CN108863900A - A kind of preparation method of 5- fluoro indole -2- ketone - Google Patents
A kind of preparation method of 5- fluoro indole -2- ketone Download PDFInfo
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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
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- C07D209/34—Oxygen atoms in position 2
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Abstract
The invention discloses a kind of preparation methods of 5- fluoro indole -2- ketone, include the following steps：With 2,4- difluoro nitrobenzene for raw material, under the conditions of aprotic polar solvent and inorganic base, condensation reaction is carried out with dimethyl malenate, it is post-treated to obtain the fluoro- 2- of 4- (malonic acid dimethyl ester group) nitrobenzene；The fluoro- 2- of 4- (malonic acid dimethyl ester group) nitrobenzene is generated into 5- fluoro- 2- nitrophenyl-acetic acid methyl esters in the presence of aprotic polar solvent and lithium chloride；The fluoro- 2- nitrophenyl-acetic acid methyl esters of 5-, catalyst and alcohols solvent are mixed and carry out adding hydrogen cyclization reaction, obtains 5- fluoro indole -2- ketone crude product；Crude product takes water as a solvent, and filters while hot through active carbon, is recrystallized to give the fluoro- indol-2-one of high-purity 5-.This method raw material is easy to get, simple process, and Raney's nickel catalyst and recrystallization aqueous solution can be applied repeatedly, and cost of material is lower, it is easy to accomplish industrialization has biggish application prospect.
Description
Technical field
The invention belongs to medicine intermediate preparation fields, and in particular to the preparation method of 5- fluoro indole -2- ketone.
Background technique
5- fluoro indole -2- ketone is a kind of important medicine intermediate, is widely used in the synthesis material of antalgic anti-inflammatory agent, closely
Again for the synthesis material as anti-cancer drugs Sutent and its derivative over year.Sutent be selectively targeting it is a variety of
First drug in the newtype drug of receptor tyrosine kinases, the drug be mainly used for treatment transfer or advanced renal cell carcinoma,
Gastrointestinal stromal tumor and progressivity pancreas neuroendocrine carcinoma, on January 26th, 2006 by United States Food and Drag Administration
(FDA) approval listing, 2011 annual sales amounts are up to 11.87 hundred million dollars.And the supplier of current domestic not mature production technology, therefore
Exploitation 5- fluoro indole -2- ketone has a vast market foreground.
5- fluoro indole -2- ketone the preparation method reported both at home and abroad at present mainly has several following：
(1) it is a kind of using para-fluoroaniline as raw material (document Sharma Ultrasonics Sonochemistry, 2011,18
(5), 1143-1147.), it is catalyst through condensation reaction occurs with chloracetyl chloride, then with alchlor, is obtained through Friedel-Crafts reaction
5- fluoro indole -2- ketone.The route steps are few, but have used and be more toxic, volatile chloracetyl chloride, and Friedel-Crafts reaction requires nothing
Water operation, reaction temperature is higher, the high requirements on the equipment, and generates hydrogen chloride tail gas, and environmental pollution is larger.In addition Fu Ke is anti-
A biggish isomers should can be generated, separation is more difficult, causes yield lower.
(2) one kind is using para-fluoroaniline as starting material (document Tetrahedron Letters, 2014,55 (14):2238-
2242. and patent CN103288709A), para-fluoroaniline and chloral hydrate, hydroxylamine hydrochloride effect, by amidation and oximate
Reaction is obtained to fluorine isonitroso aceotphenone compound, then obtains 5- fluoro indigo red by effect of sulfuric acid, under hydrazine hydrate effect, is led to
It crosses Wolff-Kishner- huang-Minlon reaction and obtains 5- fluoro indole -2- ketone.The route is relatively complicated, needs using explosive to heat
Fried and strong carcinogen hydrazine hydrate, industrialized production are subject to certain restrictions.
(3) it is a kind of with 2,4- difluoro nitrobenzene for starting material (patent CN104045592A and WO0206228), through methanol
Sodium, malonic acid dimethyl ester condensation generate the fluoro- 2- of 4- (malonic acid dimethyl ester group) nitrobenzene, then through iron powder (or palladium carbon catalytic hydrogenation)
Reduction obtains 3- methoxycarbonyl group -5- fluoro indole -2- ketone, most obtains 5- fluoro indole -2- ketone through hydrolysis decarboxylation afterwards.The preparation method
Obtained product yield is not high, and in addition each step is all made of column chromatography for separation, separating step is cumbersome and obtained product purity not
Height, industrial application value are little.
