WO2018113277A1 - 一种雷迪帕韦的制备方法及制备雷迪帕韦的中间体 - Google Patents

一种雷迪帕韦的制备方法及制备雷迪帕韦的中间体 Download PDF

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WO2018113277A1
WO2018113277A1 PCT/CN2017/093057 CN2017093057W WO2018113277A1 WO 2018113277 A1 WO2018113277 A1 WO 2018113277A1 CN 2017093057 W CN2017093057 W CN 2017093057W WO 2018113277 A1 WO2018113277 A1 WO 2018113277A1
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compound
formula
reaction
preparation
mixture
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叶方国
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上海同昌生物医药科技有限公司
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    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
    • C07F7/083—Syntheses without formation of a Si-C bond

Definitions

  • the invention relates to the field of organic synthetic pharmaceuticals, in particular to a preparation method of radipavir and an intermediate for preparing radipavir.
  • Hepatitis C is caused by hepatitis C virus infection.
  • the hepatitis C virus is a spherical particle with a diameter of about 55-65 nm. It has a lipid capsule membrane and a spinous process structure. It has a nucleocapsid composed of core protein and RNA.
  • the genome of hepatitis C virus contains 10 genes that express 10 structural proteins (including core protein, envelope protein E1 and E2, ion channel protein P7) and non-structural proteins (including NS2, NS3, NS4A, NS4B, NS5A and NS5B). .
  • NS5A is a highly phosphorylated non-structural protein that does not possess enzymatic activity, and its phosphorylation level plays a regulatory role in the replication and translation of the HCV genome.
  • the serine residues on NS5A produce two proteins with different degrees of phosphorylation, namely basal phosphorylation p56 and highly phosphorylated p58, both of which play important roles in the life cycle of HCV.
  • basal phosphorylation p56 and highly phosphorylated p58 both of which play important roles in the life cycle of HCV.
  • the importance and diversity of NS5A function make it an important target for anti-HCV, and the research and development of its inhibitors has made remarkable achievements.
  • Harvoni is a combination of sofosbuvir and redipavir. Clinical studies have shown that HCV patients receive this drug for 8 weeks or 12 weeks with a cure rate of 99%. Radipavir in the compound is a hepatitis C virus NS5A inhibitor. .
  • Patent WO2013184702 first reported Radipavir, and reported a method for synthesizing radipavir by a compound ZIII and a compound VI by Suzuki coupling reaction, and the synthetic route is shown in the following figure.
  • the invention relates to the use of expensive N-fluorobisbenzenesulfonamide as a fluoro reagent to synthesize compound X, and the compound X is further prepared by a five-step reaction of a format reaction, an esterification reaction, a cyclization reaction, a Suzuki coupling reaction and a deprotection reaction.
  • the key intermediate compound VIII of Radipavir has many reaction steps and the preparation process is too complicated.
  • the present invention provides a preparation method of radipavir which is simple in process and has few steps.
  • Another technical problem to be solved by the present invention is to provide an intermediate compound for the preparation of radipavir.
  • the technical solution adopted by the present invention is: a preparation method of a key intermediate of radipavir, comprising the following steps:
  • the basic substance in the step (1) is sodium hydride, potassium t-butoxide, sodium t-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and A mixture of one or more of bis(trimethylsilyl)amino potassium.
  • the aprotic organic solvent in the step (1) is a mixture of one or more of tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether and N,N-dimethylformamide.
  • the ratio of the substance having the structure of the formula I, the basic substance and the 2-(trimethylsilyl)ethoxymethyl chloride in the step (1) is preferably 1:1 to 4: 1 to 3.
  • the organic amine salt in the step (2) is bis(trimethylsilyl)amino potassium, bis(trimethylsilyl)amide lithium, bis(trimethylsilyl)amino sodium and diiso. a mixture of one or more of propylamino lithium.
  • the ether solvent in the step (2) is a mixture of one or more of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether and methyl tert-butyl ether.
  • the mass ratio of 2-bromo-7-chloro-9H-indole, organic amine salt and N-fluorobisbenzenesulfonamide in the step (2) is 1:2.5 to 4.5:2 to 5.
  • the temperature of the fluorination reaction in the step (2) is -60 to -100 ° C; the time of the fluorination reaction is 1.5 to 3 h.
  • the alkaline substance in the step (3) is a mixture of one or more of potassium carbonate, potassium t-butoxide, cesium carbonate and cesium acetate.
  • the palladium catalyst in the step (3) is one or more of Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(PPh 3 ) 4 and Pd(PPh 3 ) 2 Cl 2 . mixture.
  • the organophosphorus ligand in the step (3) is 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl, n-butylbis(1-adamantyl)phosphine and A mixture of one or more of 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl.
  • the compound having the structure of the formula II in the step (3) 2-bromo-7-chloro-9,9-difluoro-9H-indole, a basic substance, a palladium catalyst and an organophosphorus ligand
  • the amount ratio of the substance is 1:1 to 1.5:2 to 3:0.005 to 0.1:0.01 to 0.2.
  • the temperature of the carbon-hydrogen activation coupling reaction in the step (3) is 110 to 130 ° C; and the time of the carbon-hydrogen activation coupling reaction is 11 to 13 hours.
  • the alkaline substance in the step (4) is a mixture of one or more of potassium carbonate, sodium carbonate, cesium carbonate and sodium hydrogencarbonate.
  • the palladium catalyst in the step (4) is a mixture of one or more of Pd(OAc) 2 , Pd(dppf)Cl 2 , Pd 2 (dba) 3 and Pd(PPh 3 ) 4 .
  • the organophosphorus ligand in the step (4) is 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl, 4,5-bisdiphenylphosphine-9,9 a mixture of one or more of dimethyloxanthene and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl.
