CN102285909B - Preparation method of benzpyrole-2-ketone compound - Google Patents
Preparation method of benzpyrole-2-ketone compound Download PDFInfo
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Abstract
The invention provides a preparation method of a benzpyrole-2-ketone compound. The preparation method comprises the following steps: a), mixing a metal reducer with TiCl4 in an organic solvent so as to obtain a low-valence tiron, wherein the valence state of titanium in the low-valence tiron can be one or more of 0, +1, +2 and +3; b), mixing the low-valence tiron with an isatin compound for reduction reaction so as to obtain an intermediate product; and c), mixing the intermediate product with hydrochloric acid so as to remove a titanium salt, and purifying so as to obtain the benzpyrole-2-ketone compound. The preparation method provided by the invention is easy to operate and has short reaction time and mild conditions.
Description
Technical field
The present invention relates to the synthetic field of organic compound, be specifically related to a kind of preparation method of indole-2-ketone compound.
Background technology
The indol-2-one skeleton is similar to the VITAMIN B4 structure, and its derivative has inhibition, regulates receptor kinase and antineoplastic activity, is also the important intermediate of synthesis of natural product and medicine.For example: 5-chloro-indole-2-ketone is the initial raw material of novel non_steroidal anti_inflammatory drug tenidap (tenidap), and 5-fluoro indole-2-ketone is applied to the synthetic of monoamine re-uptake inhibitor, tyrosine protein kinase inhibitor etc.Unique biological nature due to them, caused more and more many investigators' interest.Along with agricultural chemicals and pharmaceutical prod develop to heterocyclic, will develop more and more and use containing indole ketone compound.Indol-2-one is widely used, expensive, and it is developed to the research important in inhibiting.
It by the isatin direct-reduction, is the common method for preparing indol-2-one.Existing method generally adopts yellow toot the dragon reduction (Huang of Wolff-Kishner-, M.-L.J.Am.Chem.Soc., 1946,68,2487.): in glycol ether or triglycol, isatin and 85% hydrazine hydrate (3-4equiv.) backflow 1h make the intermediate hydrazone, add highly basic after cooling again, then heating is anhydrated to reacting liquid temperature and is risen to 190-200 ℃, heating 2-3h to reduction fully.Synth.Commun. the method that (1994) are introduced is that the hydrazine hydrate backflow 30min of isatin and 98% is reacted completely, this method is without aftertreatment intermediate hydrazone, one step just obtains corresponding indol-2-one, productive rate can be brought up to 76% (C.Crestini, R.Saladino, Synth.Commun., 1994,24 (20), 2835-2841.).United States Patent (USP) (U.S.5973165) discloses a kind of method that isatin reduction prepares indol-2-one in addition, isatin and 85% hydrazine hydrate are placed in to a kind of polar solvent DMF that contains the weak base sodium-acetate, be heated to 100 ℃ of reaction 8h, without processing intermediate, directly obtain indolone, productive rate can reach 85%.PCT Int Appl 2007072841 is improved yellow toot dragon reduction again recently, adopt three steps, the first step is made solvent with butanols, isatin and 85% hydrazine hydrate are reacted to 3h at 80 ℃, and second step adds the weak base triethylamine again, and temperature is raised to 100 ℃ of reaction 16h, the final step acidifying, adjusting pH is 6, obtains final product, and productive rate is up to 98%.
Yellow toot this method synthesis technique of dragon reduction of Wolff-Kishner-is simple to operate, and productive rate is high, can amplify, but have synthesis temperature high, and long reaction time, waste raw material and wait deficiency.A large amount of anhydrous methanol and the sodium ethylates of reaction needed as J.Chem.Edu. (1993) report, in case basic active reduces, and sodium ethylate is reacted and is obtained by dehydrated alcohol and sodium sheet, to pay close attention to safety when processing sodium, highly basic participates in reacting also also very high to the requirement of experiment reaction conditions in addition, processes extremely complicated.And Synth.Commun. (1994) needs 98% hydrazine hydrate to participate in reacting although the method reaction times of introducing is shorter, the hydrazine hydrate price due to 98% is high, and the heat explosive, stores pretty troublesomely, and this method does not have practical value.All solvent and alkali are improved in above-mentioned patent in addition, but the reaction times is still very long, and temperature is very high.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of indole-2-ketone compound, and the preparation method is easy to operate, short, mild condition of reaction times.
