reaction.
Embodiment 9
the preparation of 3-hydroxyl-3-trifluoro methyl indole-2-ketone:
Aniline (2.1g, 23mmol) is dissolved in 1,2-dichlorobenzene (25mL), drips trifluoroacetone acetoacetic ester (19.6g, 115mmol), after dropwising, is warming up to oil bath about 200 DEG C.After reaction carries out 10 hours, remove oil bath, naturally cool to room temperature, visible a large amount of white solid is separated out, leach white solid, then petroleum ether, dry, obtain product (4.0g, yield 82%), do not need to be further purified and can carry out next step reaction.
1HNMR(Acetone-d
6,400MHz)δ6.51(s,1H),7.03(d,J=5.7Hz,1H),7.13(t,J=11.4Hz,5.7Hz,1H),7.42(t,J=11.4Hz,5.7Hz,1H),7.52(d,J=5.7Hz,1H),9.76(s,1H).
HRMS. calculated value C
9h
6f
3nO
2: 217.0351. measured value: 217.0353.
Claims (7)
1. a synthetic method for the chloro-2-trifluoroacetyl aniline of 4-and analogue thereof, the general structure of described 4-chloro-2-trifluoroacetyl aniline and analogue thereof is as follows:
In formula, Y is hydrogen, F, Cl or Br;
It is characterized in that being obtained by following step:
In the mixed solvent of organic solvent and water and at 0-100 DEG C, formula VI compound in the basic conditions, adds oxidizing ring-opening reaction 0.5-24 hour and obtains formula III compound;
Described formula VI compound is
wherein said Y
1for hydrogen, F, Cl or Br;
Described formula VI compound and the mol ratio of alkali and oxygenant are 1:(1-5): (1-3)
Wherein said alkali is LiOH, NaOH or KOH;
Described oxygenant is K
3[Fe (CN)
6];
Described organic solvent is tetrahydrofuran (THF), methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, t-butyl methyl ether, diethylene glycol dimethyl ether, acetonitrile, ethyl acetate, n-butyl acetate, DMF or N,N-dimethylacetamide;
Described organic solvent and the volume ratio of water are (1-5): 1.
2. synthetic method as claimed in claim 1, it is characterized in that described formula VI compound is for raw material with the aniline of formula IV, with the trifluoropropyl ketone acid methyl esters of formula V or ethyl ester without organic solvent, backflow obtains the 3-hydroxyl-3-trifluoro methyl indole-2-ketone of formula VI for 10-20 hour; The methyl esters of aniline and trifluoropropyl ketone acid or the mol ratio of ethyl ester are 1:(1-10);
Wherein said Y
1for hydrogen, F, Cl or Br, R
1for methyl or ethyl.
3. synthetic method as claimed in claim 1, is characterized in that the organic solvent in described step is tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, DMF, t-butyl methyl ether or acetonitrile.
4. method as claimed in claim 2, is characterized in that the methyl esters of the aniline described in step and trifluoropropyl ketone acid or the mol ratio of ethyl ester are 1:(1-5).
5. the method for claim 1, is characterized in that the alkali described in step is KOH.
6. a synthetic method for the bromo-2-trifluoroacetyl aniline of 4-, described 4-bromo-2-trifluoroacetyl aniline structural formula is as follows:
It is characterized in that being obtained by following step: get the bromo-3-hydroxyl of 5--3-trifluoro methyl indole-2-ketone 295mg, be dissolved in 15mL Isosorbide-5-Nitrae-dioxane, add 3mL water, then add 560mg KOH, dissolve fully, the disposable peroxy tert-butyl alcohol adding 540.7mg70%, treat that raw material reaction is complete, add extraction into ethyl acetate, organic phase washed with water, saturated common salt is washed, anhydrous sodium sulfate drying, removes solvent under reduced pressure, yield 93%.
7. a synthetic method for 2-trifluoroacetyl aniline, described 2-trifluoroacetyl aniline structural formula is as follows:
It is characterized in that being obtained by following step: get 217mg 3-hydroxyl-3-trifluoro methyl indole-2-ketone and be dissolved in 12mL tetrahydrofuran (THF), add 6mL water, then add 224mg KOH, dissolve fully, the disposable hydrogen peroxide adding 204mg30%, treat that raw material reaction is complete, add extraction into ethyl acetate, organic phase washed with water, saturated common salt is washed, anhydrous sodium sulfate drying, removes solvent under reduced pressure and obtains product, yield 90%.
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