There is respective drawback in three of the above route, cause the country to there is no producer's large-scale production, therefore develop one kind
The method for being able to achieve industrialized production 5- fluoro indole -2- ketone just seems particularly necessary.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of 5- fluoro indole -2- ketone, this method raw material is easy to get, can
5- fluoro indole -2- the ketone of high-purity is synthesized with shirtsleeve operation technique, higher yield, lower cost.
The technical solution adopted by the present invention is as follows：
A kind of preparation method of 5- fluoro indole -2- ketone, includes the following steps：
(1) under nitrogen protection, with 2,4- difluoro nitrobenzene for raw material, in aprotic polar solvent and inorganic base condition
Under, condensation reaction is carried out with dimethyl malenate, obtains the fluoro- 2- of 4- (malonic acid dimethyl ester group) nitrobenzene using post-processing；
(2) under nitrogen protection, the fluoro- 2- of 4- (malonic acid dimethyl ester group) nitrobenzene step (1) obtained is (referred to as double
Ester) mixed with aprotic polar solvent, lithium chloride and water after, decarboxylic reaction generate the fluoro- 2- nitrophenyl-acetic acid methyl esters of 5- (referred to as
Monoesters)；
(3) monoesters that step (2) obtains is mixed with catalyst and alcohols solvent and carries out adding hydrogen cyclization reaction, obtain 5-
Fluoro indole -2- ketone crude product；
(4) the 5- fluoro indole -2- ketone crude product obtained step (3) is soluble in water, through active carbon decoloring and is recrystallized to give
Product 5- fluoro indole -2- ketone.
The method of the present invention is raw material by condensation reaction generation dibasic acid esters using 2,4- difluoro nitrobenzene, and dibasic acid esters is first passed through water
Solution reaction obtains monoesters, then carries out being hydrogenated into ring and react to obtain the 5- fluoro indole -2- ketone of low-purity.
Dibasic acid esters decarboxylic reaction is first generated monoesters by the method for the present invention, then 5- can be obtained after catalytic hydrogenation cyclization in monoesters
Fluoro indole -2- ketone crude product reacts according to this specific reaction sequence, improves the purity and yield of product；Finally by crude product benefit
With active carbon decoloring and recrystallization, the purity of product is further improved, has obtained the high-purity 5- fluorine Yin that purity is 99.5%
Diindyl -2- ketone, has widened its application range.
Synthetic route of the invention is as follows：
In step (1), the inorganic base is sodium methoxide or sodium hydride, preferably sodium methoxide.
In step (1), the molar ratio of 2, the 4- difluoro nitrobenzene, dimethyl malenate and inorganic base is 1：(1~
3)：(2~4), preferably 1:2:3.
In step (1), the temperature of the condensation reaction is 0~15 DEG C, preferably 5~10 DEG C.
In step (1) and step (2), the aprotic polar solvent is selected from n,N-Dimethylformamide, N, N- diformazan
Any one in yl acetamide or dimethyl sulfoxide, preferably n,N-dimethylacetamide.
In step (2), the molar ratio of the fluoro- 2- of the 4- (malonic acid dimethyl ester group) nitrobenzene and lithium chloride is 1：(1~
3), when dibasic acid esters dosage is excessive, dibasic acid esters decarboxylic reaction is incomplete, and impurity is more in product, will affect the yield of monoesters, and works as chlorine
When change lithium dosage is excessive, reaction rate can be made too fast, by-product generated increases；The molar ratio is more preferably 1:2.
In step (2), the reaction temperature is 80~100 DEG C, further preferably 100 DEG C.
In step (3), the mass ratio of the fluoro- 2- nitrophenyl-acetic acid methyl esters of the 5-, catalyst and alcohols solvent is 1:
(0.01~0.05):(2~5), preferably 1:0.03:3.
In step (3), the catalyst is Raney's nickel or palladium carbon, preferably Raney's nickel.
In step (3), the alcohols solvent is methanol, ethyl alcohol or butanol.
In step (4), the mass ratio of the 5- fluoro indole -2- ketone crude product and water is 1：(4~8), preferably 1:5.
Compared with prior art, the invention has the advantages that：
(1) for the method for the present invention with 2,4- difluoro nitrobenzene for raw material, 2,4- difluoro nitrobenzenes are that Lin Jiang chemical industry in Zhejiang is current
Industrialization Projects, therefore there are the huge advantages such as raw material is easy to get, cost is relatively low, is easily industrialized；
(2) simple process of the method for the present invention simplifies the refining methd to crude product, has obtained high-purity product, in addition,
Reaction Raney's nickel catalyst used and recrystallization aqueous solution can be applied repeatedly, saved resource, had biggish application prospect.