In order to solve the prior art problem, the invention provides a kind of preparation method of indole-2-ketone compound, comprising:
A) by metallic reducing agent and TiCl
4mix in organic solvent, obtain low valent titanium reagent; In described low valent titanium reagent the valence state of titanium be 0 ,+1 ,+2 ,+one or more in 3;
B) low valent titanium reagent is mixed with the isatin compounds, carry out reduction reaction, obtain intermediate product;
C) by described intermediate product and 3wt%～5wt% mixed in hydrochloric acid, remove titanium salt, obtain indole-2-ketone compound after purifying.
Preferably, the general formula of described indole-2-ketone compound is suc as formula shown in I, and the general formula of described isatin compounds is suc as formula shown in II;
Wherein, R
1for CH
3or H; R
2for F, Cl, Br or CH
3.
Preferably, described metallic reducing agent is Zn, Fe, Mg, Al or Sm.
Preferably, described organic solvent is tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane.
Preferably, the described reduction reaction time is 5～10min.
Preferably, step a) is specially: in nitrogen atmosphere, by metallic reducing agent and TiCl
4be in molar ratio (1～3): 1 mixes, the 1.5～2.5h that refluxes, the valence state that obtains titanium in the described low valent titanium reagent of low valent titanium reagent can be for 0 ,+1 ,+2 ,+one or more in 3.
Preferably, step b) be specially, by described low valent titanium reagent, with the isatin compounds, be (1～5) in molar ratio: 1 mixes, and carries out reduction reaction, obtains intermediate product.
Preferably, the temperature of described reduction reaction is 0～80 ℃.
Preferably, step c) be specially:
Described 3wt% for intermediate product～5wt% hydrochloric acid is decomposed, then extract and merge organic layer;
Described organic layer is washed to neutrality, dry, filter, boil off solvent, obtain indole-2-ketone compound.
The preparation method of indole-2-ketone compound provided by the invention, first use metallic reducing agent by TiCl
4be reduced to low valent titanium reagent, the valence state of described low valent titanium reagent is 0 ,+1 ,+2 ,+one or more in 3, then react with the isatin compounds with low valent titanium reagent, then through aftertreatment, obtain indol-2-one.Due to what use, it is low valent titanium reagent, valence state in reagent is 0, + 1, + 2, + 3 titanium character is active, can with the isatin compounds on the ketone carbonyl form pentacyclic titanyl complex compound, deoxygenation then occurs, 3-position Sauerstoffatom is sloughed in reduction, the five-ring that former isatin class chemical combination is contained to the NH key forms the structure of loop-like amylene shape, and form the OTiO key at 2, under acidic conditions, described OTiO key decomposes, form hydroxyl, again due to the existence of two keys, hydroxyl is unstable, two keys are opened, hydrogen transference on hydroxyl is to the position of former double key carbon, oxygen on hydroxyl and another double key carbon form carbonyl, thereby obtain indole-2-ketone compound.This change in process is fast, can within lesser temps and shorter time, complete all reaction process.Experiment showed, that preparation method's productive rate provided by the invention is more than 80%, the reaction times is 5～10 minutes, and temperature is 0～80 ℃.
Embodiment
In order further to understand the present invention, below in conjunction with embodiment, the preferred embodiments of the present invention are described, but should be appreciated that these are described is the restriction for further illustrating the features and advantages of the present invention rather than patent of the present invention being required.
