WO2016078505A1 - 芴乙酮衍生物的制备方法 - Google Patents

芴乙酮衍生物的制备方法 Download PDF

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WO2016078505A1
WO2016078505A1 PCT/CN2015/093114 CN2015093114W WO2016078505A1 WO 2016078505 A1 WO2016078505 A1 WO 2016078505A1 CN 2015093114 W CN2015093114 W CN 2015093114W WO 2016078505 A1 WO2016078505 A1 WO 2016078505A1
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compound
formula
group
inert solvent
produce
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张锡璇
傅绍军
魏哲文
李巍
黄成军
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上海众强药业有限公司
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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
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • 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
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • 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
    • C07C45/59—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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

Definitions

  • the invention relates to the field of preparation of pharmaceutical intermediates, in particular, the invention provides a preparation method of a synthetic intermediate of Radipavir.
  • LDV Ledipasvir
  • BAST is easily decomposed by heat, which has great safety hazards; the lack of selectivity in the introduction of acetyl groups, the use of expensive Pd reagents, and the use of highly toxic organotins, the above factors limit the method. use.
  • the above method is safe to carry out the fluorination reaction, and the selectivity of acetylation is good, but the Weinreb amide (i.e., 2-chloro-N-methoxy-N-methyl-acetamide) is relatively expensive and is not suitable for industrial production.
  • Weinreb amide i.e., 2-chloro-N-methoxy-N-methyl-acetamide
  • the present invention provides a novel process for the preparation of compounds of formula I.
  • the method includes the steps of:
  • Z 1 , Z 2 are each independently selected from the group consisting of H, Cl, Br or I;
  • Z 3 is halogen or OCOR 1 ; wherein R 1 is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl;
  • R 2 and R 3 are each independently H or a C1-C2 alkyl group
  • R 4 and R 5 are each independently none, H or methyl
  • n 0 or 1
  • the deprotection reaction is a hydrolysis reaction.
  • said Z 1 and Z 2 are the same.
  • said Z 1 and Z 2 are different.
  • the reaction temperature is usually from (-40) ° C to 40 ° C.
  • the reaction time is usually from 1 to 12 hours, preferably from 1 to 4 hours.
  • the inert solvent is selected from the group consisting of dichloromethane, dichloroethane, chlorobenzene, dichlorobenzene, carbon tetrachloride, carbon disulfide, or a combination thereof.
  • the reaction temperature is usually -20 ° C to 150 ° C.
  • the reaction time is usually from 1 to 12 hours, preferably from 1 to 5 hours.
  • the inert solvent is selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane, benzene, toluene, and Toluene, or a combination thereof.
  • the reaction temperature is usually -100 ° C to 30 ° C.
  • the reaction time is usually from 5 minutes to 24 hours, preferably from 1 to 2 hours.
  • the inert solvent is selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, or a combination thereof.
  • the reaction temperature is usually from 0 ° C to 100 ° C.
  • the reaction time is usually from 0 to 24 hours, preferably from 1 to 4 hours.
  • the reaction in the step (iv), is carried out in a solvent selected from the group consisting of acetone, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetonitrile, methanol, ethanol, water. , or a combination thereof.
  • a solvent selected from the group consisting of acetone, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetonitrile, methanol, ethanol, water. , or a combination thereof.
  • M and Q are each independently F or H; the remaining groups are as defined in the first aspect of the invention.
  • the M and Q are both F, or the M and Q are both H.
  • the method further includes the steps of:
  • the catalyst in the step (i) is selected from the group consisting of AlY 3 , BY 3 , a complex of BY 3 and Et 2 O, FeY 3 , ZnY 2 , TiY 4 , H 2 SO 4 , HF, polyphosphoric acid, sulfonic acid type ion exchange resin, Or a combination thereof;
  • R 6 is H or a C1-C4 alkyl group
  • Y is selected from the group consisting of chlorine, bromine or iodine.
  • the catalyst is AlY 3 .
  • the fluorinating agent is selected from the group consisting of:
  • Ra is selected from the group consisting of CF 3 , C 2 F 5 , C 8 F 17 , C 6 F 5 , 4-FC 6 H 4 , 4-CF 3 C 6 H 4 , Ph, 4-MeC 6 H 4 , n-Bu, t-Bu;
  • Rb is selected from the group consisting of C1-C10 alkyl, 4-(2,3,5,6-tetrafluoropyridyl), 4-(2,5,6-trifluoropyridine Base), cC 6 H 11 , CH 2 Bu-t, endo-2-norbornyl, exo-2-norbornyl;
  • R is selected from the group consisting of F, OH, CH 2 Cl, CH 3 , C 2 H 5 , nC 8 H 17 , CH 2 CF 3 , CH 2 Cl; and X is selected from the group consisting of F, BF 4 , OTf , PF 6 , FSO 3 , HSO 4 , H 2 F 3 , SbF 6 .
  • the fluorinating agent is selected from the group consisting of NFSI, NFOBS, and Selectfluor.
  • the base is selected from the group consisting of MMHDS, MH, MNH 2 , R 7 OM, PhM, (Ph) 3 CM, R 7 M, LDA, DBU, DBN
  • M is Li, Na or K
  • R 7 is a C1-C4 alkyl group.
  • LiHMDS LiHMDS, NaHMDS, LDA or DBU.
  • the deprotection in the step (iv) is carried out under acid catalysis
  • the acid is selected from the group consisting of H 2 SO 4 , HX, H 3 PO 4 , polyphosphoric acid, HNO 3 , CH 3 SO 3 H, CF 3 SO 3 H, HOAc, CF 3 COOH, a sulfonic acid type ion exchange resin, HXO 4 , or a combination thereof; wherein R 6 is H or a C1-C4 alkyl group; and X is selected from the group consisting of Cl, Br, and I.
  • a method for preparing radipavir comprising the steps of:
  • the method further comprises the steps of:
  • the process further comprises the step of: (1) reacting a compound of formula I with a halogenating agent in an inert solvent.
  • the halogenating agent is selected from the group consisting of bromine, chlorine, SO 2 Cl 2 or I 2 .
  • the reaction temperature is usually -50 ° C to 50 ° C.
  • the reaction time is usually from 5 minutes to 24 hours, preferably from 0.5 to 6 hours.
  • the inert solvent is selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, or a combination thereof.
  • C1-C4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, n-butyl, t-butyl, or the like.
  • halogen means fluoro, chloro, bromo, iodo.
  • references to “halogen” are preferably chlorine, bromine or iodine.
  • room temperature means 10-40 ° C, preferably 20-25 ° C.
  • alkyl is preferably a C1-C10 alkyl group, more preferably a C1-C4 alkyl group.
  • the present invention provides a compound of the following formula A:
  • M and Q are each independently F or H; the remaining groups are as defined in the first aspect of the invention; preferably, both M and Q are F, or said M and Q All are H.
  • the compound of formula A can be prepared by the following steps:
  • Z 1 , Z 2 are each independently selected from the group consisting of H, Cl, Br or I;
  • R 2 and R 3 are each independently H or a C1-C2 alkyl group
  • R 4 and R 5 are each independently H or methyl
  • n 0 or 1
  • the Z 1 and Z 2 may be the same or different, preferably the same.
  • the reaction may optionally comprise the step (iiia): reacting a compound of formula A with a fluorinating agent and a base .
