CN104211677A - Preparation method of anti hepatitis C drug intermediate - Google Patents
Preparation method of anti hepatitis C drug intermediate Download PDFInfo
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- CN104211677A CN104211677A CN201310207680.XA CN201310207680A CN104211677A CN 104211677 A CN104211677 A CN 104211677A CN 201310207680 A CN201310207680 A CN 201310207680A CN 104211677 A CN104211677 A CN 104211677A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/60—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in six-membered rings
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
- C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
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- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
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Abstract
The invention provided a compound represented by the formula I and a method utilizing the compound to prepare an anti hepatitis C drug. The preparation method is simple and economic, and is capable of being applying to industrial production, so the preparation of an anti hepatitis C drug may be achieved. The formula I is represented in the description, wherein the R represents fluorine or hydrogen, and the n is equal to 2 or 3.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to a kind of preparation method of anti-hepatitis C pharmaceutical intermediate.
Background technology
Hepatitis C, referred to as hepatitis C, the third liver, a kind of by hepatitis C virus (Hepatitis C virus, HCV) viral hepatitis caused is infected, add up according to the World Health Organization, the infection rate of whole world HCV is about 3%, estimates that about 1.8 hundred million people have infected HCV, annual new hepatitis C case about 3.5 ten thousand example.Bromo-9, the 9-bis-fluoro-9-hydrogen-fluorenes-2-bases of 1-(7-) the chloro-ethyl ketone of-2-, No. CAS is 1378387-81-5, is the intermediate of anti-hepatitis C medicine.Structural formula is as follows:
。
Patent WO2012068234 embodiment LE discloses by bromo-9, the 9-bis-fluoro-9-hydrogen-fluorenes-2-bases of 1-(7-) the chloro-ethyl ketone of-2-prepares the route of anti-hepatitis C medicine, as follows:
Now also do not have bromo-9, the 9-bis-fluoro-9-hydrogen-fluorenes-2-bases of 1-(7-) preparation method of-2-chloro-ethyl ketone report, so be necessary the synthetic method developing this compound, for the preparation of anti-hepatitis C medicine.
Summary of the invention
The invention provides a kind of type I compound, and provide prepare bromo-9, the 9-bis-fluoro-9-hydrogen-fluorenes-2-bases of 1-(7-by formula I) method of the chloro-ethyl ketone of-2-, this preparation method's simple economy, can industrialization, provide possibility for finally preparing anti-hepatitis C medicine.
To achieve these goals, one of the technical solution used in the present invention is: provide a kind of type I compound,
, wherein R is fluorine or hydrogen, and n equals 2 or 3.
Type I compound is specially:
,
,
N equals 2 or 3.
Type I compound is more specifically:
,
,
,
。
Type I compound is preferably:
,
。
Two of the technical solution used in the present invention is: the preparation method providing formula IV compound, comprises the steps:
Formula III compound and fluorination reagent carry out addition reaction and obtain formula IV compound.
Wherein, fluorination reagent is N-F key class fluorination reagent or X-F key class fluorination reagent.
Need to add alkali in described addition reaction.
Described reaction scheme is as follows:
,
Or
,
Wherein, n equals 2 or 3.
Described N-F key class fluorination reagent is the two benzsulfamide of N-fluoro or Selectfluor.
The structural formula of Selectfluor is as follows:
。
Described X-F key class fluorination reagent is FClO
3or 2,4-bifluoride toluene iodide.
The two benzsulfamide of the preferred N-fluoro of described fluorination reagent.
Described alkali can be an alkali metal salt of alcohol, metal alkylide lithium compound or amido lithium compound.
An alkali metal salt of described alcohol can be potassium tert.-butoxide or sodium tert-butoxide.
Described metal alkylide lithium compound can be butyllithium or phenyl lithium.
Described amido lithium compound is lithium diisopropyl amido or two (trimethyl silicon based) Lithamide.
The mass ratio of described formula 3 compound, fluorination reagent and alkali is 1:2 ~ 6:2 ~ 6.