The invention provides a kind of preparation method of indole-2-ketone compound, comprising: a) by metallic reducing agent and TiCl
4mix in organic solvent, obtain low valent titanium reagent; In described low valent titanium reagent the valence state of titanium can be for 0 ,+1 ,+2 ,+one or more in 3;
B) low valent titanium reagent is mixed with the isatin compounds, carry out reduction reaction, obtain intermediate product;
C) by described intermediate product and 3wt%～5wt% mixed in hydrochloric acid, remove titanium salt, obtain indole-2-ketone compound after purifying.
According to the present invention, described indole-2-ketone compound general formula is preferably suc as formula shown in I, and the general formula of described isatin compounds is preferably suc as formula shown in II
Wherein, R
1for CH
3or H; R
2for F, Cl, Br or CH
3.
Preferred described indole-2-ketone compound is formula 1)～formula 9) shown in compound:
Table 1 formula 1) the indoles 2-ketone compounds～formula 9)
According to isatin compounds of the present invention formula 10 more preferably)～formula 18) shown in compound:
Table 2 formula 10) the isatin compounds～formula 20)
The prior art of comparing, preparation method provided by the invention, the preparation method of indole-2-ketone compound provided by the invention, first use metallic reducing agent by TiCl
4be reduced to low valent titanium reagent, the valence state of described low valent titanium reagent is 0 ,+1 ,+2 ,+one or more in 3, then react with the isatin compounds with low valent titanium reagent, then through aftertreatment, obtain indol-2-one.According to the present invention, described to prepare the concrete synthesis mechanism of indol-2-one with low valent titanium reagent reduction isatin compounds as follows, with TiCl
4, Zn, formula 10) shown in the isatin compounds be example:
Can be found out TiCl by above-mentioned reaction equation
4preferentially by zinc powder reduction, become the tiron Ti (0) of 0 valency, low valent titanium reagent has reductibility and the very strong oxygen ability of taking by force, formula 10) at first described isatin compounds is generated the titanyl complex compound by the low valent titanium reagent reduction, deoxidation occurs and generates titanium salt in the latter, finally by hydrochloric acid, decomposes and becomes indol-2-one with tautomerism.
According to the present invention, described metallic reducing agent, except Zn, can also be selected one or more in Fe, Mg, Al, Sm, and the principle that metallic reducing agent is selected is to have reductibility, Ti can be reduced into to low valent titanium reagent.Metallic reducing agent physical condition provided by the invention is preferably powder or Nano microsphere.
According to the present invention, described organic solvent is preferably tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane, more preferably anhydrous tetrahydro furan.
According to the present invention, the preparation method of indole-2-ketone compound provided by the invention is specially:
In nitrogen atmosphere, by metallic reducing agent and TiCl
4be in molar ratio (1～3): 1 mixes, the 1.5～2.5h that refluxes, the valence state that obtains titanium in the described low valent titanium reagent of low valent titanium reagent can be for 0 ,+1 ,+2 ,+one or more in 3.
Described low valent titanium reagent is preferably to (1～5) in molar ratio with the isatin compounds: 1 mixes, and carries out reduction reaction, obtains intermediate product.The temperature of described reduction reaction is preferably 0～80 ℃, more preferably 10～40 ℃, most preferably is 20～25 ℃.The mol ratio of described low valent titanium reagent and isatin compounds is (2～4) more preferably: 1.
Described intermediate product is decomposed with the hydrochloric acid of 3wt%～5wt%, then extract and merge organic layer;
Described organic layer is washed to neutrality, dry, filter, boil off solvent, obtain indole-2-ketone compound.
The preparation method's provided by the invention reduction reaction time is preferably 5～10min, more preferably 6～8min.