  • the fluorinating agent is selected from the group consisting of:
  • Ra Rb Ra Rb CF 3 4-(2,3,5,6-tetrafluoropyridyl) 4-MeC 6 H 4 Me CF 3 4-(2,5,6-trifluoropyridyl) 4-MeC 6 H 4 t-Bu CF 3 Me 4-MeC 6 H 4 cC 6 H 11 CF 3 n-Bu 4-MeC 6 H 4 Exo-2-norkel base CF 3 t-Bu 4-MeC 6 H 4 Endo-2-norborne base C 2 F 5 alkyl 4-MeC 6 H 4 CH 2 Bu-t
  • the most preferred fluorinating agent is selected from the group consisting of NFSI and Selectfluor.
  • the base is selected from the group consisting of MHMDS, MH, MNH 2 , R 7 OM, PhM, (Ph) 3 CM. , R 7 M, LDA, DBU, DBN; wherein M is Li, Na, K, R 7 is a C1-C4 alkyl group; more preferably selected from the group consisting of LiHMDS, NaHMDS, LDA or DBU.
  • reaction conditions of the step (iia) or the step (iiia), such as the temperature, the reaction time, the solvent and the like, are not particularly limited, and those skilled in the art can select an appropriate temperature according to actual needs, by a method commonly used in the art (eg, TLC) and the like determine the end point of the reaction, and the solvent may be selected from any inert solvent which does not react with the reactant.
  • the reaction temperature is usually -20 ° C to 120 ° C
  • the reaction time is usually 1 to 12 hours, preferably 1 to 5 hours
  • the inert solvent may be selected from the group consisting of Solvent: tetrahydrofuran, methyltetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane, toluene, or a combination thereof.
  • the reaction temperature is usually -100 ° C to 20 ° C
  • the reaction time is usually 5 min to 24 hours, preferably 1 to 2 hours
  • the solvent can be selected from the group consisting of the following Solvent: tetrahydrofuran, methyltetrahydrofuran, dioxane, or a combination thereof.
  • the invention also provides a process for the preparation of a compound of formula I, the process comprising the steps of:
  • Said deprotection is preferably carried out by a hydrolysis reaction; preferably, the deprotection in said step (iv) is carried out under acid catalysis;
  • the acid is not particularly limited, and is preferably an acid selected from the group consisting of H 2 SO 4 , HX, H 3 PO 4 , polyphosphoric acid, HNO 3 , CH 3 SO 4 , CF 3 SO 4 , HOAc, CF. 3 COOH, a sulfonic acid type ion exchange resin, HXO 4 , or a combination thereof; wherein R 6 is H or a C1-C4 alkyl group; and X is selected from the group consisting of Cl, Br, and I.
  • the starting compound of the formula VII can be obtained by the method of the present invention or by other methods known in the art. After the structure of the compound of the formula VII is disclosed, such preparation is carried out. It should be considered to be within the abilities of those skilled in the art. In a comparison of the present invention, the preparation of the compound of formula I is prepared by the following starting materials and routes:
  • Z 1 , Z 2 are each independently selected from the group consisting of H, Cl, Br or I;
  • Z 3 is halogen or OCOR 1 ; wherein R 1 is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl;
  • R 2 and R 3 are each independently H or a C1-C2 alkyl group
  • R 4 and R 5 are each independently H or methyl
  • n 0 or 1
  • Z 1 and Z 2 are the same or different.
  • the reaction conditions are not particularly limited.
  • the catalyst in the step (i) is selected from the group consisting of AlY 3 , BY 3 , BY 3 and Et 2 O.
  • the catalyst described in this step is AlY 3 .
  • reaction conditions of the step (i), such as the temperature, the reaction time, the solvent and the like, are not particularly limited, and those skilled in the art can select a suitable temperature according to actual needs, and determine the reaction by a method commonly used in the art (such as TLC).
  • the solvent can be selected from any inert solvent that does not react with the reactants.
  • the reaction temperature in the step (i) is usually from (-40) ° C to 40 ° C
  • the reaction time is usually from 1 to 12 hours, preferably from 1 to 4 hours
  • the inert solvent is selected from the group consisting of Group of solvents: dichloromethane, dichloroethane, chlorobenzene, dichlorobenzene, carbon tetrachloride, carbon disulfide, or a combination thereof.
  • reaction conditions in the step (ii) and the step (iii) are preferably in accordance with the above steps (iia) and (iiia), and those skilled in the art can select suitable reaction conditions depending on the reactants actually used.
  • the compound of formula I can be used as an intermediate to prepare radipavir.
  • a preferred method of preparing the Radipavir of the present invention comprises the steps of:
  • step (v) using a compound of the formula I as an intermediate to produce edipasvir (LDV); wherein said step (v) can be carried out by methods known in the art, as described in document US2013324740. The method is carried out.
  • the method may further comprise the steps of:
  • the preparation process of the compound of the formula I of the present invention does not require the use of iodination reaction, avoids the use of more expensive iodine, and reduces the waste of three raw materials while reducing the cost of raw materials;
  • the acetyl group or the ⁇ -haloacetyl group is directly introduced by the one-step reaction of the Friedel-Craft reaction, thereby avoiding the preparation of the Grignard reagent, reducing the reaction step, and improving the operating conditions.
  • the acetylation step replaces the expensive Weinreb amide with inexpensive and readily available reagents, thereby significantly reducing raw material costs;
  • the invention has simple process and good safety, and the reaction is easy to realize and enlarge, and has good industrial application value;
  • the reaction mixture was cooled to 0 ° C, and 11 g (98.4 mmol, 1.2 eq) of chloroacetyl chloride was slowly added dropwise. After the completion of the dropwise addition, the mixture was kept at 0 ° C for 1 hour, and then naturally warmed to room temperature, and stirring was continued for 2 hours. The TLC tracks until the material disappears.
  • reaction solution was poured into 100 ml of a 10% ice water-hydrochloric acid mixture, stirred for 30 minutes, and the organic layer was separated. The organic layer was washed with water, washed with aq.
  • the reaction mixture was cooled to 0 ° C, and 7.7 g (98.4 mmol, 1.2 eq) of acetyl chloride was slowly added dropwise. After the completion of the dropwise addition, the mixture was kept at 0 ° C for 1 hour, and then naturally warmed to room temperature, and stirring was continued for 2 hours. The TLC tracks until the material disappears.
  • reaction solution was poured into 100 ml of a 10% ice water-hydrochloric acid mixture, stirred for 30 minutes, and the organic layer was separated. The organic layer was washed with water, washed with 10% sodium hydrogen carbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to afford 22.0 g of compound 4-2 (yield: 93.8%).
  • the reaction mixture was cooled to -65 ° C, and 37 mL (36.9 mmol, 3.0 eq) of LiHMDS/THF solution was added dropwise. The TLC tracks until the material disappears. The reaction was quenched by the addition of 5 ml of a 7N ammonia/methanol solution.
  • reaction solution was concentrated to remove low-boiling substances, dissolved in 25 ml (5 vol) of THF, and then 50 ml of isopropanol was slowly added thereto, and crystals were precipitated.
  • the suspension was concentrated to 50 ml (10 vol), 50 ml of isopropanol was again added, and the mixture was again concentrated to 50 ml (5 vol).
  • the mixture was cooled to 20-25 ° C and stirred for 30 minutes.