Specific embodiment
Embodiment 1
(1) in N2Under atmosphere, sodium methoxide 162g (3mol) and dry N, N- dimethylacetamide are added into 2L three-necked bottle
Amine 636g, is vigorously stirred, and dimethyl malenate 264g (2mol) is slowly added dropwise under ice bath；It is warming up to 10 DEG C after being added dropwise, delays
Slowly 2,4- difluoro nitrobenzene 159g (1mol) at the uniform velocity is added dropwise, TLC tracking reaction after completion of the reaction, is cooled to 5 DEG C, is constantly stirring
Mix down be slowly added dropwise 3% dilute hydrochloric acid solution, a large amount of faint yellow solids are precipitated, filter, solid is washed with water to neutrality, vacuum drying
Obtain faint yellow intermediate product dibasic acid esters 231.2g, molar yield 85.2%；
(2) in N2Under atmosphere, dibasic acid esters 135.6g (0.5mol), n,N-Dimethylformamide are added into 1L three-necked bottle
678g, lithium chloride 42.4g (1mol), water 9g open stirring, are warming up to 100 DEG C, and TLC tracking reaction reacts 3h, in 100 DEG C of items
Solvent is recovered under reduced pressure under part, adds 500mL water, a large amount of yellow solids are precipitated, filters, be dried in vacuo to obtain yellow intermediate product list
Ester 94.3g, molar yield 88.5%；
(3) in N2Under atmosphere, monoesters 106.6g, Raney's nickel 3.2g and anhydrous methanol 320g are added into 1L three-necked bottle,
Replacing hydrogen is passed through hydrogen into reaction system more than three times, using bubbling mode, reacts at 60 DEG C；TLC tracking is reacted to list
Ester disappears, and stands after fully reacting, supernatant liquor is transferred in another three-necked bottle, concentrated hydrochloric acid is added dropwise into reaction solution, returns
Water is added dropwise at a temperature of stream into reaction system, a large amount of pulverulent solids are precipitated in slow cooling to room temperature, and it filters, be washed to neutrality,
Vacuum drying obtains the fluoro- indol-2-one crude product 72.7g of off-white color 5-, purity 97.8%, molar yield 96.2%；
(4) 150g 5- fluoro indole -2- ketone crude product and 750g water are added into 1L three-necked bottle, is warming up to 85 DEG C, it is complete to material
After portion's dissolution, 1.5g active carbon is added, continues to stir 1h, filter while hot, filtrate is gradually cooled to room temperature, and (filtrate is next for filtering
Purification is applied), solid is washed with a small amount, and is dried in vacuo to obtain white crystals 138.2g, purity 99.5%, yield 92.1%.
Embodiment 2
(1) in N2Under atmosphere, sodium methoxide 108g (2mol) and dry N, N- dimethylacetamide are added into 2L three-necked bottle
Amine 468g, is vigorously stirred, and dimethyl malenate 132g (1mol) is slowly added dropwise under ice bath；It is warming up to 15 DEG C after being added dropwise, delays
Slowly 2,4- difluoro nitrobenzene 159g (1mol) at the uniform velocity is added dropwise, TLC tracking reaction after completion of the reaction, is cooled to 5 DEG C, is constantly stirring
Mix down be slowly added dropwise 3% dilute hydrochloric acid solution, a large amount of faint yellow solids are precipitated, filter, solid is washed with water to neutrality, vacuum drying
Obtain faint yellow intermediate product dibasic acid esters 228.1g, molar yield 84.1%；
(2) in N2Under atmosphere, dibasic acid esters 135.6g (0.5mol), n,N-dimethylacetamide are added into 1L three-necked bottle
678g, lithium chloride 21.2g (0.5mol), water 9g open stirring, are warming up to 80 DEG C, and TLC tracking reaction reacts 3h, at 100 DEG C
Under the conditions of be recovered under reduced pressure solvent, 500mL water is added, a large amount of yellow solids are precipitated, filters, be dried in vacuo to obtain yellow intermediate product list
Ester 90.8g, molar yield 85.2%；
(3) in N2Under atmosphere, monoesters 106.6g, Raney's nickel 5.3g, anhydrous methanol 520g, displacement are added into 1L three-necked bottle
Hydrogen is passed through hydrogen into reaction system more than three times, using bubbling mode, reacts at 60 DEG C；TLC tracking reaction to monoesters disappears
It loses, is stood after fully reacting, supernatant liquor is transferred in another three-necked bottle, concentrated hydrochloric acid, reflux temperature are added dropwise into reaction solution
Water is added dropwise under degree into reaction system, a large amount of pulverulent solids are precipitated in slow cooling to room temperature, filter, are washed to neutrality, vacuum
It is dried to obtain the fluoro- indol-2-one crude product 71.9g of off-white color 5-, purity 97.8%, molar yield 95.2%；
(4) 150g 5- fluoro indole -2- ketone crude product and 1200g water are added into 1L three-necked bottle, 85 DEG C are warming up to, to material
All after dissolution, 1.5g active carbon is added, continues to stir 1h, filter while hot, filtrate is gradually cooled to room temperature, filters (under filtrate
Secondary purification is applied), solid is washed with a small amount, and is dried in vacuo to obtain white crystals 138.0g, purity 99.5%, yield 92%.