The mass ratio of described formula 3 compound, fluorination reagent and alkali is preferably 1:2 ~ 4:2 ~ 4.
Described reaction solvent for use can be ether solvent, alkane solvents or aromatic hydrocarbon solvent; Described ether solvent can be tetrahydrofuran (THF), methyltetrahydrofuran, cyclopentyl-methyl ether or ether; The preferred tetrahydrofuran (THF) of described ether solvent; Described alkane solvents can be normal hexane, hexanaphthene; Described aromatic hydrocarbon solvent can be toluene.
The temperature of described reaction is-90 DEG C ~ 10 DEG C, is preferably-80 DEG C ~-30 DEG C.
Three of the technical solution used in the present invention is: the preparation method providing formula III compound, comprises the steps:
The bromo-7-chloracetyl-fluorenes of formula II compound 2-and glycols formula II ' compound carry out ring-closure reaction and obtain formula III compound.
Described ring-closure reaction carries out under the effect of acid catalyst.
Its reaction scheme is as follows:
,
Wherein n equals 2 or 3.
Described acid catalyst can be sulphonic acids or Lewis acid, and described sulphonic acids catalyzer is a water tosic acid preferably, the preferred aluminum chloride of described Lewis acid.
The mass ratio of the bromo-7-chloracetyl-fluorenes of described 2-and glycol compound is 1:1 ~ 15.
The mass ratio of the bromo-7-chloracetyl-fluorenes of described 2-and glycol compound is preferably 1:2 ~ 5.
The solvent that described ring-closure reaction uses can be arene, alkanes or halogenated hydrocarbon solvent.Described aromatic hydrocarbon solvent is toluene or dimethylbenzene; Described alkane solvents is hexanaphthene; Described halogenated hydrocarbon solvent is chloroform or methylene dichloride.
The temperature of described ring-closure reaction is 60 DEG C ~ 90 DEG C.
Wherein, the bromo-7-chloracetyl-fluorenes of 2-can be reacted by 2-bromine fluorenes and chloroacetyl chloride to be prepared, and its reaction scheme is as follows:
,
2-bromine fluorenes can be reacted by fluorenes and N-bromosuccinimide to be prepared, and its reaction scheme is as follows:
。
Four of the technical solution used in the present invention is: provide bromo-9, the 9-bis-fluoro-9-hydrogen-fluorenes-2-bases of anti-hepatitis C pharmaceutical intermediate compound 1-(7-) method of the chloro-ethyl ketone of-2-, namely obtained by the reaction under the catalysis of acid or salt of formula IV compound.Its reaction scheme is as follows:
,
Wherein, n equals 2 or 3.
Described acid catalyst can be mineral acid example hydrochloric acid, sulfuric acid, methylsulfonic acid or perchloric acid, can be that organic acid is as acetic acid, oxalic acid, tosic acid.
Described salt catalyst can be pyridinium p-toluenesulfonate, Iodotrimethylsilane, titanium tetrachloride, tri-chlorination pyridine or a tetrafluoro borate.
The solvent of described reaction can be ether solvent, chloroparaffin kind solvent, ketones solvent, alcoholic solvent.
Described ether solvent can be tetrahydrofuran (THF), methyl tertiary butyl ether, ether or cyclopentyl methyl ether.
Described chloroparaffin kind solvent can be methylene dichloride, chloroform or 1,2-methylene dichloride.
Described ketones solvent can be acetone or methyl tertbutyl ketone.
Described alcoholic solvent can be methyl alcohol, ethanol, propyl alcohol or the trimethyl carbinol.
Type I compound provided by the invention and prepared the method for anti-hepatitis C pharmaceutical intermediate by type I compound, simple economy, can industrialization, provides possibility for finally preparing anti-hepatitis C medicine.
Embodiment
In order to understand the present invention further, below in conjunction with embodiment, the preparation method to anti-hepatitis C pharmaceutical intermediate provided by the invention is described in detail.It is to be appreciated that these embodiments describe just for further describing feature of the present invention, instead of the restriction to the scope of the invention or the claims in the present invention scope.
