CN104211677B - A kind of preparation method of anti-hepatitis C pharmaceutical intermediate - Google Patents
A kind of preparation method of anti-hepatitis C pharmaceutical intermediate Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- 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
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
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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
- C07C45/59—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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- C—CHEMISTRY; METALLURGY
- 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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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
A kind of method that anti-hepatitis C pharmaceutical intermediate is prepared the invention provides type I compound and by type I compound.Preparation method simple economy, can industrialization, provide possibility finally to prepare anti-hepatitis C medicine.The structural formula of type I compound is as follows：
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of preparation method of anti-hepatitis C pharmaceutical intermediate.
Background technology
Viral hepatitis type C, referred to as hepatitis C, hepatitis are one kind by HCV (Hepatitis C
Virus, HCV) virus hepatitis caused by infection, counted according to the World Health Organization, global HCV infection rate is about 3%, estimation
About 1.8 hundred million people have infected HCV, annual new hair hepatitis C case about 3.5 ten thousand.1-（The fluoro- 9- hydrogen-fluorenes -2- of the bromo- 9,9- bis- of 7-
Base）The chloro- ethyl ketones of -2-, No. CAS is 1378387-81-5, is the intermediate of anti-hepatitis C medicine.Structural formula is as follows：
。
Patent WO2012068234 embodiments LE is disclosed by 1-（The fluoro- 9- hydrogen of the bromo- 9,9- bis- of 7--fluorenes -2- bases）- 2- is chloro-
Ethyl ketone prepares the route of anti-hepatitis C medicine, as follows：
There is not 1- also now（The fluoro- 9- hydrogen of the bromo- 9,9- bis- of 7--fluorenes -2- bases）The preparation method report of the chloro- ethyl ketones of -2-, so having
Necessity develops the synthetic method of the compound, the preparation for anti-hepatitis C medicine.
The content of the invention
The invention provides a kind of type I compound, and provide and 1- is prepared by compound of formula I（The bromo- bis- fluoro- 9- of 9,9- of 7-
Hydrogen-fluorenes -2- bases）The method of the chloro- ethyl ketones of -2-, the preparation method simple economy, can industrialization, finally to prepare anti-hepatitis C
Medicine provides possibility.
To achieve these goals, one of the technical solution adopted by the present invention is：A kind of type I compound is provided,
, wherein R is fluorine or hydrogen, and n is equal to 2 or 3.
Type I compound is specially：
,,
N is equal to 2 or 3.
Type I compound is more specifically：
,,
,。
Type I compound is preferably：
,。
The two of the technical solution adopted by the present invention are：The preparation method of the compound of formula IV is provided, is comprised the following steps：
The compound of formula III carries out addition reaction with fluorination reagent and obtains the compound of formula IV.
Wherein, fluorination reagent is N-F key class fluorination reagents or X-F key class fluorination reagents.
Need to add alkali in the addition reaction.
The reaction scheme is as follows：
,
Or
,
Wherein, n is equal to 2 or 3.
The N-F keys class fluorination reagent is the double benzsulfamides of N- fluoro or Selectfluor.
Selectfluor structural formula is as follows：
。
The X-F keys class fluorination reagent is FClO3Or 2,4- bifluoride iodotoluene.
The double benzsulfamides of the preferred N- fluoro of fluorination reagent.
The alkali can be alkali metal salt, metal alkyl lithium compound or the amido lithium compound of alcohol.
The alkali metal salt of the alcohol can be potassium tert-butoxide or sodium tert-butoxide.
The metal alkyl lithium compound can be butyl lithium or phenyl lithium.
The amido lithium compound is lithium diisopropyl amido or two（Trimethyl silicon substrate）Lithium amide.
The mass ratio of the compound of formula 3, fluorination reagent and alkali is 1：2~6：2~6.
The mass ratio of the compound of formula 3, fluorination reagent and alkali is preferably 1：2~4：2~4.
The reaction solvent for use can be ether solvent, alkane solvents or aromatic hydrocarbon solvent；The ether solvent
Can be tetrahydrofuran, methyltetrahydrofuran, cyclopentyl-methyl ether or ether；The preferred tetrahydrofuran of ether solvent；It is described
Alkane solvents can be n-hexane, hexamethylene；The aromatic hydrocarbon solvent can be toluene.
The temperature of the reaction is -90 DEG C ~ 10 DEG C, is preferably -80 DEG C ~ -30 DEG C.