  • the amount ratio of the compound having the structure represented by Formula V, the compound having the structure represented by Formula VI, the basic substance, the palladium catalyst, and the organophosphorus ligand in the step (4) is 1:1 to 1.5: 2 to 3: 0.005 to 0.1: 0.001 to 0.2.
  • the temperature of the Suzuki coupling reaction in the step (4) is 100 to 110 ° C; the time of the Suzuki coupling reaction is 6 to 8 h.
  • the acidic substance in the step (5) is a mixture of one or more of hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid.
  • the temperature of the deprotection group reaction in the step (5) is 70 to 90 ° C; and the deprotection group reaction time is 5 to 7 h.
  • the step (4) is: the reaction liquid obtained in the step (3) is represented by the formula VI
  • the compound of the structure is mixed with a palladium catalyst, and subjected to a Suzuki coupling reaction to obtain a compound having a structure represented by the formula VII.
  • the present invention provides a method for preparing radipavir by using a key intermediate prepared by the preparation method according to any one of the above aspects, comprising the steps of:
  • the redipavir key intermediate is condensed with Moc-L-valine in a polar solvent under the action of a basic substance and a condensing agent to obtain radipavir.
  • the temperature of the condensation reaction is 0 to 40 ° C; the time of the condensation reaction is 2 to 3 h.
  • the invention also provides an intermediate compound for the preparation of radipavir having the structure of formula XV:
  • R is H
  • the invention provides a preparation method of radipavir, which comprises a compound having the structure of formula I and 2-bromo-7-chloro-9H-indole as starting materials, respectively, and having the structure represented by formula II.
  • the compound and 2-bromo-7-chloro-9,9-difluoro-9H-indole are subjected to carbon-hydrogen activation coupling reaction, Suzuki coupling reaction and deprotection reaction to obtain synthetic radiipavir.
  • Key intermediate - has the structure shown in formula VIII
  • the compound having a structure of the formula VIII is further subjected to a condensation reaction with Moc-L-proline to obtain radipavir.
  • the preparation method of the Radipavir provided by the invention is simple and the steps are few, and the key compound 2-bromo-7-chloro-9,9-difluoro-9H-indole (formula IV) only needs to undergo a carbon-hydrogen activation coupling reaction.
  • the Suzuki coupling reaction and the deprotection group reaction can be used to prepare the key intermediate VIII of radifivir in three steps, which improves the utilization rate of the fluorine compound and reduces the preparation cost.
  • the present invention provides intermediate compounds for the preparation of radipavir having the structure shown in formula XV.
  • the intermediate compound provided by the invention for preparing radipavir can be directly used as a starting material for the preparation of ridipalvir, which can reduce the preparation steps, improve the synthesis efficiency and reduce the cost.
  • Figure 1 is a road diagram for synthesizing radipavir in accordance with an embodiment of the present invention.
  • the invention provides a preparation method of a key intermediate of Radipavir, comprising the following steps:
  • the present invention is a compound having the structure of the formula I ((S)-6-(1H-imidazol-2-yl)-5-spirohetero[2.4]heptane-5-carboxylate under the action of a basic substance.
  • Imidazole ring protecting reaction with 2-(trimethylsilyl)ethoxymethyl chloride in an aprotic organic solvent to obtain a compound having the structure of formula II ((S)-6-[1 -((2-(Trimethylsilyl)ethoxy)methyl-1H-imidazol-2-yl]-5-spirohetero[2.4]heptane-5-carboxylic acid tert-butyl ester).
  • the basic substance for the imidazole ring protecting reaction is preferably sodium hydride, potassium t-butoxide, sodium t-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and a mixture of one or more of bis(trimethylsilyl)amino potassium;
  • the aprotic organic solvent for the imidazole ring protecting reaction is preferably tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether and N , a mixture of one or more of N-dimethylformamide.
  • the amount ratio of the compound having a structure represented by Formula I, a basic substance, and 2-(trimethylsilyl)ethoxymethyl chloride is preferably 1:1 to 4:1 to 3 More preferably, it is 1:2 to 3:1.5 to 2.5; and the volume ratio of the mass of the compound having the structure of Formula I to the aprotic organic solvent is preferably 1 g: 15 to 25 ml, more preferably 1 g: 20 ml.
  • the temperature of the imidazole ring protecting reaction is preferably room temperature; the time of the imidazole ring protecting reaction is preferably from 1.5 to 3 h, more preferably 2 h.
  • the imidazole ring protecting reaction is preferably carried out under stirring; the stirring rate is preferably from 300 to 500 r/min, more preferably from 350 to 450 r/min.
  • a compound having the structure of Formula I and an aprotic organic solvent may be mixed to obtain a compound solution having the structure of Formula I; the alkaline substance and the 0 to 5 ° C conditions are The compound solution having the structure of formula I is mixed, stirred for 0.5 to 1 h to obtain a first mixed solution; 2-(trimethylsilyl)ethoxymethyl chloride is added dropwise to the first mixed solution to control the dropping process
  • the temperature of the first mixed liquid is 0 to 5 ° C to obtain a second mixed solution; the second mixed solution is naturally heated to room temperature to carry out an imidazole ring protecting reaction, which is calculated from the temperature rise to room temperature.
  • the temperature at which the mixed solution is controlled during the dropwise addition is preferably 0 to 5 ° C; the speed of the dropwise addition is preferably 1 to 5 drops / sec, more preferably 2 to 3 drops / sec.
  • the present invention preferably obtains an imidazole ring protecting reaction solution for post-treatment to obtain a compound having the structure of the formula II.