Embodiment 3
(1) in N2Under atmosphere, sodium methoxide 216g (4mol) and dry N, N- dimethylacetamide are added into 3L three-necked bottle
Amine 879g, is vigorously stirred, and dimethyl malenate 396g (3mol) is slowly added dropwise under ice bath；0 DEG C is warming up to after being added dropwise, slowly
2,4- difluoro nitrobenzene 159g (1mol) at the uniform velocity is added dropwise, TLC tracking reaction after completion of the reaction, is cooled to 5 DEG C, is being stirred continuously
Under be slowly added dropwise 3% dilute hydrochloric acid solution, a large amount of faint yellow solids are precipitated, filter, solid is washed with water to neutrality, is dried in vacuo
Faint yellow intermediate product dibasic acid esters 221.5g, molar yield 81.7%；
(2) in N2Under atmosphere, dibasic acid esters 135.6g (0.5mol), n,N-dimethylacetamide are added into 1L three-necked bottle
678g, lithium chloride 63.6g (1.5mol), water 9g open stirring, are warming up to 90 DEG C, and TLC tracking reaction reacts 3h, at 100 DEG C
Under the conditions of be recovered under reduced pressure solvent, 500mL water is added, a large amount of yellow solids are precipitated, filters, be dried in vacuo to obtain yellow intermediate product list
Ester 91.2g, molar yield 85.6%；
(3) in N2Under atmosphere, monoesters 106.6g is added into 1L three-necked bottle, Raney's nickel 1.1g (above criticizes bottom of bottle recovery set
With), anhydrous methanol 220g, replacing hydrogen is passed through hydrogen into reaction system more than three times, using bubbling mode, anti-at 60 DEG C
It answers；TLC tracking reaction to monoesters disappears, and stands after fully reacting, supernatant liquor is transferred in another three-necked bottle, to reaction
Concentrated hydrochloric acid is added dropwise in liquid, water is added dropwise under reflux temperature into reaction system, slow cooling to room temperature is precipitated a large amount of powdered solid
Body filters, is washed to neutrality, is dried in vacuo and obtains the fluoro- indol-2-one crude product 72.2g of off-white color 5-, purity 97.8%, mole
Yield is 95.6%；
(4) 150g 5- fluoro indole -2- ketone crude product and 600g water are added into 1L three-necked bottle, is warming up to 85 DEG C, it is complete to material
After portion's dissolution, 1.5g active carbon is added, continues to stir 1h, filter while hot, filtrate is gradually cooled to room temperature, and (filtrate is next for filtering
Purification is applied), solid is washed with a small amount, and is dried in vacuo to obtain white crystals 137.7g, purity 99.5%, yield 91.8%.
Comparative example 1
(1) dibasic acid esters is made according to method described in step (1) in embodiment 1；
(2) in N2Under atmosphere, 2.71g (10.0mmol) dibasic acid esters and 0.24g (10%pd, 55%H are added in reaction flask2O)
Palladium carbon, after replacing hydrogen, the ethyl acetate of 50mL is added, temperature is adjusted to 20 DEG C and is reacted, TLC tracking, after completion of the reaction
Diatomite is added to be filtered, is directly concentrated, column chromatography for separation uses ethyl acetate：Petroleum ether=1:1 (V/V) elution, is changed
Close object 3- methoxycarbonyl group -5- fluoro indole -2- ketone, yield 92%；
(3) methanol of 3- methoxycarbonyl group -5- fluoro indole -2- ketone 2.09g (10.0mmol) and 50mL are added in reaction flask,
The hydrochloric acid 5mL (30.0mmol) of 6M is added, goes under reflux and is reacted, TLC tracking, 2h end of reaction, decompression, which is revolved, removes solvent
Methanol is added ethyl acetate and is extracted, after washed with saturated common salt and dry with anhydrous sodium sulfate, then be concentrated, column layer
Analysis separation, uses ethyl acetate：Petroleum ether=3:1 (V/V) is eluted, and white solid 5- fluoro indole -2- ketone is obtained, and purity is
95.1%, yield 95%.