The three of the technical solution adopted by the present invention are：The preparation method of the compound of formula III is provided, is comprised the following steps：
The bromo- 7- chloracetyls-fluorenes of the compound 2- of formula II obtains formula III with the compound of glycols formula II ' progress ring-closure reaction and changed
Compound.
The ring-closure reaction is carried out in the presence of acid catalyst.
Its reaction scheme is as follows：
,
Wherein n is equal to 2 or 3.
The acid catalyst can be sulphonic acids or lewis acid, and a sulphonic acids catalyst preferably water is to toluene sulphur
Acid, the preferred alchlor of lewis acid.
The mass ratio of the bromo- 7- chloracetyls-fluorenes of the 2- and glycol compound is 1：1~15.
The mass ratio of the bromo- 7- chloracetyls-fluorenes of the 2- and glycol compound is preferably 1：2~5.
Solvent used in the ring-closure reaction can be arene, alkanes or halogenated hydrocarbon solvent.The fragrance
Varsol is toluene or dimethylbenzene；The alkane solvents are hexamethylene；The halogenated hydrocarbon solvent is chloroform or dichloromethane
Alkane.
The temperature of the ring-closure reaction is 60 DEG C ~ 90 DEG C.
Wherein, the bromo- 7- chloracetyls-fluorenes of 2- can be prepared by 2- bromines fluorenes and chloracetyl chloride reaction, and its reaction scheme is as follows：
,
2- bromines fluorenes can be prepared by fluorenes and N-bromosuccinimide reaction, and its reaction scheme is as follows：
。
The four of the technical solution adopted by the present invention are：Provide anti-hepatitis C pharmaceutical intermediate compound 1-（7- bromo- 9,
The fluoro- 9- hydrogen of 9- bis--fluorenes -2- bases）The method of the chloro- ethyl ketones of -2-, i.e., reacted and be made under the catalysis of acid or salt by the compound of formula IV.
Its reaction scheme is as follows：
,
Wherein, n is equal to 2 or 3.
The acid catalyst can be inorganic acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid or perchloric acid, can be organic acid such as second
Acid, oxalic acid, p-methyl benzenesulfonic acid.
The salt catalyst can be pyridinium p-toluenesulfonate, Iodotrimethylsilane, titanium tetrachloride, tri-chlorination pyridine or
Tetrafluoroborate.
The solvent of the reaction can be ether solvent, alkyl chloride varsol, ketones solvent, alcohols solvent.
The ether solvent can be tetrahydrofuran, methyl tertiary butyl ether(MTBE), ether or cyclopentyl methyl ether.
The alkyl chloride varsol can be dichloromethane, chloroform or 1,2- dichloromethane.
The ketones solvent can be acetone or methyl tertbutyl ketone.
The alcohols solvent can be methanol, ethanol, propyl alcohol or the tert-butyl alcohol.
Type I compound provided by the invention and the method that anti-hepatitis C pharmaceutical intermediate is prepared by type I compound, simply
Economy, can industrialization, provide possibility finally to prepare anti-hepatitis C medicine.
Embodiment
For a further understanding of the present invention, with reference to embodiment to anti-hepatitis C pharmaceutical intermediate provided by the invention
Preparation method be described in detail.It is to be appreciated that the description of these embodiments is simply of the invention to be further described
Feature, rather than the limitation to the scope of the invention or scope of the invention as claimed.
Embodiment 1：
30g fluorenes is added in 500ml four-hole bottles, 200ml propene carbonate, 40-50 DEG C is warming up under stirring, in batches
Add 33gNBS, after adding again 40-50 DEG C react 10h, GC detect it is complete to raw material fundamental reaction, add 200ml water in 20-25
DEG C stirring 3h, filtering, 50 DEG C of forced air drying 10h, obtain 2- bromine fluorenes, then product 37g, yield 85%, GC 90% are obtained with alcohol crystal.