  • the post-treatment process of the imidazole ring protecting reaction solution preferably comprises quenching the imidazole ring protecting reaction, and sequentially extracting, washing, concentrating and purifying the obtained reaction liquid to obtain a compound of the structure of the formula II.
  • the quenching reaction quenching agent is preferably water; in the present invention, the reaction course is preferably detected by thin layer chromatography, and the thin layer chromatography test indicates that the reaction is quenched at the end of the reaction.
  • the extracting agent for extraction is preferably ethyl acetate; the number of extractions is preferably 2 to 5 times, more preferably 3 to 4 times; the present invention washes the extract to obtain an organic phase,
  • the detergent to be washed is preferably a saturated sodium chloride solution; the number of washings is preferably from 1 to 3 times.
  • the concentration is preferably concentrated under reduced pressure; the present invention preferably concentrates the washed product to dryness.
  • the purification is preferably silica gel column purification;
  • the silica gel column purification developing agent is preferably a mixture of ethyl acetate and petroleum ether;
  • the ethyl acetate and petroleum ether mixture is ethyl acetate and petroleum ether.
  • the volume ratio is preferably 1:1 to 5, and more preferably 1:2 to 4.
  • the present invention has no particular requirement for the source of the compound of the formula I, and can be synthesized using commercially available products or by a conventional method in the art.
  • the invention fluorinates 2-bromo-7-chloro-9H-indole (formula III) with N-fluorobisbenzenesulfonamide in an ether solvent under the action of an organic amine salt to obtain 2-bromo- 7-Chloro-9,9-difluoro-9H-indole (Formula IV).
  • the organic amine salt for the fluorination reaction is preferably bis(trimethylsilyl) a mixture of one or more of potassium amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and lithium diisopropylamide; ether solvent for the fluororeaction Preference is given to a mixture of one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether and methyl tert-butyl ether.
  • the amount ratio of the substance of the 2-bromo-7-chloro-9H-indole, the organic amine salt and the N-fluorobisbenzenesulfonamide is preferably 1:2.5 to 4.5:2 to 5, more preferably
  • the ratio of the mass of the 2-bromo-7-chloro-9H-indole to the ether solvent is preferably 1 g: 20 to 25 ml, more preferably 1 g: 21 to 23 ml.
  • the present invention has no particular requirement for the source of 2-bromo-7-chloro-9H-indole, and can be synthesized by a conventional method in the art or directly using a commercially available product.
  • the temperature of the fluorination reaction is preferably -60 to -100 ° C, more preferably -70 to -80 ° C; the time of the fluorination reaction is preferably 1.5 to 3 h, more preferably 2 h;
  • the invention preferably carries out the fluorination reaction under the protection of an inert gas.
  • a compound having the structure of Formula III, N-fluorobisbenzenesulfonamide, and a first partial ether solvent may be mixed to obtain a mixed solution; and the basic compound is dissolved in the second portion.
  • an alkali solution is obtained; the alkali solution is added dropwise to the mixed solution to carry out a fluorination reaction.
  • the temperature of the mixed solution is controlled during the dropwise addition to be -70 to -80 ° C;
  • the speed of the dropwise addition is preferably 1 to 5 drops / sec, more preferably 2 to 3 drops / sec;
  • the total volume of a portion of the ether solvent and the second portion of the ether solvent is in accordance with the above ratio, and is not described herein again;
  • the volume ratio of the first partial ether solvent to the second partial ether solvent is preferably 1:0.9 to 1.2, more Preferably, it is 1:1 to 1.1;
  • the reaction time of the present invention is calculated from the completion of the dropwise addition of the alkali solution.
  • the present invention preferably post-treats the obtained fluorinated reaction solution to obtain 2-bromo-7-chloro-9,9-difluoro-9H-indole.
  • the post-processing preferably includes the following steps:
  • the fluorination reaction solution is naturally heated to -10 to -20 ° C, and water is added to the reaction solution, followed by concentration to obtain a concentrate;
  • the concentrate is filtered to obtain a first filter cake, the first filter cake is mixed with methanol, stirred at 30 to 50 ° C for 0.5 to 1 h, and filtered to obtain a second filter cake;
  • the fourth filter cake was washed with isopropyl alcohol and dried to give 2-bromo-7-chloro-9,9-difluoro-9H-indole.
  • the amount of water added is preferably 0.5 to 2.0 times, more preferably 1.0 to 1.5 times the volume of the reaction liquid; the concentration is preferably concentrated under reduced pressure; the present invention preferably concentrates the reaction liquid to the original volume. 1/5 to 1/3;
  • the volume ratio of the methanol to the first filter cake is preferably 2 to 5 ml: 1 g, more preferably 3 to 4 ml: 1 g; and the stirring rotation speed is preferably 300 to 500 r/min, more preferably 350 to 450r/min;
  • the volume of the toluene and the weight ratio of the second filter cake is preferably 2 to 5 ml: 1 g, more preferably 3 to 4 ml: 1 g;
  • the volume of the isopropanol and the weight ratio of the third filter cake is preferably 4 to 7 ml: 1 g, more preferably 5 to 6 ml: 1 g;
  • the number of times of washing with isopropyl alcohol is preferably 2 to 5 times, more preferably 3 to 4 times; and the drying temperature is preferably 40 to 60 ° C, more preferably 50 ° C, and drying is constant. Heavy;
  • the rotational speed of the stirring in each step is preferably 300 to 500 r/min, more preferably 350 to 450 r/min.
  • the present invention is subjected to the action of a basic substance, a palladium catalyst and an organophosphorus ligand.