  • the solid was filtered and washed with 10 ml of isopropyl alcohol. Drying in vacuo to give compound 7-1: 5.0 g (yield: 91.9%)
  • the reaction mixture was cooled to -65 ° C, and 40.3 mL (40.3 mmol, 3.0 eq) of LiHMDS/THF solution was added dropwise.
  • the TLC tracks until the material disappears.
  • the reaction was quenched by the addition of 5 ml of a 7N ammonia/methanol solution.
  • reaction solution was concentrated to remove low-boiling substances, dissolved in 25 ml (5 vol) of THF, and then 50 ml of isopropanol was slowly added thereto, and crystals were precipitated.
  • the suspension was concentrated to 50 ml (10 vol), 50 ml of isopropanol was again added, and the mixture was again concentrated to 50 ml (5 vol).
  • the mixture was cooled to 20-25 ° C and stirred for 30 minutes.
  • the solid was filtered and washed with 10 ml of isopropyl alcohol. Drying in vacuo gave compound 7-2: 5.0 g (yield: 90.0%)
  • the reaction mixture was cooled to -65 ° C and 42 mL (41.25 mmol, 3.0 eq).
  • the TLC tracks until the material disappears.
  • the reaction was quenched by the addition of 5 ml of a 7N ammonia/methanol solution.
  • reaction solution was concentrated to remove low-boiling substances, dissolved in 25 ml (5 vol) of THF, and then 50 ml of isopropanol was slowly added thereto, and crystals were precipitated.
  • the suspension was concentrated to 50 ml (10 vol), 50 ml of isopropanol was again added, and the mixture was again concentrated to 50 ml (5 vol).
  • the mixture was cooled to 20-25 ° C and stirred for 30 minutes.
  • the solid was filtered and washed with 10 ml of isopropyl alcohol. Drying in vacuo gave compound 7-3: 4.4 g (yield: 80.0%)
  • the reaction mixture was cooled to -65 ° C, and 45.5 ml (45.45 mmol, 3.0 eq) of LiHMDS/THF solution was added dropwise. The TLC tracks until the material disappears. The reaction was quenched by the addition of 5 ml of a 7N ammonia/methanol solution.
  • reaction solution was concentrated to remove low-boiling substances, dissolved in 25 ml (5 vol) of THF, and then 50 ml of isopropanol was slowly added thereto, and crystals were precipitated.
  • the suspension was concentrated to 50 ml (10 vol), 50 ml of isopropanol was again added, and the mixture was again concentrated to 50 ml (5 vol).
  • the mixture was cooled to 20-25 ° C and stirred for 30 minutes.
  • the solid was filtered and washed with 10 ml of isopropyl alcohol. Drying in vacuo gave compound 7-4: 5.0 g (yield: 90.0%)
  • the reaction mixture was added to 50 ml of a saturated sodium hydrogensulfite solution and the excess of bromine was added, and the organic phase was separated.
  • the aqueous phase was extracted twice with 20 ml of ethyl acetate.
  • the crude product was purified by beating with 42.5 ml (5 vol) of isopropanol to give the title compound 1-2 (yield: 70%).

Abstract

本发明提供了一种芴乙酮衍生物的制备方法，具体地，本发明提供了一种式I化合物的制备方法，其中，各基团的定义如说明书中所述。所述的化合物可以作为雷迪帕韦制备的中间体，用于制备雷迪帕韦合成关键中间体，进而制备雷迪帕韦。本发明方法成本低廉，反应条件温和，适合工业化生产。

Description

芴乙酮衍生物的制备方法 技术领域
本发明涉及药物中间体制备领域，具体地，本发明提供了一种雷迪帕韦合成中间体的制备方法。
背景技术
雷迪帕韦(Ledipasvir，LDV)是Gilead开发的丙肝治疗药物，FDA已授予LDV/SOF(Sofosbuvir)固定剂量组合药物突破性疗法认定，该组合疗法有望在短至8周的时间里治愈基因型1HCV患者，同时无需注射干扰素或联合利巴韦林(ribavirin)。
目前，本领域已知的雷迪帕韦制备方法中，大多需经过如下式I所示的关键中间体
Figure PCTCN2015093114-appb-000001
(其中Z1、Z2均为卤素)。因此，为了工业化生产雷迪帕韦，本领域需要一种能够高效率地合成式5化合物的方法。
US20100310512报道式I的合成如下：
Figure PCTCN2015093114-appb-000002
该法氟化反应过程中BAST受热易分解，有较大安全隐患；乙酰基引入过程中缺乏选择性，还用到昂贵的Pd试剂，且使用剧毒的有机锡，以上因素限制了该法的使用。