Embodiment 1:
In 500ml four-hole bottle, add 30g fluorenes, the propylene carbonate of 200ml, under stirring, be warming up to 40-50 DEG C, add 33gNBS in batches, detect complete to raw material primitive reaction at 40-50 DEG C of reaction 10h, GC again after adding, add 200ml water and stir 3h in 20-25 DEG C, filter, 50 DEG C of forced air drying 10h, obtain 2-bromine fluorenes, then obtain product 37g with alcohol crystal, yield 85%, GC 90%.
Embodiment 2:
10g 2-bromine fluorenes is added in 250ml four-hole bottle,-25 ~-20 DEG C are cooled to after 100ml methylene dichloride and 6.9g chloroacetyl chloride stirring and dissolving, slowly add 11g aluminum trichloride (anhydrous), finish again at-25 ~-20 DEG C of reaction 2h, reaction solution is poured in 300ml frozen water and be stirred to the precipitation of a large amount of solid, filter, 50 DEG C of forced air dryings obtain product 10.5g yield 80.2%, GC 98%.
Embodiment 3: the preparation of formula III-1 compound
,
The bromo-7-chloracetyl-fluorenes of 36g2-is added in 1000ml four-hole bottle; 700ml toluene; 25g ethylene glycol, 11g mono-water tosic acid, is heated to 90 DEG C of back flow reaction 5h and uses water trap reflux water-dividing complete to raw material reaction again; add 200mL washing once; organic phase is concentrated into dry in 50 DEG C of water-baths, adds 100ml ethanol in 20-25 DEG C of making beating 1h, filters; dry formula 3 compound 27.5g, yield 100%.
LCMS-ESI
+:364.99(M
+H
+),
1H-NMR:300MHZ,(CDCl3):δ:7.76-7.49(m,6H),4.25-4.20(d,2H),4.02-3.96(d,2H),3.89(s,2H),3.84(s,2H)。
Embodiment 4: the preparation of formula III-2 compound
,
The bromo-7-chloracetyl-fluorenes of 36g2-is added in 1000ml four-hole bottle; 700ml toluene, 30g 1,3-PD; 11g aluminum chloride; being heated to 90 DEG C of back flow reaction 5h uses water trap reflux water-dividing complete to raw material reaction again, and add 200mL washing once, organic phase is concentrated into dry in 50 DEG C of water-baths; add 100ml ethanol in 20-25 DEG C of making beating 1h; filter, dry formula 3 compound 42g, yield 94.1%.
Embodiment 5: the preparation of formula IV-1 compound
。
10g formula III-1 compound is added in 250ml four-hole bottle, the two benzsulfamide of 25.7gN-fluoro, 100g tetrahydrofuran (THF),-60 DEG C are cooled to by dry ice acetone bath, drip the tetrahydrofuran solution of two (trimethyl silicon based) Lithamide of 81g1mol/L, drip off and react 2h at-60 DEG C, the methanolic ammonia solution and the 35g normal heptane that add 0.5g15% stir 1h in-30 DEG C, be warming up to 20-25 DEG C, stir 1h, filter, filtrate 0-5 DEG C is stirred 1h, filter, again filtrate is concentrated into dry in 40 DEG C, add 200ml hexane and stir 30min, filter, filtrate is concentrated into dry in 40 DEG C, add the making beating of 30ml hexane, filter, 50 DEG C of dry formula IV-1 compound 10.5g, yield 95.5%, GC 93%.