Embodiment 2：
10g 2- bromine fluorenes is added in 250ml four-hole bottles, it is cold after 100ml dichloromethane and 6.9g chloracetyl chloride stirring and dissolvings
But to -25 ~ -20 DEG C, 11g aluminum trichloride (anhydrous)s are slowly added into, finishes and reacts 2h at -25 ~ -20 DEG C again, reaction solution is poured into
Stirred in 300ml frozen water to there are a large amount of solids to separate out, filtering, 50 DEG C of forced air dryings obtain product 10.5g yields 80.2%, GC
98%。
Embodiment 3：The preparation of the compound of formula III -1
,
The bromo- 7- chloracetyls-fluorenes of 36g2-, 700ml toluene, 25g ethylene glycol, the water of 11g mono- are added in 1000ml four-hole bottles
P-methyl benzenesulfonic acid, it is heated to 90 DEG C of back flow reaction 5h and reacts complete with water knockout drum reflux water-dividing to raw material again, add 200mL to wash one
Secondary, organic phase is concentrated to dryness in 50 DEG C of water-baths, adds 100ml ethanol to be beaten 1h, filtering, dry the compound of formula 3 in 20-25 DEG C
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 the compound of formula III -2
,
The addition bromo- 7- chloracetyls-fluorenes of 36g2- in 1000ml four-hole bottles, 700ml toluene, 30g 1,3-PDs,
11g alchlors, it is heated to 90 DEG C of back flow reaction 5h and reacts complete with water knockout drum reflux water-dividing to raw material again, add 200mL to wash
Once, organic phase is concentrated to dryness in 50 DEG C of water-baths, adds 100ml ethanol to be beaten 1h, filtering, dry the compound of formula 3 in 20-25 DEG C
42g, yield 94.1%.
Embodiment 5：The preparation of the compound of formula IV -1
。
The compound of 10g formulas III -1, the double benzsulfamides of 25.7gN- fluoro, 100g tetrahydrochysene furans are added in 250ml four-hole bottles
Mutter, -60 DEG C are cooled to dry ice acetone bath, be added dropwise the two of 81g1mol/L（Trimethyl silicon substrate）The tetrahydrofuran solution of lithium amide,
Drip off and react 2h at -60 DEG C, the methanolic ammonia solution and 35g normal heptanes for adding 0.5g15% stir 1h in -30 DEG C, are warming up to 20-25
DEG C, 1h, filtering, 0-5 DEG C of stirring 1h of filtrate, filtering are stirred, then filtrate is concentrated to dryness in 40 DEG C, add 200ml hexanes to stir
30min, filtering, filtrate is concentrated to dryness in 40 DEG C, adds 30ml hexanes to be beaten, filtering, 50 DEG C of dry compounds of formula IV -1
10.5g, yield 95.5%, GC 93%.
LCMS-ESI+：340.99(M+H+)；
19F-NMR：282 MHZ, (CDCl3) δ：-111.20；
1H-NMR：300MHZ, (CDCl3) 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 the compound of formula IV -1
The compound of 10g formulas III -1,17.5g2,4- bifluoride iodotoluenes, 100g tetrahydrochysene furans are added in 250ml four-hole bottles
Mutter, -60 DEG C are cooled to dry ice acetone bath, be added dropwise the two of 79g1mol/L（Trimethyl silicon substrate）The tetrahydrofuran solution of lithium amide,
Drip off and react 2h at -60 DEG C, the methanolic ammonia solution and 35g normal heptanes for adding 0.5g15% stir 1h in -30 DEG C, are warming up to 20-25
DEG C, 1h, filtering, 0-5 DEG C of stirring 1h of filtrate, filtering are stirred, then filtrate is concentrated to dryness in 40 DEG C, add 200ml hexanes to stir
30min, filtering, filtrate is concentrated to dryness in 40 DEG C, adds 30ml hexanes to be beaten, filtering, 50 DEG C of dry compound 10g of formula IV -1,
Yield 91%.
Embodiment 7：The preparation of the compound of formula IV -2
,
The compound of 10g formulas III -2 is added in 250ml four-hole bottles, 24.7gSelectfluor, 100g tetrahydrofurans, is used
Dry ice acetone bath is cooled to -60 DEG C, is added dropwise the two of 78g1mol/L（Trimethyl silicon substrate）The tetrahydrofuran solution of lithium amide, is dripped off
2h is reacted at -60 DEG C, the methanolic ammonia solution and 35g normal heptanes for adding 0.5g15% stir 1h in -30 DEG C, are warming up to 20-25 DEG C,
1h, filtering, 0-5 DEG C of stirring 1h of filtrate, filtering are stirred, then filtrate is concentrated to dryness in 40 DEG C, adds 200ml hexanes to stir 30min,
Filtering, filtrate is concentrated to dryness in 40 DEG C, adds 30ml hexanes to be beaten, filtering, 50 DEG C of dry compound 10.7g of formula IV -2, yield
93.86% 。
Embodiment 8：The preparation of the compound of formula IV -2
The compound of 10g formulas III -2,17.5g2,4-24.7gFClO are added in 250ml four-hole bottles3, 100g tetrahydrofurans,
- 5 DEG C are cooled to ice bath salt, the solution of 9.6g potassium tert-butoxides and 20g tetrahydrofurans is added dropwise, drips off and reacts 2h at -5-0 DEG C,
The methanolic ammonia solution and 35g normal heptanes for adding 0.5g15% stir 1h in -30 DEG C, are warming up to 20-25 DEG C, stir 1h, filtering, filtrate
0-5 DEG C of stirring 1h, filtering, then filtrate is concentrated to dryness in 40 DEG C, add 200ml to stir 30min, filtering, filtrate is in 40 DEG C of concentrations
To dry, 30ml hexanes are added to be beaten, filtering, 50 DEG C of dry compound 5g of formula IV -2, yield 45.4%.