US2013324740报道了如下制备方法：
Figure PCTCN2015093114-appb-000003
上述方法进行氟化反应比较安全，且乙酰化的选择性较好，但Weinreb酰胺(即2-氯-N-甲氧基-N-甲基-乙酰胺)比较昂贵，不适合工业化生产。
综上所述，本领域迫切需要开发新的制备式I化合物的方法。
发明内容
本发明提供了一种新的制备式I化合物的方法。
本发明的第一方面，提供了一种式I化合物的制备方法，
Figure PCTCN2015093114-appb-000004
所述方法包括步骤：
(i)在惰性溶剂中，在催化剂作用下，将式II化合物与式III化合物反应，制得式IV化合物；
Figure PCTCN2015093114-appb-000005
(ii)在惰性溶剂中，将式IV化合物与式V化合物反应，制得式VI化合物；
Figure PCTCN2015093114-appb-000006
(iii)在惰性溶剂中，将式VI化合物与氟化剂和碱反应，制得式VII化合物；
Figure PCTCN2015093114-appb-000007
(iv)在惰性溶剂中，用式VII化合物进行脱保护基反应，制得式I化合物；
Figure PCTCN2015093114-appb-000008
上述各式中：
Z1、Z2各自独立地选自下组：H、Cl、Br或I；
Z3为卤素或者OCOR1；其中，R1选自下组：C1-C4的烷基、C1-C4的卤代烷基；
R2、R3各自独立地为H或C1-C2的烷基；
R4、R5各自独立地为无、H或甲基；
n为0或1；
附加条件是，当n为0时，R4和R5为无。
在另一优选例中，所述的脱保护反应为水解反应。
在另一优选例中，所述的Z1和Z2是相同的。
在另一优选例中，所述的Z1和Z2是不同的。
在另一优选例中，步骤(i)中，反应温度通常为(-40)℃～40℃
在另一优选例中，步骤(i)中，反应时间通常为1～12小时，较佳地为1～4小时。
在另一优选例中，步骤(i)中，所述的惰性溶剂选自下组：二氯甲烷、二氯乙烷、氯苯、二氯苯、四氯化碳、二硫化碳，或其组合。
在另一优选例中，步骤(ii)中，反应温度通常为-20℃至150℃。
在另一优选例中，步骤(ii)中，反应时间通常为1～12小时，较佳地为1～5小时。
在另一优选例中、步骤(ii)中、所述的惰性溶剂选自下组：四氢呋喃、甲基四氢呋喃、二氧六环、乙腈、二氯甲烷、二氯乙烷、苯、甲苯、二甲苯，或其组合。
在另一优选例中，步骤(iii)中，反应温度通常为-100℃至30℃。
在另一优选例中，步骤(iii)中，反应时间通常为5min～24小时，较佳地为1～2小时。
在另一优选例中，步骤(iii)中，所述的惰性溶剂选自下组：四氢呋喃、甲基四氢呋喃、二氧六环、***、异丙醚、甲基叔丁基醚，或其组合。
在另一优选例中，步骤(iv)中，反应温度通常为0℃至100℃。
在另一优选例中，步骤(iv)中，反应时间通常为0～24小时，较佳地为1～4小时。
在另一优选例中，步骤(iv)中，所述的反应在选自下组的溶剂中进行：丙酮，四氢呋喃，二氧六环、乙二醇二甲醚、乙腈，甲醇，乙醇，水，或其组合。
本发明的第二方面，提供了一种如下式A所示的化合物：
Figure PCTCN2015093114-appb-000009
其中，M、Q各自独立地为F或H；其余各基团的定义如本发明第一方面中 所述；较佳地，所述的M和Q均为F，或所述的M和Q均为H。
本发明的第三方面，提供了一种如本发明第二方面所述的式A化合物的制备方法，所述方法包括步骤：
(iia)在惰性溶剂中，将式A1化合物与式V化合物反应，制得式A化合物；
Figure PCTCN2015093114-appb-000010
和任选的步骤(iiia)：用式A化合物与氟化剂和碱反应；
其中，各基团的定义如本发明第二方面中所述。
在另一优选例中，当进行所述任选步骤(iiia)时，式A1化合物中，M、Q不同时为F。
在另一优选例中，所述方法还包括步骤：
(i)在惰性溶剂中，在催化剂作用下，将式II化合物与式III化合物反应，制得式IV化合物；
Figure PCTCN2015093114-appb-000011
其中，各基团的定义如本发明第一方面中所述。
本发明的第四方面，提供了一种式I化合物的制备方法，所述方法包括步骤：
Figure PCTCN2015093114-appb-000012
(iv)在惰性溶剂中，用式VII化合物进行脱保护，得到式I化合物；其中，各基团的定义如本发明第一方面中所述。
在另一优选例中，所述步骤(i)中的催化剂选自下组：AlY3、BY3、BY3与Et2O的络合物、FeY3、ZnY2、TiY4、H2SO4、HF、多聚磷酸、磺酸型离子交换树脂、
Figure PCTCN2015093114-appb-000013
或其组合；
其中，R6为H或C1-C4的烷基；
Y选自下组：氯、溴或碘。
在另一优选例中，所述的催化剂为AlY3。
在另一优选例中，所述的步骤(iii)或步骤(iiia)中，所述的氟化剂选自下组：
Figure PCTCN2015093114-appb-000014
Figure PCTCN2015093114-appb-000015
其中，Ra选自下组：CF3、C2F5、C8F17、C6F5、4-FC6H4、4-CF3C6H4、Ph、4-MeC6H4、n-Bu、t-Bu；Rb选自下组：C1-C10烷基、4-(2,3,5,6-四氟吡啶基)、4-(2,5,6-三氟吡啶基)、c-C6H11、CH2Bu-t、endo-2-降冰片基、exo-2-降冰片基；
Figure PCTCN2015093114-appb-000016
Figure PCTCN2015093114-appb-000017
其中，R选自下组：F、OH、CH2Cl、CH3、C2H5、n-C8H17、CH2CF3、CH2Cl；X选自下组：F、BF4、OTf、PF6、FSO3、HSO4、H2F3、SbF6。
在另一优选例中，所述的氟化剂选自下组：NFSI、NFOBS、Selectfluor。
在另一优选例中，所述的步骤(iii)或步骤(iiia)中，所述的碱选自下组：MHMDS、MH、MNH2、R7OM、PhM、(Ph)3CM、R7M、LDA、
Figure PCTCN2015093114-appb-000018
Figure PCTCN2015093114-appb-000019
DBU、DBN
其中M为Li、Na或K，R7为C1-C4的烷基。
优选LiHMDS、NaHMDS、LDA或DBU。
在另一优选例中，所述步骤(iv)中的脱保护在酸催化下进行；
较佳地，所述的酸选自下组：H2SO4、HX、H3PO4、多聚磷酸、HNO3、CH3SO3H、CF3SO3H、HOAc、CF3COOH、
Figure PCTCN2015093114-appb-000020
磺酸型离子交换树脂、HXO4，或其组合；其中，R6为H或者C1-C4的烷基；X选自下组：Cl、Br、I。
本发明的第五方面，提供了一种雷迪帕韦的制备方法，所述方法包括步骤：
(iv)将式VII化合物进行脱保护，得到式I化合物；
(v)将式I化合物作为中间体，从而制得雷迪帕韦(Ledipasvir，LDV)；
较佳地，所述的方法还包括步骤：
(iii)在惰性溶剂中，将式VI化合物与氟化剂和碱反应，制得式VII化合物；
Figure PCTCN2015093114-appb-000022
在另一优选例中，当所述式I化合物中Z2为H时，所述的方法还包括步骤：(1)在惰性溶剂中，将式I化合物与卤化剂反应。
在另一优选例中，步骤(1)中，所述的卤化剂选自下组：溴素、氯气、SO2Cl2或I2。
在另一优选例中，步骤(1)中，反应温度通常为-50℃至50℃。
在另一优选例中，步骤(1)中，反应时间通常5分钟～24小时，较佳地为0.5-6小时。