Be below specific embodiment provided by the invention, in order to elaborate the present invention program:
Embodiment 1
1, add zinc powder 0.78g in the 100mL three-necked flask, 12mmol and anhydrous THF 20mL, nitrogen protection, stir under room temperature, slowly injects TiCl
40.7mL 6mmol, mixture backflow 2h, be cooled to room temperature and get final product to obtain the low valent titanium reagent of black pasty state, in described three-necked flask, slowly adds formula 10) shown in the 10mL THF solution of isatin compounds 2mmol, finish, room temperature reaction 5min, TLC detects.
2,, after reaction finishes, decompose with the hydrochloric acid of 20mL 3wt%, then use chloroform extraction 3 times, each 50mL.Merge organic layer, be washed to neutral 2 each 50mL, use anhydrous sodium sulfate drying, after the elimination siccative, the pressure reducing and steaming solvent, crude product obtains solid type 1 through ethyl alcohol recrystallization) shown in indole-2-ketone compound: indol-2-one, 0.25g.
Indol-2-one: m.p.124-125 ℃ (lit.126 ℃).
1h NMR (400MHz, CDCl
3for solvent, TMS is interior mark) δ 8.97 (s, 1H, NH), 7.22 (t, J=7.2Hz, 2H, ArH), 7.02 (t, J=7.6Hz, 1H, ArH), 6.09 (d, J=8.0Hz, 1H, ArH), 3.55 (s, 2H, CH
2). productive rate 94%.
Embodiment 2
1, add zinc powder 0.78g in the 100mL three-necked flask, 12mmol and anhydrous THF 20mL, nitrogen protection, stir under room temperature, slowly injects TiCl
40.7mL 6mmol, mixture backflow 2h, be cooled to room temperature and get final product to obtain the low valent titanium reagent of black pasty state, in described three-necked flask, slowly adds formula 11) shown in the 10mL THF solution of isatin compounds 2mmol, finish, room temperature reaction 5min, TLC detects.
2,, after reaction finishes, decompose with the hydrochloric acid of 20mL 3wt%, then use chloroform extraction 3 times, each 50mL.Merge organic layer, be washed to neutral 2 each 50mL, use anhydrous sodium sulfate drying, after the elimination siccative, the pressure reducing and steaming solvent, crude product obtains solid type 2 through ethyl alcohol recrystallization) shown in indole-2-ketone compound: 4-chloro-indole-2-ketone 0.31g.
4-chloro-indole-2-ketone: m.p.125-126 ℃.
1h NMR (400MHz, CDCl
3for solvent, TMS is interior mark) δ 8.52 (s, 1H, NH), 7.18 (t, J=7.2Hz, 1H, ArH), 7.01 (d, J=7.6Hz, 1H, ArH), 6.79 (d, J=6.8Hz, 1H, ArH), 3.55 (s, 2H, CH
2). tight rate 93%.
Embodiment 3
1, add zinc powder 0.78g in the 100mL three-necked flask, 12mmol and anhydrous THF 20mL, nitrogen protection, stir under room temperature, slowly injects TiCl
40.7mL 6mmol, mixture backflow 2h, be cooled to room temperature and get final product to obtain the low valent titanium reagent of black pasty state, in described three-necked flask, slowly adds formula 12) shown in the 10mL THF solution of isatin compounds 2mmol, finish, room temperature reaction 5min, TLC detects.
2,, after reaction finishes, decompose with the hydrochloric acid of 20mL 3wt%, then use chloroform extraction 3 times, each 50mL.Merge organic layer, be washed to neutral 2 each 50mL, use anhydrous sodium sulfate drying, after the elimination siccative, the pressure reducing and steaming solvent, crude product obtains solid type 3 through ethyl alcohol recrystallization) shown in indole-2-ketone compound: 4-bromo indole-2-ketone 0.39g.
4-bromo indole-2-ketone m.p.190-192 ℃.
1h NMR (400MHz, CDCl
3for solvent, TMS is interior mark) δ 8.56 (s, 1H, NH), 7.08-7.17 (m, 2H, ArH), 6.83 (d, J=7.6Hz, 1H, ArH), 3.50 (s, 2H, CH
2). productive rate 92%.