Embodiment 9：The preparation of the compound of formula IV -2
The compound of addition 10g formulas III -2 in 250ml four-hole bottles, 17.5g2, the double benzsulfamides of 4-24.7gN- fluoro,
100g tetrahydrofurans, -5 DEG C are cooled to ice bath salt, be added dropwise 82ml 1mol/L lithium diisopropyl amidos tetrahydrofuran it is molten
Liquid, drip off and react 2h at -5-0 DEG C, the methanolic ammonia solution and 35g normal heptanes for adding 0.5g15% stir 1h in -30 DEG C, are warming up to
20-25 DEG C, 1h, filtering, 0-5 DEG C of stirring 1h of filtrate, filtering are stirred, then filtrate is concentrated to dryness in 40 DEG C, adds 200ml hexanes to stir
30min is mixed, is filtered, filtrate is concentrated to dryness in 40 DEG C, adds 30ml hexanes to be beaten, filtering, 50 DEG C of dry compounds of formula IV -2
9.8g, yield 89.17%.
Embodiment 10：
The perchloric acid of the compound of 9.8g formulas IV -1,400ml dichloromethane and 6.8g72% is added in 500ml four-hole bottles, is risen
Temperature is cooled to 20-25 DEG C, adds 80ml water and the stirring 5min layerings of 5g sodium acid carbonates, organic layer is in 40 DEG C to 40 DEG C of reaction 6h
Water-bath is decompressed to dry, adds 20ml isopropanols to crystallize, filtering, 50 DEG C of dry 1-（The fluoro- 9- hydrogen of the bromo- 9,9- bis- of 7--fluorenes -2- bases）-
The chloro- ethyl ketone 8.5g yields 90.4% of 2-, GC 93%.
Embodiment 11：
The hydrochloric acid of the compound of 9.8g formulas IV -1,400ml dichloromethane and 7g30% is added in 500ml four-hole bottles, is warming up to
40 DEG C of reaction 10h, are cooled to 20-25 DEG C, add 80ml water and the stirring 5min layerings of 5g sodium acid carbonates, organic layer is in 40 DEG C of water
Bath is decompressed to dry, adds 20ml isopropanols to crystallize, filtering, 50 DEG C of dry 1-（The fluoro- 9- hydrogen of the bromo- 9,9- bis- of 7--fluorenes -2- bases）-2-
Chloro- ethyl ketone 5g yields 52.17%.
Embodiment 12：
The compound of 9.8g formulas IV -1,400ml dichloromethane and 9.7g Iodotrimethylsilanes are added in 500ml four-hole bottles,
20-25 DEG C of reaction 20h is warming up to, is cooled to 20-25 DEG C, adds 80ml water and the stirring 5min layerings of 5g sodium acid carbonates, organic layer
It is decompressed in 40 DEG C of water-baths dry, adds 20ml isopropanols to crystallize, filtering, 50 DEG C of dry 1-（The fluoro- 9- hydrogen-fluorenes-of the bromo- 9,9- bis- of 7-
2- bases）The chloro- ethyl ketone 7g yields 63.7% of -2-.
Embodiment 13：
The perchloric acid of the compound of 9.8g formulas IV -2,300ml acetone and 6.8g72% is added in 500ml four-hole bottles, is warming up to
40 DEG C of reaction 6h, are cooled to 20-25 DEG C, add 80ml water and the stirring 5min layerings of 5g sodium acid carbonates, organic layer is in 40 DEG C of water-baths
It is decompressed to dry, adds 20ml isopropanols to crystallize, filtering, 50 DEG C of dry 1-（The fluoro- 9- hydrogen of the bromo- 9,9- bis- of 7--fluorenes -2- bases）- 2- is chloro-
Ethyl ketone 8.0g yields 72.8%.