在另一优选例中，所述的惰性溶剂选自下组：二氯甲烷、氯仿、1,2-二氯乙烷、氯苯，或其组合。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地发现，采用如式II所示的化合物进行傅克反应，然后在羰基保护基存在下进行氟化的方法，可以简单方便、低成本地制备如式I所示的雷迪帕韦中间体。所述的方法原子经济性好，且容易实现，反应条件温和，具有较好的工业化价值。基于上述发现，发明人完成了本发明。
术语
如本文所用，术语“C1-C4烷基”指具有1-4个碳原子的烷基，如甲基、乙基、丙基、正丁基、叔丁基，或类似基团。
术语“卤素”指氟、氯、溴、碘。特别地，在本文中，若无特别说明，提及“卤素”之处均优选为氯、溴或碘。
本文中，术语“室温”指10-40℃，优选为20-25℃。
若无特别说明，术语“烷基”优选为C1-C10的烷基，更优选为C1-C4的烷基。
式A化合物及其制备
本发明提供了一种如下式A所示的化合物：
Figure PCTCN2015093114-appb-000023
其中，M、Q各自独立地为F或H；其余各基团的定义如本发明第一方面中所述；较佳地，所述的M和Q均为F，或所述的M和Q均为H。
所述的式A化合物可以通过以下步骤制备：
(iia)在惰性溶剂中，将式A1化合物与式V化合物反应，制得式A化合物；
Figure PCTCN2015093114-appb-000024
上述各式中：
Z1、Z2各自独立地选自下组：H、Cl、Br或I；
R2、R3各自独立地为H或C1-C2的烷基；
R4、R5各自独立地为H或甲基；
n为0或1；
附加条件是，当n为0时，R4和R5为无。
所述的Z1和Z2可以是相同的，也可以是不同的，优选为相同。特别地，当所使用的式A1化合物中，M、Q中的一个或两个为H时，所述的反应还可以任选地包括步骤(iiia)：用式A化合物与氟化剂和碱反应。
上述各步骤中，各种反应条件没有特别的限制。优选地，在所述的步骤(iia)或步骤(iiia)中，所述的氟化剂选自下组：
Figure PCTCN2015093114-appb-000025
Ra Rb Ra Rb
CF3 4-(2,3,5,6-四氟吡啶基) 4-MeC6H4 Me
CF3 4-(2,5,6-三氟吡啶基) 4-MeC6H4 t-Bu
CF3 Me 4-MeC6H4 c-C6H11
CF3 n-Bu 4-MeC6H4 exo-2-降冰片基
CF3 t-Bu 4-MeC6H4 endo-2-降冰片基
C2F5 烷基 4-MeC6H4 CH2Bu-t
C8F17 烷基 4-MeC6H4 n-Bu
C6F5 n-Pr 4-MeC6H4 n-Pr
C6F5 CH2Bu-t n-Bu CH2Bu-t
4-FC6H4 烷基 t-Bu Me
4-CF3C6H4 烷基 t-Bu n-Bu
Ph t-Bu t-Bu CH2Bu-t
Figure PCTCN2015093114-appb-000026
其中，最为优选的所述的氟化剂选自下组：NFSI、Selectfluor。
在优选的本发明实施例中，所述的步骤(iii)或步骤(iiia)中，所述的碱选自下组：MHMDS、MH、MNH2、R7OM、PhM、(Ph)3CM、R7M、LDA、
Figure PCTCN2015093114-appb-000027
Figure PCTCN2015093114-appb-000028
DBU、DBN；其中M为Li、Na、K，R7为C1-C4的烷基；更优选地选自下组：LiHMDS、NaHMDS、LDA或DBU。
所述步骤(iia)或步骤(iiia)的反应条件，如温度，反应时间，溶剂等没有特别的限制，本领域技术人员可以根据实际需要，选择合适的温度，通过本领域常用的方法(如TLC)等确定反应终点，溶剂可以选择任意不与反应物反应的惰性溶剂。在另一优选例中，步骤(iia)中，反应温度通常为-20℃至120℃，反应时间通常为1～12小时，较佳地为1～5小时；惰性溶剂可使用选自下组的溶剂：四氢呋喃、甲基四氢呋喃、二氧六环、乙腈、二氯甲烷、二氯乙烷、甲苯，或其组合。在另一优选例中，步骤(iiia)中，反应温度通常为-100℃至20℃，反应时间通常为5min～24小时，较佳地为1～2小时；性溶剂可使用选自下组的溶剂：四氢呋喃、甲基四氢呋喃、二氧六环，或其组合。
式I化合物及其制备
本发明还提供了一种式I化合物的制备方法，所述方法包括步骤：
Figure PCTCN2015093114-appb-000029
(iv)在惰性溶剂中，用式VII化合物进行脱保护，得到式I化合物；其中，各基团的定义如上文中所述。
所述的脱保护优选地通过水解反应进行；较佳地，所述步骤(iv)中的脱保护在酸催化下进行；
所述的酸没有特别的限制，优选为选自下组的酸：H2SO4、HX、H3PO4、多聚磷酸、HNO3、CH3SO4、CF3SO4、HOAc、CF3COOH、
Figure PCTCN2015093114-appb-000030
磺酸型离子交换树脂、HXO4，或其组合；其中，R6为H或者C1-C4的烷基；X选自下组：Cl、Br、I。
上述的反应中，所述的原料式VII化合物可以通过本发明所述的方法制得，也可以通过现有技术中已知的其他方法制备，在式VII化合物的结构被揭示后，这样的制备应当被认为是在本领域技术人员的能力范围内的。在本发明的一个较 为优选的实施例中，所述的式I化合物的制备通过以下起始原料和路径制得：
(i)在惰性溶剂中，在催化剂作用下，将式II化合物与式III化合物反应，制得式IV化合物；
Figure PCTCN2015093114-appb-000031
(ii)在惰性溶剂中，将式IV化合物与式V化合物反应，制得式VI化合物；
Figure PCTCN2015093114-appb-000032
(iii)在惰性溶剂中，将式VI化合物与氟化剂和碱反应，制得式VII化合物；
Figure PCTCN2015093114-appb-000033
(iv)用式VII化合物进行脱保护基反应，制得式I化合物；
Figure PCTCN2015093114-appb-000034
上述各式中：
Z1、Z2各自独立地选自下组：H、Cl、Br或I；
Z3为卤素或者OCOR1；其中，R1选自下组：C1-C4的烷基、C1-C4的卤代烷基；
R2、R3各自独立地为H或C1-C2的烷基；
R4、R5各自独立地为H或甲基；
n为0或1；
附加条件是，当n为0时，R4和R5为无。
各式中，所述的Z1和Z2是相同的或不同的。
各步骤中，反应条件并没有特别的限制，在本发明的一个优选实施例中，所述步骤(i)中的催化剂选自下组：AlY3、BY3、BY3与Et2O的络合物、FeY3、ZnY2、 TiY4、H2SO4、HF、多聚磷酸、磺酸型离子交换树脂、
Figure PCTCN2015093114-appb-000035
或其组合；其中，R6为H或C1-C4的烷基；Y选自下组：氯、溴或碘。最优选地，该步骤中所述的催化剂为AlY3。
所述步骤(i)的反应条件，如温度，反应时间，溶剂等没有特别的限制，本领域技术人员可以根据实际需要，选择合适的温度，通过本领域常用的方法(如TLC)等确定反应终点，溶剂可以选择任意不与反应物反应的惰性溶剂。在另一优选例中，步骤(i)中反应温度通常为(-40)℃～40℃，反应时间通常为1～12小时，较佳地为1～4小时；惰性溶剂可选用选自下组的溶剂：二氯甲烷、二氯乙烷、氯苯、二氯苯、四氯化碳、二硫化碳，或其组合。
步骤(ii)，步骤(iii)中的反应条件优选地和上述的步骤(iia)、步骤(iiia)一致，本领域技术人员可以根据实际所使用的反应物选择合适的反应条件。
雷迪帕韦的制备
所述的式I化合物可以作为中间体制备雷迪帕韦。一种优选的本发明雷迪帕韦的制备方法包括步骤：
(iv)将式VII化合物进行脱保护，得到式I化合物：
Figure PCTCN2015093114-appb-000036
(v)将式I化合物作为中间体，从而制得雷迪帕韦(Ledipasvir，LDV)；其中，所述的步骤(v)可以采用现有技术中已知的方法，如文献US2013324740中所述的方法进行。
较佳地，所述的方法还可以包括步骤：
(iii)在惰性溶剂中，将式VI化合物与氟化剂和碱反应，制得式VII化合物；
Figure PCTCN2015093114-appb-000037