Embodiment 4
1, add zinc powder 0.78g in the 100mL three-necked flask, 12mmol and anhydrous THF 20mL, nitrogen protection, stir under room temperature, slowly injects TiCl
40.7mL 6mmol, mixture backflow 2h, be cooled to room temperature and get final product to obtain the low valent titanium reagent of black pasty state, in described three-necked flask, slowly adds formula 13) shown in the 10mL THF solution of isatin compounds 2mmol, finish, room temperature reaction 5min, TLC detects.
2,, after reaction finishes, decompose with the hydrochloric acid of 20mL 3wt%, then use chloroform extraction 3 times, each 50mL.Merge organic layer, be washed to neutral 2 each 50mL, use anhydrous sodium sulfate drying, after the elimination siccative, the pressure reducing and steaming solvent, crude product obtains solid type 4 through ethyl alcohol recrystallization) shown in indole-2-ketone compound: 5-chloro-indole-2-ketone 0.30g.
5-chloro-indole-2-ketone: m.p.190-191 ℃ (lit.194 ℃).
1h NMR (400MHz, CDCl
3for solvent, TMS is interior mark) δ 8.85 (s, 1H, NH) 7.19 (d, J=8.4Hz, 2H, ArH), 6.81 (d, J=8.0Hz, 1H, ArH), 3.54 (s, 2H, CH
2), productive rate 90%.
Embodiment 5
1, add zinc powder 0.78g in the 100mL three-necked flask, 12mmol and anhydrous THF 20mL, nitrogen protection, stir under room temperature, slowly injects TiCl
40.7mL 6mmol, mixture backflow 2h, be cooled to room temperature and get final product to obtain the low valent titanium reagent of black pasty state, in described three-necked flask, slowly adds formula 14) shown in the 10mL THF solution of isatin compounds 2mmol, finish, room temperature reaction 5min, TLC detects.
2,, after reaction finishes, decompose with the hydrochloric acid of 20mL 3wt%, then use chloroform extraction 3 times, each 50mL.Merge organic layer, be washed to neutral 2 each 50mL, use anhydrous sodium sulfate drying, after the elimination siccative, the pressure reducing and steaming solvent, crude product obtains solid type 5 through ethyl alcohol recrystallization) shown in indole-2-ketone compound: 5-bromo indole-2-ketone 0.37g.
5-bromo indole-2-ketone m.p.188-190 ℃.
1h NMR (400MHz, CDCl
3for solvent, TMS is interior mark) δ 8.48 (s, 1H, NH), 7.35 (d, J=7.2Hz, 2H, ArH), 6.77 (d, J=8.8Hz, 1H, ArH), 3.55 (s, 2H, CH
2), productive rate 88%.
Embodiment 6
1, add zinc powder 0.78g in the 100mL three-necked flask, 12mmol and anhydrous THF 20mL, nitrogen protection, stir under room temperature, slowly injects TiCl
40.7mL 6mmol, mixture backflow 2h, be cooled to room temperature and get final product to obtain the low valent titanium reagent of black pasty state, in described three-necked flask, slowly adds formula 15) shown in the 10mL THF solution of isatin compounds 2mmol, finish, room temperature reaction 5min, TLC detects.
2,, after reaction finishes, decompose with the hydrochloric acid of 20mL 3wt%, then use chloroform extraction 3 times, each 50mL.Merge organic layer, be washed to neutral 2 each 50mL, use anhydrous sodium sulfate drying, after the elimination siccative, the pressure reducing and steaming solvent, obtain formula 6) shown in the indole-2-ketone compound crude product.
3, silica gel column chromatography [eluent V (acetone): V (sherwood oil)=1: 3] separates to obtain product 5-fluoro indole-2-ketone 0.27g.
5-fluoro indole-m.p.143-144 ℃ of 2-ketone (lit.140-141 ℃).