  • the compound having the structure of the formula II and the 2-bromo-7-chloro-9,9-difluoro-9H-indole are subjected to a carbon-hydrogen activation coupling reaction in a polar solvent to obtain a formula V Structure of the compound ((S)-6-(4-(7-chloro-9,9-difluoro-9H-indol-2-yl)-1-[(2-(trimethylsilyl))ethoxy) )methyl-1H-imidazol-2-yl]-5-spiroheterocycle [2.4] heptane-5-carboxylic acid tert-butyl ester).
  • the basic substance for the carbon-hydrogen activation coupling reaction is preferably a mixture of one or more of potassium carbonate, potassium t-butoxide, cesium carbonate and cesium acetate; the carbon-hydrogen activation couple
  • the palladium catalyst for the coupling reaction is preferably a mixture of one or more of Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(PPh 3 ) 4 and Pd(PPh 3 ) 2 Cl 2 ;
  • the organophosphorus ligand for activating the coupling reaction is preferably 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl (SPhos), n-butylbis(1-adamantyl)phosphine (P( a mixture of one or more of n-Bu)Ad 2 ) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (XPhos
  • the amount of the compound having the structure of the formula II, the substance of 2-bromo-7-chloro-9,9-difluoro-9H-indole, a basic substance, a palladium catalyst and an organophosphorus ligand is preferably 1:1 to 1.5:2 to 3:0.005 to 0.1:0.01 to 0.2, and more preferably 1:1.2 to 1.3:2.3 to 2.5:0.01 to 0.05:0.05 to 0.15;
  • the volume ratio of the mass of the compound of the structure to the polar solvent is preferably from 1:10 to 20 ml, more preferably from 1:13 to 16 ml.
  • the temperature of the carbon-hydrogen activation coupling reaction is preferably from 110 to 130 ° C, more preferably from 115 to 125 ° C, most preferably 120 ° C; the time of the carbon-hydrogen activation coupling reaction is preferably 11 to 13 h, most preferably 12 h.
  • the obtained carbon-hydrogen activation coupling reaction liquid is preferably filtered, and the obtained filtrate is quenched by adding water, and then the quenched filtrate is sequentially extracted. Washing and concentration give a crude product of the compound having the structure of formula V, and the crude product can be directly applied to the next step.
  • the extracting agent for extraction is preferably ethyl acetate; the volume ratio of the extracting agent to the filtrate is preferably from 1.5 to 3.5:1, more preferably from 2 to 3:1; the number of extractions is preferably 2 to 5 times, more preferably 3 to 4 times.
  • the present invention preferably combines the extracted organic phases for washing; the washed detergent is preferably a saturated sodium chloride solution; and the number of washings is preferably 1 to 3 times.
  • the concentration is preferably concentrated under reduced pressure; the specific operation method of the present invention for concentration under reduced pressure is not particularly required, and the present invention is preferably concentrated to dryness to obtain a crude product. .
  • the present invention has a compound having a structure represented by Formula V and a compound having a structure represented by Formula VI under the action of a basic substance, a palladium catalyst, and an organophosphorus ligand ( (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole 2-(4-[beta]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester) is subjected to a Suzuki coupling reaction in a polar solvent to give a compound having the structure of formula VII ((S) - 6-(4-(7-(2-((1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H) -benzo[d]imidazole-6
  • the basic substance for the Suzuki coupling reaction is preferably potassium carbonate or sodium carbonate. a mixture of one or more of cesium carbonate and sodium hydrogencarbonate; the Suzuki coupling reaction cannot be Pd(PPh 3 ) 2 Cl 2 with a palladium catalyst, and the balance is the same as the palladium catalyst used in the step (3) , and may also be Pd (dppf) Cl 2; the Suzuki coupling reaction
  • the organophosphorus ligand is preferably 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl (SPhos), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxime a mixture of (XantePhos) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (XPhos); the polarity of the polar solvent in the Suzuki coupling reaction Preferably, it is 4.5 to 7.2, more preferably 5 to 6.5; and the polar solvent
  • the amount ratio of the compound having a structure represented by Formula V, a compound having a structure represented by Formula VI, a basic substance, a palladium catalyst, and an organophosphorus ligand is preferably 1:1 to 1.5:2. ⁇ 3: 0.005 to 0.1: 0.001 to 0.2, more preferably 1:1.2 to 1.3: 2.3 to 2.5: 0.01 to 0.05: 0.005 to 0.1; the mass of the compound having the structure represented by Formula V and the volume of the polar solvent It is preferably 1 g: 20 to 30 ml, more preferably 1 g: 25 ml.
  • the present invention has no particular requirement for the source of the compound having the structure represented by the formula VI, and can be synthesized by a method in the art or directly used as a commercially available product.
  • the temperature of the Suzuki coupling reaction is preferably from 100 to 110 ° C, more preferably from 103 to 105 ° C; and the time of the Suzuki coupling reaction is preferably from 6 to 8 h, more preferably 7 h.
  • the present invention also provides a method for realizing a carbon-hydrogen activation coupling reaction and a Suzuki coupling reaction by a "one-pot method", that is, a basic substance and an organic phosphorus compound used in the step (3) and the step (4).
  • a "one-pot method” that is, a basic substance and an organic phosphorus compound used in the step (3) and the step (4).
  • the reaction liquid of the step (3) is mixed with a compound having a structure represented by the formula VI and a palladium catalyst to carry out a Suzuki coupling reaction; and the step (3) is obtained.
  • the compound having the structure of the formula V does not need to be subjected to separation and purification treatment; the palladium catalyst used herein is identical to the palladium catalyst in the above step (4), and will not be described herein.
  • the preparation method provided by the present invention realizes the synthesis of the compound having the structure of the formula VII by a "one-pot method", and combines the steps (3) and (4) into one reactor without separating and purifying the intermediate product. Further simplifies the preparation steps and reduces production costs.