与现有技术相比，本发明的主要优点包括：
(1)本发明的式I化合物制备过程无需采用碘化反应，避免了较贵的碘的使用，在降低原材料成本的同时，减少了三废排放；
(2)本发明的制备方法在乙酰化过程中，通过傅克反应一步反应直接引入乙酰基或α-卤代乙酰基，避免了格氏试剂的制备，减少了反应步骤，同时改善了操作条件；乙酰化步骤以廉价易得的试剂替代昂贵的Weinreb酰胺，从而大幅度地降低了原材料成本；
(3)本发明方法的羰基保护、氟化、水解等步骤均能够得到较高的收率；
(4)本发明工艺简单，安全性好，，反应易于实现和放大，具有较好的工业应用价值；
(5)制备得到了新中间体式VI及式VII化合物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1化合物4-1的合成
Figure PCTCN2015093114-appb-000038
在250ml的四口瓶中加入16.2g(123mmol，1.5eq)三氯化铝，150ml二氯甲烷，开动搅拌，慢慢滴加20g化合物2(82mmol，1.0eq)，搅拌30分钟，直至大部分三氯化铝溶解。
反应混合物冷却到0℃，缓慢滴加11g(98.4mmol，1.2eq)氯乙酰氯，滴加完成后，在0℃保持1小时，然后自然升温到室温，继续搅拌2小时。TLC跟踪至原料消失。
将反应液倒入100ml 10％冰水-盐酸混合物中，搅拌30分钟，分出有机层。有机相经水洗，10％碳酸氢钠溶液洗，饱和食盐水洗，无水硫酸钠干燥，浓缩得到粗品，粗品经重结晶得到19.3g化合物4-1(收率：73.5％)。
实施例2化合物4-2的合成
Figure PCTCN2015093114-appb-000039
在250ml的四口瓶中加入16.2g(123mmol，1.5eq)三氯化铝，150ml二氯甲烷，开动搅拌，慢慢滴加20g化合物2(82mmol，1.0eq)，搅拌30分钟，直至大部分三氯化铝溶解。
反应混合物冷却到0℃，缓慢滴加7.7g(98.4mmol，1.2eq)乙酰氯，滴加完成后，在0℃保持1小时，然后自然升温到室温，继续搅拌2小时。TLC跟踪至原料消失。
将反应液倒入100ml 10％冰水-盐酸混合物中，搅拌30分钟，分出有机层。有机相经水洗，10％碳酸氢钠溶液洗，饱和食盐水洗，无水硫酸钠干燥，浓缩得到22.0g化合物4-2(收率：93.8％)。
实施例3化合物6-1的合成
Figure PCTCN2015093114-appb-000040
在100ml的四口瓶中加入5g(15.6mmol，1.0eq)化合物4-1，6.0g(57.7mmol，3.7eq)新戊二醇，3.6g(24.2mmol，1.55eq)原甲酸三乙酯和50ml二氯甲烷，室温搅拌20分钟，然后加入0.16g(1.1mmol，0.07eq)三氟化硼***。
反应混合物加热到回流，保持2小时。TLC跟踪至原料消失，加入三乙胺调节反应液pH值至8-9。减压浓缩回收溶剂，得到浆状物。加入50ml水在50℃打浆以除去过量的新戊二醇。过滤出淡黄色固体，50℃干燥，得到5.8g化合物6-1(收率92.4％)。
1H NMR(400MHz,CDCl3)：δ7.80(d,J＝8.0Hz,1H),7.71(s,1H),7.67(d,J＝8.1Hz,1H),7.64(s,1H),7.52(dd,J＝10.8,4.2Hz,2H),3.68–3.49(m,6H),1.36(s,3H),0.62(s,3H).
实施例4化合物6-2的合成
Figure PCTCN2015093114-appb-000041
在100ml的四口瓶中加入5g(17.5mmol，1.0eq)化合物4-2，6.73g(64.7mmol，3.7eq)新戊二醇，4.0g(27.1mmol，1.55eq)原甲酸三乙酯和50ml二氯甲烷，室温搅拌20分钟，然后加入0.17g(1.1mmol，0.07eq)三氟化硼***。
反应混合物加热到回流，保持2小时。TLC跟踪至原料消失，加入三乙胺调节反应液pH值至8-9。减压浓缩回收溶剂，得到浆状物。加入50ml水在50℃打浆以除去过量的新戊二醇。过滤出淡黄色固体，50℃干燥，得到5.95g化合物6-2(收率91.5％)。
1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.9Hz,1H),7.69(s,1H),7.64(d,J＝8.1Hz,1H),7.60(s,1H),7.53–7.43(m,2H),3.93(d,J＝18.0Hz,2H),3.45(dd,J＝29.4,10.9Hz,4H),2.66(s,1H),1.58(s,3H),1.29(s,3H),0.59(s,3H).
实施例5化合物6-3的合成：
Figure PCTCN2015093114-appb-000042
在100ml的四口瓶中加入1.6g(5.24mmol，1.0eq)化合物4-1，1.2g(19.4mmol，3.7eq)乙二醇5-2，1.2g(8.13mmol，1.55eq)原甲酸三乙酯和25ml二氯甲烷，室温搅拌20分钟，然后加入0.05g(0.35mmol，0.07eq)三氟化硼***。
反应混合物加热到回流，保持2小时。TLC跟踪至原料消失，加入三乙胺调节反应液pH值至8-9。减压浓缩回收溶剂，得到浆状物。加入20ml水在50℃打浆以除去过量的乙二醇。过滤出淡黄色固体，50℃干燥，得到1.59g化合物6-4(收率91.9％)。
1H NMR(400MHz,)δ7.74(d,J＝7.9Hz),7.69(s),7.64(d,J＝8.1Hz),7.55(d,J＝8.0Hz),7.50(d,J＝8.2Hz),4.21(s),4.00–3.93(m),3.90(s),3.80(s).
实施例6化合物6-4的合成
Figure PCTCN2015093114-appb-000043
在100ml的四口瓶中加入1.5g(5mmol，1.0eq)化合物4-2，1.15g(18.5mmol，3.7eq)乙二醇5-2，1.5g(7.75mmol，1.55eq)原甲酸三乙酯和25ml二氯甲烷，室温搅拌20分钟，然后加入0.05g(0.35mmol，0.07eq)三氟化硼***。
反应混合物加热到回流，保持2小时。TLC跟踪至原料消失，加入三乙胺调节反应液pH值至8-9。减压浓缩回收溶剂，得到浆状物。加入20ml水在50℃打浆以除去过量的乙二醇。过滤出淡黄色固体，50℃干燥，得到1.62g化合物6-1(收率89％)。
1H NMR(400MHz,)δ7.72(d,J＝7.9Hz),7.67(s),7.65(s),7.63(d,J＝8.1Hz),7.50(t,J＝8.5Hz),4.10–4.04(m),3.87(d,J＝7.4Hz),3.85–3.79(m),1.70(s).
实施例7化合物7-1的合成
Figure PCTCN2015093114-appb-000044
在250ml的四口瓶中加入5g(12.3mmol，1.0eq)化合物6-1，11.44g(36.3mmol，2.95eq)NFSI和100ml无水THF，反应混合物脱气三次，氮气破真空。
反应混合物降温到-65℃，滴加37ml(36.9mmol，3.0eq)LiHMDS/THF溶液。TLC跟踪至原料消失。加入5ml 7N氨气/甲醇溶液淬灭反应。
反应液浓缩除去低沸物，加入25ml(5vol)THF溶解，然后慢慢加入50ml异丙醇，有晶体析出。悬浊液浓缩到50ml(10vol)，再次加入50ml异丙醇，再次将混浊液浓缩到50ml(5vol)。此混合液被冷却到20-25℃搅拌30分钟，过滤出固体，用10ml异丙醇洗涤。真空干燥得化合物7-1：5.0g(收率91.9％)
1H NMR(400MHz,CDCl3)δ7.78(d,J＝1.2Hz,1H),7.72(s,1H),7.62(d,J＝8.4Hz,3H),7.47(d,J＝8.0Hz,1H),3.60(d,J＝5.7Hz,2H),3.54(d,J＝11.1Hz,2H),3.45(d,J＝10.9Hz,2H),1.33(d,J＝7.7Hz,3H),0.64(s,3H).