1h NMR (400MHz, CDCl
3for solvent, TMS is interior mark) δ 8.98 (s, 1H, NH), 6.99-6.89 (m, 2H, ArH), 6.83-6.79 (m, 1H, ArH), 3.55 (s, 2H, CH
2). productive rate 89%.
Embodiment 7
1, add zinc powder 0.78g in the 100mL three-necked flask, 12mmol and anhydrous THF 20mL, nitrogen protection, stir under room temperature, slowly injects TiCl
40.7mL 6mmol, mixture backflow 2h, be cooled to room temperature and get final product to obtain the low valent titanium reagent of black pasty state, in described three-necked flask, slowly adds formula 16) shown in the 10mL THF solution of isatin compounds 2mmol, finish, room temperature reaction 5min, TLC detects.
2,, after reaction finishes, decompose with the hydrochloric acid of 20mL 3wt%, then use chloroform extraction 3 times, each 50mL.Merge organic layer, be washed to neutral 2 each 50mL, use anhydrous sodium sulfate drying, after the elimination siccative, the pressure reducing and steaming solvent, obtain formula 7) shown in the indole-2-ketone compound crude product.
3, silica gel column chromatography [eluent V (acetone): V (sherwood oil)=1: 3] separates to obtain product 5-skatole-2-ketone 0.25g.
5-skatole-m.p.186-188 ℃ of 2-ketone (lit.189 ℃).
1h NMR (400MHz, CDCl
3for solvent, TMS is interior mark) δ 8.47 (s, 1H, NH), 7.02 (t, J=5.6Hz, 2H, ArH), 6.77 (d, J=7.6Hz, 1H, ArH), 3.50 (s, 2H, CH
2), 2.31 (s, 3H, CH
3). productive rate 85%.
Embodiment 8
1, add zinc powder 0.78g in the 100mL three-necked flask, 12mmol and anhydrous THF 20mL, nitrogen protection, stir under room temperature, slowly injects TiCl
40.7mL 6mmol, mixture backflow 2h, be cooled to room temperature and get final product to obtain the low valent titanium reagent of black pasty state, in described three-necked flask, slowly adds formula 17) shown in the 10mL THF solution of isatin compounds 2mmol, finish, room temperature reaction 5min, TLC detects.
2,, after reaction finishes, decompose with the hydrochloric acid of 20mL 3wt%, then use chloroform extraction 3 times, each 50mL.Merge organic layer, be washed to neutral 2 each 50mL, use anhydrous sodium sulfate drying, after the elimination siccative, the pressure reducing and steaming solvent, crude product obtains solid type 8 through ethyl alcohol recrystallization) shown in indole-2-ketone compound: 6-bromo indole-2-ketone 0.38g.
6-bromo indole-m.p.211-213 ℃ of 2-ketone (lit.214-215 ℃).
1h NMR (400MHz, CDCl
3for solvent, TMS is interior mark) δ 8.34 (s, 1H, NH), 7.15 (dd, J
1=1.6Hz, J2=11.2Hz, 1H, ArH), 7.07 (t, J=8.0Hz, 2H, ArH), 3.48 (s, 2H, CH
2), tight rate 90%.
Embodiment 9
1, add zinc powder 0.78g in the 100mL three-necked flask, 12mmol and anhydrous THF 20mL, nitrogen protection, stir under room temperature, slowly injects TiCl
40.7mL 6mmol, mixture backflow 2h, be cooled to room temperature and get final product to obtain the low valent titanium reagent of black pasty state, in described three-necked flask, slowly adds formula 18) shown in the 10mL THF solution of isatin compounds 2mmol, finish, room temperature reaction 5min, TLC detects.