LCMS-ESI
+:340.99(M
+H
+);
19F-NMR:282?MHZ,(CDCl
3)?δ:-111.20;
1H-NMR:300MHZ,(CDCl
3)?δ:7.78-7.44(m,6H),4.23-4.19(d,2H),3.96-3.93(d,2H),3.76(s,2H)。
Embodiment 6: the preparation of formula IV-1 compound
10g formula III-1 compound is added in 250ml four-hole bottle, 17.5g2, 4-bifluoride toluene iodide, 100g tetrahydrofuran (THF),-60 DEG C are cooled to by dry ice acetone bath, drip the tetrahydrofuran solution of two (trimethyl silicon based) Lithamide of 79g1mol/L, drip off and react 2h at-60 DEG C, the methanolic ammonia solution and the 35g normal heptane that add 0.5g15% stir 1h in-30 DEG C, be warming up to 20-25 DEG C, stir 1h, filter, filtrate 0-5 DEG C is stirred 1h, filter, again filtrate is concentrated into dry in 40 DEG C, add 200ml hexane and stir 30min, filter, filtrate is concentrated into dry in 40 DEG C, add the making beating of 30ml hexane, filter, 50 DEG C of dry formula IV-1 compound 10g, yield 91%.
Embodiment 7: the preparation of formula IV-2 compound
,
10g formula III-2 compound is added in 250ml four-hole bottle, 24.7gSelectfluor, 100g tetrahydrofuran (THF),-60 DEG C are cooled to by dry ice acetone bath, drip the tetrahydrofuran solution of two (trimethyl silicon based) Lithamide of 78g1mol/L, drip off and react 2h at-60 DEG C, the methanolic ammonia solution and the 35g normal heptane that add 0.5g15% stir 1h in-30 DEG C, be warming up to 20-25 DEG C, stir 1h, filter, filtrate 0-5 DEG C is stirred 1h, filter, again filtrate is concentrated into dry in 40 DEG C, add 200ml hexane and stir 30min, filter, filtrate is concentrated into dry in 40 DEG C, add the making beating of 30ml hexane, filter, 50 DEG C of dry formula IV-2 compound 10.7g, yield 93.86%.
Embodiment 8: the preparation of formula IV-2 compound
10g formula III-2 compound is added, 17.5g2,4-24.7gFClO in 250ml four-hole bottle
3100g tetrahydrofuran (THF), be cooled to-5 DEG C with ice bath salt, drip the solution of 9.6g potassium tert.-butoxide and 20g tetrahydrofuran (THF), drip off and react 2h at-5-0 DEG C, the methanolic ammonia solution and the 35g normal heptane that add 0.5g15% stir 1h in-30 DEG C, be warming up to 20-25 DEG C, stir 1h, filter, filtrate 0-5 DEG C is stirred 1h, filter, then filtrate is concentrated into dry in 40 DEG C, add 200ml and stir 30min, filter, filtrate is concentrated into dry in 40 DEG C, adds the making beating of 30ml hexane, filters, 50 DEG C of dry formula IV-2 compound 5g, yield 45.4%.
Embodiment 9: the preparation of formula IV-2 compound
10g formula III-2 compound is added in 250ml four-hole bottle, 17.5g2, the two benzsulfamide of 4-24.7gN-fluoro, 100g tetrahydrofuran (THF),-5 DEG C are cooled to ice bath salt, drip the solution of the tetrahydrofuran (THF) of 82ml 1mol/L lithium diisopropyl amido, drip off and react 2h at-5-0 DEG C, the methanolic ammonia solution and the 35g normal heptane that add 0.5g15% stir 1h in-30 DEG C, be warming up to 20-25 DEG C, stir 1h, filter, filtrate 0-5 DEG C is stirred 1h, filter, again filtrate is concentrated into dry in 40 DEG C, add 200ml hexane and stir 30min, filter, filtrate is concentrated into dry in 40 DEG C, add the making beating of 30ml hexane, filter, 50 DEG C of dry formula IV-2 compound 9.8g, yield 89.17%.
Embodiment 10:
9.8g formula IV-1 compound is added in 500ml four-hole bottle, the perchloric acid of 400ml methylene dichloride and 6.8g72%, be warming up to 40 DEG C of reaction 6h, be cooled to 20-25 DEG C, add 80ml water and 5g sodium bicarbonate stirring 5min layering, organic layer is decompressed to dry in 40 DEG C of water-baths, add the crystallization of 20ml Virahol, filter, 50 DEG C of dry 1-(7-bromo-9,9-bis-fluoro-9-hydrogen-fluorenes-2-base)-2-chloro-ethyl ketone 8.5g yield 90.4%, GC 93%.