Claims (10)
1. a kind of preparation method of 5- fluoro indole -2- ketone, includes the following steps：
(1) under nitrogen protection, with 2,4- difluoro nitrobenzene for raw material, under the conditions of aprotic polar solvent and inorganic base, with
Dimethyl malenate carries out condensation reaction, obtains the fluoro- 2- of 4- (malonic acid dimethyl ester group) nitrobenzene using post-processing；
(2) under nitrogen protection, the fluoro- 2- of 4- (malonic acid dimethyl ester group) nitrobenzene and aprotonic polar step (1) obtained
After solvent, lithium chloride and water mixing, decarboxylic reaction generates the fluoro- 2- nitrophenyl-acetic acid methyl esters of 5-；
(3) the fluoro- 2- nitrophenyl-acetic acid methyl esters of 5- that step (2) obtains is mixed with catalyst and alcohols solvent and carries out adding hydrogen ring
Reaction is closed, 5- fluoro indole -2- ketone crude product is obtained；
(4) the 5- fluoro indole -2- ketone crude product obtained step (3) is soluble in water, through active carbon decoloring and is recrystallized to give product
5- fluoro indole -2- ketone.
2. the preparation method of 5- fluoro indole -2- ketone according to claim 1, which is characterized in that described in step (1)
Inorganic base is sodium methoxide or sodium hydride.
3. the preparation method of 5- fluoro indole -2- ketone according to claim 1, which is characterized in that described in step (1)
The molar ratio of 2,4- difluoro nitrobenzene, dimethyl malenate and inorganic base is 1：1~3：2~4.
4. the preparation method of 5- fluoro indole -2- ketone according to claim 1, which is characterized in that in step (1), the contracting
The temperature for closing reaction is 0~15 DEG C.
5. the preparation method of 5- fluoro indole -2- ketone according to claim 1, which is characterized in that step (1) and step (2)
In, the aprotic polar solvent is n,N-Dimethylformamide, n,N-dimethylacetamide or dimethyl sulfoxide.
6. the preparation method of 5- fluoro indole -2- ketone according to claim 1, which is characterized in that described in step (2)
The molar ratio of the fluoro- 2- of 4- (malonic acid dimethyl ester group) nitrobenzene and lithium chloride is 1：1~3.
7. the preparation method of 5- fluoro indole -2- ketone according to claim 1, which is characterized in that described in step (2)
The reaction temperature of hydrolysis is 80~100 DEG C.
8. the preparation method of 5- fluoro indole -2- ketone according to claim 1, which is characterized in that described in step (3)
The mass ratio of the fluoro- 2- nitrophenyl-acetic acid methyl esters of 5-, catalyst and alcohols solvent is 1:0.01~0.05:2~5.
9. the preparation method of 5- fluoro indole -2- ketone according to claim 1, which is characterized in that described in step (3)
Catalyst is Raney's nickel or palladium carbon.
10. the preparation method of 5- fluoro indole -2- ketone according to claim 1, which is characterized in that in step (4), the 5-
The mass ratio of fluoro indole -2- ketone crude product and water is 1：4~8.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112079764A (en) * | 2020-10-12 | 2020-12-15 | 山东汇海医药化工有限公司 | Synthesis method of sunitinib intermediate 5-fluoroindole-2-ketone |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104045592A (en) * | 2014-05-07 | 2014-09-17 | 华东理工大学 | 5-fluoroindole-2-one preparation method |
-
2018
- 2018-08-27 CN CN201810981136.3A patent/CN108863900A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104045592A (en) * | 2014-05-07 | 2014-09-17 | 华东理工大学 | 5-fluoroindole-2-one preparation method |
Non-Patent Citations (2)
| Title |
|---|
| GEORGE J. QUALLICH, P.M. MORRISSEY: "A General Oxindole Synthesis", 《SYNTHESIS》 * |
| 河北化工学校 田铁牛: "《有机合成单元过程》", 31 July 1999, 化学工业出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112079764A (en) * | 2020-10-12 | 2020-12-15 | 山东汇海医药化工有限公司 | Synthesis method of sunitinib intermediate 5-fluoroindole-2-ketone |
| CN112079764B (en) * | 2020-10-12 | 2023-08-01 | 山东汇海医药化工有限公司 | Synthesis method of sunitinib intermediate 5-fluoroindol-2-one |
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