  • the present invention preferably quenches the reaction and sequentially reacts the reaction.
  • the solution is subjected to extraction, washing, concentration and purification to give a compound of the formula VII.
  • the methods of extraction, washing, concentration, and purification are the same as those in the case of isolating the imidazole ring protecting reaction product, and will not be described herein.
  • the present invention deprotects the compound having the structure of the formula VII and an acidic substance in an aprotic polar solvent to obtain a key intermediate of the Radipavir.
  • the acidic substance is preferably a mixture of one or more of hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid; the hydrochloric acid preferably has a mass concentration of 36 to 38.
  • the hydrobromic acid is preferably concentrated hydrobromic acid having a mass concentration of 47.5%
  • the methanesulfonic acid is preferably methanesulfonic acid having a purity greater than 98%
  • the p-toluenesulfonic acid preferably has a purity greater than 96 % p-toluenesulfonic acid
  • the trifluoroacetic acid is preferably a concentrated trifluoroacetic acid having a purity of more than 99%
  • the aprotic polar solvent for the deprotection group reaction preferably has a polarity of 4.5 to 7.2, more preferably 5 ⁇ 6.5
  • the aprotic polar solvent is specifically preferably a mixture of one or more of ethylene glycol dimethyl ether, acetone and acetonitrile.
  • the molar ratio of the compound having the structure of the formula VII to the acidic substance is preferably 1:4.0 to 6.0, more preferably 1:4.3 to 5.0; the mass of the compound having the structure represented by the formula VII
  • the volume ratio to the aprotic polar solvent is preferably 1 g: 15 to 25 ml, more preferably 1 g: 20 ml.
  • the temperature of the deprotection group reaction is preferably 70 to 90 ° C, more preferably 75 to 85 ° C, most preferably 80 ° C; and the time of the deprotection group reaction is preferably 5 to 7 h, more preferably It is 5.5 to 6.5 h, and most preferably 6 h; in the present invention, the deprotection reaction is preferably carried out under reflux under heating.
  • a compound having a structure of the formula VII and an aprotic polar solvent may be mixed to obtain a solution of a compound having the structure of the formula VII; and an acidic substance is added dropwise to have a formula VII.
  • the deprotecting agent is reacted in a solution of the compound of the structure to obtain a compound having the structure of the formula VIII.
  • the dropping rate is preferably from 1 to 5 drops/second, more preferably from 2 to 3 drops/second; and the reaction time of the present invention is calculated from the completion of the dropwise addition of the acidic substance.
  • the present invention preferably post-treats the deprotection reaction solution to obtain a key intermediate of Radipavir.
  • the method for post-treatment of the deprotection group reaction liquid is preferably specifically: filtering the reaction liquid to obtain a filter cake; washing the filter cake with ethyl acetate and concentrating to remove the residual solvent.
  • the invention provides a method for preparing radipavir by using a key intermediate prepared by the preparation method described in the above scheme, comprising the following steps:
  • the redipavir key intermediate is condensed with Moc-L-valine in a polar solvent under the action of a basic substance and a condensing agent to obtain radipavir.
  • the basic substance for the condensation reaction is preferably an organic base; more preferably a mixture of one or more of N-methylmorpholine, triethylamine and diisopropylethylamine;
  • the condensing agent is preferably 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (EDC.HCl) and 1-hydroxybenzotriazole (HOBt) or 2-(7-oxidation a mixture of one or more of benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU);
  • the polarity of the polar solvent used in the condensation reaction Preferably, it is 4.5 to 7.2, more preferably 5.0 to 6.5; and the polar solvent is specifically preferably N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dichloro a mixture of one or more of methane.
  • the amount ratio of the key intermediate of the Radipavir, the condensing agent, the basic substance and the Moc-L-proline is preferably 1:3 to 8:8 to 14:2 to 4, More preferably, it is 1:4 to 6:9 to 11:2.5 to 3.5; and the volume ratio of the mass of the compound having the structure of the formula VIII to the polar solvent is preferably 1 g: 8 to 12 ml, more preferably 1 g: 9 ⁇ 11 ml, most preferably 1 g: 10 ml.
  • the temperature of the condensation reaction is preferably 0 to 40 ° C, more preferably 10 to 30 ° C; and the time of the condensation reaction is preferably 2 to 3 h, more preferably 2.5 to 2.8 h.
  • the acidic substance, Moc-L-proline and a polar solvent are preferably mixed and stirred at 0 to 40 ° C for 0.5 to 1 hour to obtain an acidic substance and Moc-L-protonium.
  • a mixed solution of an acid the temperature of the mixed solution is lowered to 0 to 5 ° C, and a compound having a structure represented by Formula VIII is added to the mixed solution to obtain a reaction stock solution; an organic base is added dropwise to the reaction stock solution, After the completion of the dropwise addition, the temperature of the solution was raised to 2 to 30 ° C to carry out a condensation reaction to obtain Radipavir.
  • the dropping speed is preferably from 1 to 5 drops/second, more preferably from 2 to 3 drops/second; the time of the condensation reaction is calculated from the temperature rise to the desired temperature; the steps of the present invention (
  • the organic bases used in 6) are all liquid substances, which can be directly added dropwise without using a solvent for dissolution.
  • the present invention preferably separates the condensation reaction product to give radipavir.
  • the separation and condensation reaction product is preferably specifically: adding ethyl acetate and water to the reaction liquid, stirring for 0.5 to 1 hour, and then standing to separate the layer to obtain an aqueous phase and a first organic phase; Extracting with ethyl acetate to obtain a second organic phase; the second organic phase and the first organic phase After mixing, it is mixed with the water-absorbing substance, stirred for 1 to 1.5 hours, and then filtered to obtain a filtrate; the filtrate is concentrated to obtain a concentrate; the concentrate is mixed with acetone, and stirred at 5 to 15 ° C for 12 to 24 hours.