Embodiment 14：
The perchloric acid of the compound of 9.8g formulas IV -2,350ml tetrahydrofurans and 6.8g72% is added in 500ml four-hole bottles, is risen
Temperature is cooled to 20-25 DEG C, adds 80ml water and the stirring 5min layerings of 5g sodium acid carbonates, organic layer is in 40 DEG C to 40 DEG C of reaction 4h
Water-bath is decompressed to dry, adds 20ml isopropanols to crystallize, filtering, 50 DEG C of dry 1-（The fluoro- 9- hydrogen of the bromo- 9,9- bis- of 7--fluorenes -2- bases）-
The chloro- ethyl ketone 8.7g yields 79.1% of 2-.
Embodiment 15：
The perchloric acid of the compound of 9.8g formulas IV -2,250ml propyl alcohol and 6.8g72% is added in 500ml four-hole bottles, is warming up to
60 DEG C of reaction 15h, are cooled to 20-25 DEG C, add 80ml water and the stirring 5min layerings of 5g sodium acid carbonates, organic layer is in 40 DEG C of water
Bath is decompressed to dry, adds 20ml isopropanols to crystallize, filtering, 50 DEG C of dry 1-（The fluoro- 9- hydrogen of the bromo- 9,9- bis- of 7--fluorenes -2- bases）-2-
Chloro- ethyl ketone 7.1g yields 64.6%.
Claims (10)
- A kind of 1. compound with following structure：, wherein R is fluorine or hydrogen, and n is equal to 2 or 3.
- 2. a kind of preparation method of the compound of formula IV, it is characterised in that addition is carried out by the compound of following formula III and fluorination reagent Reaction is prepared,,,Wherein, n definition is identical with claim 1.
- 3. the preparation method of the compound of formula IV according to claim 2, it is characterised in that added in the addition reaction Alkali.
- 4. the preparation method of the compound of formula IV according to claim 2, it is characterised in that the fluorination reagent is N-F keys Class fluorination reagent or X-F key class fluorination reagents, the N-F keys class fluorination reagent be the double benzsulfamides of N- fluoro or Selectfluor, the X-F keys class fluorination reagent are FClO3Or 2,4- bifluoride iodotoluene.
- 5. the preparation method of the compound of formula IV according to claim 3, it is characterised in that the alkali is the alkali metal of alcohol Salt, metal alkyl lithium compound or amido lithium compound；The alkali metal salt of the alcohol is potassium tert-butoxide or sodium tert-butoxide, the alkane Base Metal lithium compound is butyl lithium or phenyl lithium, and the amido lithium compound is lithium diisopropyl amido or two（Trimethyl silicane Base）Lithium amide.
- 6. the preparation method of the compound of formula IV according to claim 2, it is characterised in that the compound of formula III is by the bromo- 7- of 2- Chloro- acetyl group-fluorenes carries out ring-closure reaction with the glycol compound shown in following II ' and is prepared,,N definition is identical with claim 1.
- 7. the preparation method of the compound of formula IV according to claim 6, it is characterised in that added in the ring-closure reaction Acid catalyst.
- 8. the preparation method of the compound of formula IV according to claim 7, it is characterised in that the acid catalyst be sulfonic acid or Lewis acid, the sulfonic acid are a water p-methyl benzenesulfonic acid, and the lewis acid is alchlor.
- 9. the preparation method of the compound of formula IV according to claim 2, it is characterised in that the compound of formula IV is in catalyst Effect is lower to prepare anti-hepatitis C pharmaceutical intermediate compound 1-（The fluoro- 9- hydrogen of the bromo- 9,9- bis- of 7--fluorenes -2- bases）The chloro- ethyl ketones of -2-.
- 10. the preparation method of the compound of formula IV according to claim 9, it is characterised in that the catalyst is sour or salt, The acid is inorganic acid or organic acid；The inorganic acid be hydrochloric acid, acetic acid, methanesulfonic acid, perchloric acid, the organic acid be oxalic acid, P-methyl benzenesulfonic acid, the salt are pyridinium p-toluenesulfonate, Iodotrimethylsilane, titanium tetrachloride, tri-chlorination pyridine or tetrafluoro boron Hydrochlorate.
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| 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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| US4079062A (en) * | 1974-11-18 | 1978-03-14 | Janssen Pharmaceutica N.V. | Triazole derivatives |
| WO2012068234A2 (en) * | 2010-11-17 | 2012-05-24 | Gilead Sciences, Inc. | Antiviral compounds |
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