实施例8化合物7-2的合成
Figure PCTCN2015093114-appb-000045
在250ml的四口瓶中加入5g(13.44mmol，1.0eq)化合物6-2，12.5g(39.65mmol，2.95eq)NFSI和100ml无水THF，反应混合物脱气三次，氮气破真空。
反应混合物降温到-65℃，滴加40.3ml(40.3mmol，3.0eq)LiHMDS/THF溶液。TLC跟踪至原料消失。加入5ml 7N氨气/甲醇溶液淬灭反应。
反应液浓缩除去低沸物，加入25ml(5vol)THF溶解，然后慢慢加入50ml异丙醇，有晶体析出。悬浊液浓缩到50ml(10vol)，再次加入50ml异丙醇，再次将混浊液浓缩到50ml(5vol)。此混合液被冷却到20-25℃搅拌30分钟，过滤出固体，用10ml异丙醇洗涤。真空干燥得化合物7-2：5.0g(收率90.0％)
1H NMR(400MHz,CDCl3)δ7.78(d,J＝1.2Hz,1H),7.72(s,1H),7.62(d,J＝8.4Hz,3H),7.47(d,J＝8.0Hz,1H),3.54(d,J＝11.1Hz,2H),3.45(d,J＝10.9Hz,2H),1.58(s,3H),1.33(d,J＝7.7Hz,3H),0.64(s,3H).
实施例9化合物7-3的合成
Figure PCTCN2015093114-appb-000046
在250ml的四口瓶中加入5g(13.75mmol，1.0eq)化合物6-1，13g(40.56mmol，2.95eq)NFSI和100ml无水THF，反应混合物脱气三次，氮气破真空。
反应混合物降温到-65℃，滴加42ml(41.25mmol，3.0eq)LiHMDS/THF溶液。TLC跟踪至原料消失。加入5ml 7N氨气/甲醇溶液淬灭反应。
反应液浓缩除去低沸物，加入25ml(5vol)THF溶解，然后慢慢加入50ml异丙醇，有晶体析出。悬浊液浓缩到50ml(10vol)，再次加入50ml异丙醇，再次将混浊液浓缩到50ml(5vol)。此混合液被冷却到20-25℃搅拌30分钟，过滤出固体，用10ml异丙醇洗涤。真空干燥得化合物7-3：4.4g(收率80.0％)
1H NMR(400MHz)δ7.79(s),7.76(d,J＝1.4Hz),7.65(d,J＝7.9Hz),7.61(d, J＝8.1Hz),7.55(d,J＝7.9Hz),7.45(d,J＝8.1Hz),4.21(td,J＝6.2,4.0Hz),3.98–3.92(m),3.76(s).
实施例10化合物7-4的合成
Figure PCTCN2015093114-appb-000047
在250ml的四口瓶中加入5.0g(15.15mmol，1.0eq)化合物6-2，14.1g(44.70mmol，2.95eq)NFSI和100ml无水THF，反应混合物脱气三次，氮气破真空。
反应混合物降温到-65℃，滴加45.5ml(45.45mmol，3.0eq)LiHMDS/THF溶液。TLC跟踪至原料消失。加入5ml 7N氨气/甲醇溶液淬灭反应。
反应液浓缩除去低沸物，加入25ml(5vol)THF溶解，然后慢慢加入50ml异丙醇，有晶体析出。悬浊液浓缩到50ml(10vol)，再次加入50ml异丙醇，再次将混浊液浓缩到50ml(5vol)。此混合液被冷却到20-25℃搅拌30分钟，过滤出固体，用10ml异丙醇洗涤。真空干燥得化合物7-4：5.0g(收率90.0％)
1H NMR(400MHz)δ7.75(s),7.60(t,J＝6.8Hz),7.52(d,J＝7.9Hz),7.43(d,J＝8.1Hz),4.10–4.04(m),3.85–3.78(m),1.68(s).
实施例11化合物1-3的合成
Figure PCTCN2015093114-appb-000048
在100ml的四口瓶中加入5.0g(15.5mmol，1.0eq)化合物7-1，加入45ml 70％醋酸水溶液，反应混合物加热到70℃，保温搅拌12小时，TLC跟踪至原料消失。将反应液倒入450ml水中，抽滤出淡黄色固体，真空干燥，得4.4g(收率88％)
1H NMR(400MHz,CDCl3)δ8.20(d,J＝1.1Hz,1H),8.13(d,J＝7.9Hz,1H),7.82(d,J＝1.5Hz,1H),7.70–7.63(m,2H),7.52(d,J＝8.1Hz,1H),2.66(d,J＝5.8Hz,3H).
实施例12化合物1-2的合成
Figure PCTCN2015093114-appb-000049
在500ml的三口瓶中加入6.9g(21.4mmol，1.0eq)化合物1-3，200ml醋酸异丙酯和20ml异丙醇，反应混合物降温到0-10℃，加入0.57g(10mol％)三溴化磷，然后滴加3.3g(20.6mmol，0.96eq)溴素的醋酸异丙酯溶液，约30分钟滴加完。
反应液加入50ml饱和亚硫酸氢钠溶液中和过量的溴素，分出有机相，水相用20ml乙酸乙酯萃取一次，合并有机相，无水硫酸钠干燥。浓缩得粗品8.5g(含原料，一溴代物和二溴代物)。粗品用42.5ml(5vol)异丙醇打浆纯化，得到6.0g目标化合物1-2(收率：70％)。
1H NMR(400MHz,CDCl3)δ8.21(d,J＝1.0Hz,1H),8.14(d,J＝8.0Hz,1H),7.81(d,J＝1.4Hz,1H),7.65(t,J＝10.3Hz,2H),7.51(d,J＝8.1Hz,1H),4.52–4.39(m,2H),1.59(s,1H).