  • the volume ratio of ethyl acetate to the reaction liquid added to the reaction liquid is preferably 1.8 to 2.2:1, more preferably 2:1; the volume of ethyl acetate and water added to the reaction liquid The ratio is preferably 2 to 3:1, more preferably 2.3 to 2.5:1;
  • the volume ratio of the ethyl acetate to the aqueous phase for extraction is preferably from 1.5 to 3.5:1, more preferably from 2 to 3:1; and the number of extractions is preferably from 2 to 3 times;
  • the water-absorbing substance is preferably anhydrous sodium sulfate and/or silica gel; the water-absorbing substance is preferably added in an amount of 0.05 to 0.2 g/ml, more preferably 0.1 to 0.15 g/ml;
  • the temperature of the concentrated filtrate is preferably from 70 to 100 ° C, more preferably from 80 to 90 ° C;
  • the time of the concentrated filtrate is preferably from 1 to 3 h, more preferably 2 h; in the present invention, the filtrate is preferably concentrated to 1/5 to 1/3 of the original volume, more preferably 1/4 of the original volume;
  • the volume ratio of the acetone to the concentrate is preferably 4 to 5:1, more preferably 4.5:1;
  • the drying temperature of the crude product of the Radipavir is preferably 70 to 90 ° C, more preferably 75 ⁇ 85°C, drying time is preferably 1-3h, more preferably 1.5-2.5h;
  • the mass ratio of the crude product of redipavir to ethyl acetate is preferably 1:3 to 3.5, more preferably 1:3.1 to 3.3;
  • the concentration in the step of concentrating to obtain a concentrated solid is preferably 70 to 100 ° C, more preferably 80 to 90 ° C.
  • the present invention has no special requirement for concentration time, and is concentrated to dryness;
  • the mass ratio of the concentrated solid to acetone is preferably 1:10 to 12, more preferably 1:11;
  • the drying temperature and time of the crude product of Radipavir are consistent with the drying temperature and time of the crude product of Radipavir, and will not be described herein.
  • a novel intermediate compound for the preparation of radipavir is synthesized during the preparation of the present invention, having the structure shown by formula XV:
  • R is H
  • the intermediate compound is used for synthesizing radipavir, which can reduce the synthesis step and improve the synthesis efficiency.
  • the obtained product is indeed a compound having the structure shown in Formula II;
  • the product was separated and purified: the reaction solution was naturally warmed to -20 ° C, 108 mL of water was added dropwise to clarify, concentrated under reduced pressure to a large amount of solids, and 840 mL of water was added to the mixture in three portions, cooled to 20 ° C, filtered; Adding to 180g of methanol, heating to 40 ° C for 30 minutes, cooling to 20 ° C for 30 minutes, filtration; filter cake was added to 192g of toluene, warmed to 90 ° C for 1 hour; a small amount of silica gel in a Buchner funnel, hot filtered; The filter cake was washed twice with hot toluene; most of the toluene was concentrated under reduced pressure, 300 g of isopropanol was added dropwise, and the mixture was cooled to 5 ° C for 1 hour, filtered, and the filter cake was washed twice with isopropyl alcohol, and the filter cake was drummed at 50 ° C. The air was dried to
  • the obtained product is indeed a compound having the structure shown in Formula IV;
  • the product was separated and purified: a small amount of diatomaceous earth was added to the reaction solution, and the black insoluble matter was removed by filtration; the reaction was quenched with 150 mL of water, and extracted twice with 300 mL of ethyl acetate; It was washed twice and concentrated to dryness under reduced pressure; a crude product of the compound of the structure of formula V was obtained, and the crude product was directly used for the next reaction.
  • the obtained product is indeed a compound having the structure represented by Formula V;
  • the product was separated and purified: the reaction was quenched with EtOAc (EtOAc) (EtOAc)
  • EtOAc EtOAc
  • the purity is 98%, and the yield is 82%;
  • the product was separated and purified: the reaction solution was filtered, and the filter cake was washed twice with 25 mL of ethyl acetate and concentrated under reduced pressure to remove residual solvent to obtain 1.87 g of the key intermediate of Radipavir (having the structure of formula VIII). The rate is 94%, the purity is 97%;
  • the obtained product was indeed a compound having a structure represented by the formula VIII.
  • the product was separated and purified: after the reaction was completed, the reaction solution was transferred to a 5 L reaction flask, and 2000 g of ethyl acetate and 800 g of water were added to the reaction solution, and the mixture was stirred for 30 minutes, and then allowed to stand to separate the organic phase; the aqueous layer was used for 1440 g. The ethyl acetate was extracted twice, and the obtained organic phases were combined.
  • the organic phase was washed once with 2000 g of 5% sodium hydrogen carbonate solution, the organic phase was washed once with 1000 g of water, and the organic phase was washed once with 1000 g of saturated sodium chloride solution; After adding 380 g of Yuanming powder and 380 g of silica gel to the organic phase, the mixture was stirred at 25 ° C for 1 hour. After filtration, the filtrate was concentrated to no obvious droplets (about 240 g); 1120 g of acetone was slowly added dropwise to the concentrate.
  • the utilization rate of N-fluorobisbenzenesulfonamide in the whole reaction process was calculated, and the utilization ratio of N-fluorobisbenzenesulfonamide was 59.4%.
  • the utilization rate of N-fluorobisbenzenesulfonamide in the whole reaction process was calculated, and the utilization ratio of N-fluorobisbenzenesulfonamide was 70.0%.