Embodiment 11:
9.8g formula IV-1 compound is added in 500ml four-hole bottle, the hydrochloric acid of 400ml methylene dichloride and 7g30%, be warming up to 40 DEG C of reaction 10h, be cooled to 20-25 DEG C, add 80ml water and 5g sodium bicarbonate stirring 5min layering, organic layer is decompressed to dry in 40 DEG C of water-baths, add the crystallization of 20ml Virahol, filter, 50 DEG C of dry bromo-9,9-bis-fluoro-9-hydrogen-fluorenes-2-bases of 1-(7-)-2-chloro-ethyl ketone 5g yield 52.17%.
Embodiment 12:
9.8g formula IV-1 compound is added in 500ml four-hole bottle, 400ml methylene dichloride and 9.7g Iodotrimethylsilane, be warming up to 20-25 DEG C of reaction 20h, be cooled to 20-25 DEG C, add 80ml water and 5g sodium bicarbonate stirring 5min layering, organic layer is decompressed to dry in 40 DEG C of water-baths, add the crystallization of 20ml Virahol, filter, 50 DEG C of dry bromo-9,9-bis-fluoro-9-hydrogen-fluorenes-2-bases of 1-(7-)-2-chloro-ethyl ketone 7g yield 63.7%.
Embodiment 13:
9.8g formula IV-2 compound is added in 500ml four-hole bottle, the perchloric acid of 300ml acetone and 6.8g72%, be warming up to 40 DEG C of reaction 6h, be cooled to 20-25 DEG C, add 80ml water and 5g sodium bicarbonate stirring 5min layering, organic layer is decompressed to dry in 40 DEG C of water-baths, add the crystallization of 20ml Virahol, filter, 50 DEG C of dry bromo-9,9-bis-fluoro-9-hydrogen-fluorenes-2-bases of 1-(7-)-2-chloro-ethyl ketone 8.0g yield 72.8%.
Embodiment 14:
9.8g formula IV-2 compound is added in 500ml four-hole bottle, the perchloric acid of 350ml tetrahydrofuran (THF) and 6.8g72%, be warming up to 40 DEG C of reaction 4h, be cooled to 20-25 DEG C, add 80ml water and 5g sodium bicarbonate stirring 5min layering, organic layer is decompressed to dry in 40 DEG C of water-baths, add the crystallization of 20ml Virahol, filter, 50 DEG C of dry bromo-9,9-bis-fluoro-9-hydrogen-fluorenes-2-bases of 1-(7-)-2-chloro-ethyl ketone 8.7g yield 79.1%.
Embodiment 15:
9.8g formula IV-2 compound is added in 500ml four-hole bottle, the perchloric acid of 250ml propyl alcohol and 6.8g72%, be warming up to 60 DEG C of reaction 15h, be cooled to 20-25 DEG C, add 80ml water and 5g sodium bicarbonate stirring 5min layering, organic layer is decompressed to dry in 40 DEG C of water-baths, add the crystallization of 20ml Virahol, filter, 50 DEG C of dry bromo-9,9-bis-fluoro-9-hydrogen-fluorenes-2-bases of 1-(7-)-2-chloro-ethyl ketone 7.1g yield 64.6%.
Claims (10)
1. one kind has the compound of following structure:
, wherein R is fluorine or hydrogen, and n equals 2 or 3.
2. a preparation method for formula IV compound, is characterized in that, carries out addition reaction prepare by following formula III compound and fluorination reagent,
,
,
Wherein, the definition of n and identical in claim 1.
3. the preparation method of formula IV compound according to claim 2, is characterized in that, in described addition reaction, add alkali.