2,, after reaction finishes, decompose with the hydrochloric acid of 20mL 3wt%, then use chloroform extraction 3 times, each 50mL.Merge organic layer, be washed to neutral 2 each 50mL, use anhydrous sodium sulfate drying, after the elimination siccative, the pressure reducing and steaming solvent, crude product obtains solid type 9 through ethyl alcohol recrystallization) shown in indole-2-ketone compound: fluoro-7 skatoles of 5--2-ketone 0.29g.
The fluoro-7-skatole of 5--2-ketone m.p.198-200 ℃.
1h NMR (400MHz, CDCl
3for solvent, TMS is interior mark) δ 9.25 (s, 1H, NH), 7.05 (s, 2H, ArH), 3.55 (s, 2H, CH
2), 2.28 (s, 3H, CH
3). tight rate 87%.
By the described specific embodiment of embodiment 1～embodiment 9, to reach a conclusion, the resulting indole-2-ketone compound productive rate of the preparation method of indole-2-ketone compound provided by the invention is all more than 80%.Because the present invention has only reduced a carbonyl on the indoles five-ring in the isatin compounds, and do not change other structure, so the isatin compounds of unlisted other types reduction prepares the productive rate of indole-2-ketone compound and scheme release that reaction process can be set forth according to the present invention for the present invention, the present invention does not all describe.
The above preparation method to a kind of indole-2-ketone compound provided by the invention is described in detail; having applied specific case herein sets forth principle of the present invention and embodiment; the explanation of above scheme is just for helping to understand method of the present invention and core concept thereof; should be understood that; for those skilled in the art; under the premise without departing from the principles of the invention; can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
Claims (7)
1. the preparation method of an indole-2-ketone compound, is characterized in that, comprising:
A) by metallic reducing agent and TiCl
4mix in organic solvent, obtain low valent titanium reagent; In described low valent titanium reagent the valence state of titanium be 0 ,+1 ,+2 ,+one or more in 3; Described metallic reducing agent is Zn;
B) low valent titanium reagent is mixed with the isatin compounds, carry out reduction reaction, obtain intermediate product;
The general formula of described indole-2-ketone compound is suc as formula shown in I, and the general formula of described isatin compounds is suc as formula shown in II;
Wherein, R
1for CH
3or H; R
2for F, Cl, Br or CH
3;
C) by described intermediate product and mixed in hydrochloric acid, remove titanium salt, obtain indole-2-ketone compound after purifying.
2. preparation method according to claim 1, is characterized in that, described organic solvent is tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane.
3. preparation method according to claim 1, is characterized in that, the described reduction reaction time is 5～10min.
4. preparation method according to claim 1, is characterized in that, step a) is specially:
In nitrogen atmosphere, by metallic reducing agent and TiCl
4be in molar ratio (1～3): 1 mixes, and the 1.5～2.5h that refluxes, obtain low valent titanium reagent, in described low valent titanium reagent the valence state of titanium be 0 ,+1 ,+2 ,+one or more in 3.
5. preparation method according to claim 1, is characterized in that, step b) is specially, and by described low valent titanium reagent, with the isatin compounds, be (1～5) in molar ratio: 1 mixes, and carries out reduction reaction, obtains intermediate product.
6. preparation method according to claim 5, is characterized in that, the temperature of described reduction reaction is 0～80 ℃.
7. preparation method according to claim 1, is characterized in that, step c) is specially:
Described 3wt% for intermediate product～5wt% hydrochloric acid is decomposed, then extract and merge organic layer; Described organic layer is washed to neutrality, dry, filter, boil off solvent, obtain indole-2-ketone compound.
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| CN106083690A (en) * | 2016-06-07 | 2016-11-09 | 青岛科技大学 | A kind of preparation method of polysubstituted 3 methylene indolones |
| CN108486183A (en) * | 2018-03-20 | 2018-09-04 | 安徽大学 | A method of synthesizing isatin using catalyst and copper ion |
| CN118754844A (en) * | 2024-09-09 | 2024-10-11 | 世华合创生物技术开发(山东)有限公司 | Preparation method of diclofenac sodium intermediate |
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