  • the utilization rate of N-fluorobisbenzenesulfonamide in the whole reaction process was calculated, and the utilization ratio of N-fluorobisbenzenesulfonamide was 50.0%.
  • the preparation method provided by the invention is simple and has few steps, and the key compound 2-bromo-7-chloro-9,9-difluoro-9H-indole (formula IV) only needs to undergo carbon-hydrogen activation coupling.
  • the reaction, the Suzuki coupling reaction and the deprotection group reaction can be used to prepare the key intermediate VIII of radifivir in three steps, and the carbon-hydrogen activation reaction and the Suzuki coupling reaction can be realized by the "one-pot method".
  • the utilization rate of the fluorine compound reduces the production cost.

Abstract

提供了一种雷迪帕韦关键中间体的制备方法，以具有式Ⅰ所示结构的化合物和2-溴-7-氯-9H-芴为起始物，分别制得具有式II所示结构的化合物和2-溴-7-氯-9,9-二氟-9H-芴，再经过碳-氢活化偶联反应、Suzuki偶联反应和脱保护基反应，即可得到合成雷迪帕韦的关键中间体—具有式Ⅷ所示结构的化合物，关键中间体再与Moc-L-缬氨酸进行缩合反应，即可得到雷迪帕韦。所述雷迪帕韦关键中间体的制备方法简单、步骤少，关键化合物2-溴-7-氯-9,9-二氟-9H-芴(式Ⅳ)仅需三步反应即可得到制备雷迪帕韦的关键中间体VIII，提高了氟化合物的利用率，降低了制备成本。

Description

一种雷迪帕韦的制备方法及制备雷迪帕韦的中间体
本申请要求于2016年12月20日提交中国专利局、申请号为CN201611186648.8、发明名称为“一种雷迪帕韦的制备方法及制备雷迪帕韦的中间体”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及有机合成制药领域，尤其涉及一种雷迪帕韦的制备方法及制备雷迪帕韦的中间体。
背景技术
丙型肝炎是由丙肝病毒感染引起的，丙肝病毒为直径约55～65nm球形颗粒，外有脂质囊膜和棘突结构，内有核心蛋白(core)和RNA组成的核衣壳。丙肝病毒的基因组含10个基因，表达产生10个结构蛋白(包含核心蛋白、包膜蛋白E1和E2、离子通道蛋白P7)和非结构蛋白(包含NS2、NS3、NS4A、NS4B、NS5A和NS5B)。其中NS5A是一种高度磷酸化的非结构蛋白，不具备酶催化活性，其磷酸化水平在HCV基因组的复制和翻译过程中都起着调节的作用。NS5A上丝氨酸残基产生两种磷酸化程度不同的蛋白，即基础磷酸化p56和高度磷酸化p58，均在HCV的生命周期中发挥重要作用。NS5A功能的重要性和多样性使它成为抗HCV的重要靶点，其抑制剂的研究开发已经取得了非常引人瞩目的成就。
Harvoni是索非布韦和雷迪帕韦的复方，临床研究显示，HCV患者接受这个药物治疗8周或12周，治愈率可达99％；复方中的雷迪帕韦是丙肝病毒NS5A抑制剂。
专利WO2013184702最早报道了雷迪帕韦，并且报道了由化合物XIII与化合物VI进行Suzuki偶联反应来合成雷迪帕韦的方法，合成路线如下图所示。其中涉及到使用昂贵的N-氟代双苯磺酰胺作为氟代试剂合成化合物X，化合物X再经过格式反应、酯化反应、环化反应、Suzuki偶合反应和脱保护反应共五步反应得到制备雷迪帕韦的关键中间体化合物VIII，该方法反应步骤多，制备过程过于复杂。
Figure PCTCN2017093057-appb-000001
发明内容
为了克服现有技术的上述缺点，本发明提供一种工艺简便、步骤少的雷迪帕韦的制备方法。
本发明另一个要解决的技术问题是提供一种用于制备雷迪帕韦的中间体化合物。
为了解决上述技术问题，本发明采用的技术方案是：一种雷迪帕韦关键中间体的制备方法，包括以下步骤：
(1)在碱性物质的作用下，将具有式I所示结构的化合物和2-(三甲基硅烷基)乙氧甲基氯在非质子有机溶剂中进行咪唑环保护反应，得到具有式Ⅱ所示结构的化合物；
Figure PCTCN2017093057-appb-000002
(2)在有机胺盐的作用下，将2-溴-7-氯-9H-芴与N-氟代双苯磺酰胺在醚类溶剂中进行氟代反应，得到2-溴-7-氯-9,9-二氟-9H-芴；
(3)在碱性物质、钯催化剂和有机磷配体的作用下，将所述具有式Ⅱ所示结构的化合物和2-溴-7-氯-9,9-二氟-9H-芴在极性溶剂中进行碳-氢 活化偶联反应，得到具有式Ⅴ所示结构的化合物；
Figure PCTCN2017093057-appb-000003