实施例13化合物1-1的合成
Figure PCTCN2015093114-appb-000050
在500ml的三口瓶中，6.9g(21.4mmol，1.0eq)化合物1-3，69ml乙腈，1ml醋酸，升温到30-35℃，滴加3.1g(1.1eq)磺酰氯(预先溶解在10ml乙腈中)，滴加完成后，在30-35℃保持3小时，TLC跟踪至原料消失。反应液倒入100ml的水中，过滤得到淡黄色固体。
粗品用42.5ml(5vol)异丙醇打浆纯化，得到7.0g目标化合物1-2(收率：81.7％)。
实施例14化合物1-1的合成
Figure PCTCN2015093114-appb-000051
在100ml的四口瓶中加入4.5g(11.3mmol，1.0eq)化合物7-1，加入45ml 70％醋酸水溶液，反应混合物加热到70℃，保温搅拌12小时，TLC跟踪至原料消失。将反应液倒入450ml水中，抽滤得到淡黄色固体，真空干燥，得3.2g目标化合物1-1(收率88％)。
实施例15化合物1-1的合成
Figure PCTCN2015093114-appb-000052
在100ml的四口瓶中加入4.5g(11.3mmol，1.0eq)化合物7-1，加入45ml乙醇，45ml 36％盐酸，反应混合物加热到75-80℃，保温搅拌12小时，TLC跟踪至原料消失。将反应液浓缩除去乙醇，加入450ml水打浆，抽滤出淡黄色固体，真空干燥，得3.3g目标化合物1-1(收率91％)。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I化合物的制备方法，
    Figure PCTCN2015093114-appb-100001
    其特征在于，包括步骤：
    (i)在惰性溶剂中，在催化剂作用下，将式II化合物与式III化合物反应，制得式IV化合物；
    Figure PCTCN2015093114-appb-100002
    (ii)在惰性溶剂中，将式IV化合物与式V化合物反应，制得式VI化合物；
    Figure PCTCN2015093114-appb-100003
    (iii)在惰性溶剂中，将式VI化合物与氟化剂和碱反应，制得式VII化合物；
    Figure PCTCN2015093114-appb-100004
    (iv)在惰性溶剂中，用式VII化合物进行脱保护基反应，制得式I化合物；
    Figure PCTCN2015093114-appb-100005
    上述各式中：
    Z1、Z2各自独立地选自下组：H、Cl、Br或I；
    Z3为卤素或者OCOR1；其中，R1选自下组：C1-C4的烷基、C1-C4的卤代烷基；
    R2、R3各自独立地为H或C1-C2的烷基；
    R4、R5各自独立地为无、H或甲基；
    n为0或1；
    附加条件是，当n为0时，R4和R5为无。
  2. 一种如下式A所示的化合物：
    Figure PCTCN2015093114-appb-100006
    其中，M、Q各自独立地为F或H；其余各基团的定义如权利要求1中所述；较佳地，所述的M和Q均为F，或所述的M和Q均为H。
  3. 如权利要求2所述的式A化合物的制备方法，其特征在于，包括步骤：
    (iia)在惰性溶剂中，将式A1化合物与式V化合物反应，制得式A化合物；
    Figure PCTCN2015093114-appb-100007
    和任选的步骤(iiia)：用式A化合物与氟化剂和碱反应；
    其中，各基团的定义如权利要求2中所述。
  4. 如权利要求3所述的制备方法，其特征在于，所述方法还包括步骤：
    (i)在惰性溶剂中，在催化剂作用下，将式II化合物与式III化合物反应，制得式IV化合物；
    Figure PCTCN2015093114-appb-100008
    其中，各基团的定义如权利要求1中所述。
  5. 一种式I化合物的制备方法，其特征在于，包括步骤：
    Figure PCTCN2015093114-appb-100009
    (iv)在惰性溶剂中，用式VII化合物进行脱保护，得到式I化合物；其中，各基团的定义如权利要求1中所述。
  6. 如权利要求1所述的方法，其特征在于，所述步骤(i)中的催化剂选自下组：AlY3、BY3、BY3与Et2O的络合物、FeY3、ZnY2、TiY4、H2SO4、HF、多聚磷酸、磺酸型离子交换树脂、
    Figure PCTCN2015093114-appb-100010
    或其组合；
    其中，R6为H或C1-C4的烷基；
    Y选自下组：氯、溴或碘。
  7. 如权利要求1或3所述的方法，其特征在于，所述的步骤(iii)或步骤(iiia)中，所述的氟化剂选自下组：
    Figure PCTCN2015093114-appb-100011
    Figure PCTCN2015093114-appb-100012
    其中，Ra选自下组：CF3、C2F5、C8F17、C6F5、4-FC6H4、4-CF3C6H4、Ph、4-MeC6H4、n-Bu、t-Bu；Rb选自下组：C1-C10烷基、4-(2,3,5,6-四氟吡啶基)、4-(2,5,6-三氟吡啶基)、c-C6H11、CH2Bu-t、endo-2-降冰片基、exo-2-降冰片基；
    Figure PCTCN2015093114-appb-100013
    Figure PCTCN2015093114-appb-100014
    其中，R选自下组：F、OH、CH2Cl、CH3、C2H5、n-C8H17、CH2CF3、CH2Cl；X选自下组：F、BF4、OTf、PF6、FSO3、HSO4、H2F3、SbF6。
  8. 如权利要求1或3所述的方法，其特征在于，所述的步骤(iii)或步骤(iiia)中，所述的碱选自下组：MHMDS、MH、MNH2、R7OM、PhM、(Ph)3CM、R7M、LDA、
    Figure PCTCN2015093114-appb-100015
    DBU、DBN
    其中M为Li、Na或K，R7为C1-C4的烷基；
    优选的碱为LiHMDS、NaHMDS、LDA、DBU，或其组合。
  9. 如权利要求1或5所述的方法，其特征在于，所述步骤(iv)中的脱保护在酸催化下进行；
    较佳地，所述的酸选自下组：H2SO4、HX、H3PO4、多聚磷酸、HNO3、CH3SO3H、CF3SO3H、HOAc、CF3COOH、
    Figure PCTCN2015093114-appb-100016
    磺酸型离子交换树脂、HXO4，或其组合；其中，R6为H或者C1-C4的烷基；X选自下组：Cl、Br、I。
  10. 一种雷迪帕韦的制备方法，其特征在于，所述方法包括步骤：
    (iv)将式VII化合物进行脱保护，得到式I化合物；
    Figure PCTCN2015093114-appb-100017
    (v)将式I化合物作为中间体，从而制得雷迪帕韦(Ledipasvir，LDV)；
    较佳地，所述的方法还包括步骤：
    (iii)在惰性溶剂中，将式VI化合物与氟化剂和碱反应，制得式VII化合物；
    Figure PCTCN2015093114-appb-100018
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WO2017048060A1 (ko) * 2015-09-15 2017-03-23 주식회사 엘지화학 헤테로고리 화합물 및 이를 포함하는 유기 발광 소자
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CN106800501A (zh) * 2017-02-16 2017-06-06 海门慧聚药业有限公司 雷迪帕韦中间体的制备
CN109053400A (zh) * 2018-08-24 2018-12-21 江苏工程职业技术学院 一种雷迪帕韦关键中间体的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4079062A (en) * 1974-11-18 1978-03-14 Janssen Pharmaceutica N.V. Triazole derivatives
US20130324740A1 (en) * 2012-06-05 2013-12-05 Gilead Sciences, Inc. Synthesis of antiviral compound
US20130324496A1 (en) * 2012-06-05 2013-12-05 Gilead Sciences, Inc. Solid forms of an antiviral compound
CN104211677A (zh) * 2013-05-30 2014-12-17 浙江九洲药业股份有限公司 一种抗丙型肝炎药物中间体的制备方法
CN104513223A (zh) * 2014-11-20 2015-04-15 上海众强药业有限公司 芴乙酮衍生物的制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4079062A (en) * 1974-11-18 1978-03-14 Janssen Pharmaceutica N.V. Triazole derivatives
US20130324740A1 (en) * 2012-06-05 2013-12-05 Gilead Sciences, Inc. Synthesis of antiviral compound
US20130324496A1 (en) * 2012-06-05 2013-12-05 Gilead Sciences, Inc. Solid forms of an antiviral compound
CN104211677A (zh) * 2013-05-30 2014-12-17 浙江九洲药业股份有限公司 一种抗丙型肝炎药物中间体的制备方法
CN104513223A (zh) * 2014-11-20 2015-04-15 上海众强药业有限公司 芴乙酮衍生物的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MINABE, M. ET AL.: "Formation of 2,2'-Diacyl-9,9'-bifluorenylidene Isomersfrom 2-Acyl-9-bromofluorene and Base-Catalyzed Isomerization of the Formed Alkenes", BULL. CHEM. SOC. JPN., vol. 79, no. 11, 9 November 2006 (2006-11-09), pages 1758 - 1765 *

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