4. the preparation method of formula IV compound according to claim 2, it is characterized in that, described fluorination reagent is N-F key class fluorination reagent or X-F key class fluorination reagent, and described N-F key class fluorination reagent is the two benzsulfamide of N-fluoro or Selectfluor, and described X-F key class fluorination reagent is FClO
3or 2,4-bifluoride toluene iodide.
5. the preparation method of formula IV compound according to claim 3, is characterized in that, described alkali is an alkali metal salt of alcohol, metal alkylide lithium compound or amido lithium compound; An alkali metal salt of described alcohol is potassium tert.-butoxide or sodium tert-butoxide, and described metal alkylide lithium compound is butyllithium or phenyl lithium, and described amido lithium compound is lithium diisopropyl amido or two (trimethyl silicon based) Lithamide.
6. the preparation method of formula IV compound according to claim 2, is characterized in that, formula III compound carries out ring-closure reaction by the glycol compound shown in the chloro-ethanoyl of the bromo-7-of 2--fluorenes and following II ' and prepares,
,
The definition of n is identical with claim 1.
7. the preparation method of formula IV compound according to claim 6, is characterized in that, in described ring-closure reaction, add acid catalyst.
8. the preparation method of formula IV compound according to claim 7, is characterized in that, described acid catalyst is sulfonic acid or Lewis acid, and described sulfonic acid is a water tosic acid, and described Lewis acid is aluminum chloride.
9. the preparation method of formula IV compound according to claim 2, is characterized in that, formula IV compound prepares bromo-9, the 9-bis-fluoro-9-hydrogen-fluorenes-2-bases of anti-hepatitis C pharmaceutical intermediate compound 1-(7-under the effect of catalyzer) the chloro-ethyl ketone of-2-.
10. the preparation method of formula IV compound according to claim 9, is characterized in that, described catalyzer is acid or salt, and described acid is mineral acid or organic acid; Described mineral acid is hydrochloric acid, acetic acid, methylsulfonic acid, perchloric acid, and described organic acid is oxalic acid, tosic acid, and described salt is pyridinium p-toluenesulfonate, Iodotrimethylsilane, titanium tetrachloride, tri-chlorination pyridine or a tetrafluoro borate.
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Cited By (4)
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CN104513223A (en) * | 2014-11-20 | 2015-04-15 | 上海众强药业有限公司 | Preparation method of fluorene ethyl ketone derivative |
CN106800501A (en) * | 2017-02-16 | 2017-06-06 | 海门慧聚药业有限公司 | The preparation of Lei Dipawei intermediates |
CN108530262A (en) * | 2018-06-15 | 2018-09-14 | 贾红琴 | A kind of synthetic method of 2- bromines fluorenes |
CN109053400A (en) * | 2018-08-24 | 2018-12-21 | 江苏工程职业技术学院 | A kind of preparation method of Lei Dipawei key intermediate |
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MOHAMMAD REZA POOR HERAVI: ""An efficient fluorination of beta-ketosulfones promoted by a room-temperature ionic liquid at ambient conditions under ultrasound irradiation using Selectfluor TM F-TEDA-BF4", 《CHINESE CHEMICAL LETTERS》 * |
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CN104513223A (en) * | 2014-11-20 | 2015-04-15 | 上海众强药业有限公司 | Preparation method of fluorene ethyl ketone derivative |
WO2016078505A1 (en) * | 2014-11-20 | 2016-05-26 | 上海众强药业有限公司 | Preparation method of fluorene ethyl ketone derivative |
CN104513223B (en) * | 2014-11-20 | 2017-07-14 | 上海众强药业有限公司 | The preparation method of fluorenes ethanone derivatives |
CN106800501A (en) * | 2017-02-16 | 2017-06-06 | 海门慧聚药业有限公司 | The preparation of Lei Dipawei intermediates |
CN108530262A (en) * | 2018-06-15 | 2018-09-14 | 贾红琴 | A kind of synthetic method of 2- bromines fluorenes |
CN109053400A (en) * | 2018-08-24 | 2018-12-21 | 江苏工程职业技术学院 | A kind of preparation method of Lei Dipawei key intermediate |
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