(4)在碱性物质、钯催化剂和有机磷配体的作用下，将所述具有式Ⅴ所示结构的化合物和具有式Ⅵ所示结构的化合物在极性溶剂中进行进行Suzuki偶联反应，得到具有式Ⅶ所示结构的化合物；
Figure PCTCN2017093057-appb-000004
(5)将所述具有式Ⅶ所示结构的化合物和酸性物质在非质子极性溶剂中进行脱保护基反应，得到雷迪帕韦关键中间体，具有式Ⅷ所示结构；
Figure PCTCN2017093057-appb-000005
所述步骤(1)和步骤(2)之间没有时间顺序限制。
优选的，所述步骤(1)中的碱性物质为氢化钠、叔丁醇钾、叔丁醇钠、双(三甲基硅烷基)氨基锂、双(三甲基硅烷基)氨基钠和双(三甲基硅烷基)氨基钾中的一种或几种的混合物。
优选的，所述步骤(1)中的非质子有机溶剂为四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚和N,N-二甲基甲酰胺中的一种或几种的混合物。
优选的，所述步骤(1)中具有式I所示结构的化合物、碱性物质和2-(三甲基硅烷基)乙氧甲基氯的物质的量比优选为1:1～4:1～3。
优选的，所述步骤(2)中的有机胺盐为双(三甲基硅烷基)氨基钾、双(三甲基硅烷基)氨基锂、双(三甲基硅烷基)氨基钠和二异丙基氨基锂中的一种或几种的混合物。
优选的，所述步骤(2)中的醚类溶剂为四氢呋喃、2-甲基四氢呋喃、异丙醚和甲基叔丁基醚中的一种或几种的混合物。
优选的，所述步骤(2)中2-溴-7-氯-9H-芴、有机胺盐和N-氟代双苯磺酰胺的质量比为1:2.5～4.5:2～5。
优选的，所述步骤(2)中氟代反应的温度为-60～-100℃；氟代反应的时间为1.5～3h。
优选的，所述步骤(3)中的碱性物质为碳酸钾、叔丁醇钾、碳酸铯和醋酸铯中的一种或几种的混合物。
优选的，所述步骤(3)中的钯催化剂为Pd(OAc)2、Pd2(dba)3、Pd(PPh3)4和Pd(PPh3)2Cl2中的一种或几种的混合物。
优选的，所述步骤(3)中的有机磷配体为2-二环己基膦-2′,6′-二甲氧基-联苯、正丁基二(1-金刚烷基)膦和2-二环己基磷-2,4,6-三异丙基联苯中的一种或几种的混合物。
优选的，所述步骤(3)中具有式Ⅱ所示结构的化合物、2-溴-7-氯-9,9-二氟-9H-芴、碱性物质、钯催化剂和有机磷配体的物质的量比为1:1～1.5:2～3：0.005～0.1:0.01～0.2。
优选的，所述步骤(3)中碳-氢活化偶联反应的温度为110～130℃；碳-氢活化偶联反应的时间为11～13h。
优选的，所述步骤(4)中的碱性物质为碳酸钾、碳酸钠、碳酸铯和碳酸氢钠中的一种或几种的混合物。
优选的，所述步骤(4)中的钯催化剂为Pd(OAc)2、Pd(dppf)Cl2、Pd2(dba)3和Pd(PPh3)4中的一种或几种的混合物。
优选的，所述步骤(4)中的有机磷配体为2-二环己基膦-2′,6′-二甲氧基-联苯、4,5-双二苯基膦-9,9-二甲基氧杂蒽和2-二环己基磷-2,4,6-三异丙基联苯中的一种或几种的混合物。
优选的，所述步骤(4)中具有式Ⅴ所示结构的化合物、具有式Ⅵ所示结构的化合物、碱性物质、钯催化剂和有机磷配体的物质的量比为 1:1～1.5:2～3:0.005～0.1:0.001～0.2。
优选的，所述步骤(4)中Suzuki偶联反应的温度为100～110℃；Suzuki偶联反应的时间为6～8h。
优选的，所述步骤(5)中的酸性物质为盐酸、氢溴酸、甲磺酸、对甲苯磺酸和三氟醋酸中的一种或几种的混合物。
优选的，所述步骤(5)中脱保护基反应的温度为70～90℃；脱保护基反应的时间为5～7h。
优选的，当步骤(3)和步骤(4)中的碱和有机磷配体种类一致时，所述步骤(4)为：将所述步骤(3)得到的反应液与具有式Ⅵ所示结构的化合物和钯催化剂混合，进行Suzuki偶联反应，得到具有式Ⅶ所示结构的化合物。
本发明提供了利用上述方案任意一项所述制备方法制备的关键中间体制备雷迪帕韦的方法，包括以下步骤：
在碱性物质和缩合剂的作用下，将所述雷迪帕韦关键中间体与Moc-L-缬氨酸在极性溶剂中进行缩合反应，得到雷迪帕韦。
优选的，所述缩合反应的温度为0～40℃；所述缩合反应的时间为2～3h。
本发明还提供了用于制备雷迪帕韦的中间体化合物，具有式XV所示结构：
Figure PCTCN2017093057-appb-000006
式XV中，R为H、
Figure PCTCN2017093057-appb-000007
本发明提供了一种雷迪帕韦的制备方法，以具有式Ⅰ所示结构的化合物和2-溴-7-氯-9H-芴为起始物，分别制得具有式II所示结构的化合物和2-溴-7-氯-9,9-二氟-9H-芴，再经过碳-氢活化偶联反应、Suzuki偶联反应和脱保护基反应，即可得到合成雷迪帕韦的关键中间体—具有式Ⅷ所示结构 的化合物，具有式Ⅷ所示结构的化合物再与Moc-L-缬氨酸进行缩合反应，即可得到雷迪帕韦。本发明提供的雷迪帕韦的制备方法简单、步骤少，关键化合物2-溴-7-氯-9,9-二氟-9H-芴(式Ⅳ)仅需经过碳-氢活化偶联反应、Suzuki偶联反应和去保护基反应，三步即可得到制备雷迪帕韦的关键中间体VIII，提高了氟化合物的利用率，降低了制备成本。
本发明提供了用于制备雷迪帕韦的中间体化合物，具有式XV所示结构。本发明提供的用于制备雷迪帕韦的中间体化合物可以直接作为起始物进行雷迪帕韦的制备，可以减少制备步骤，提高合成效率，降低成本。
说明书附图
图1为本发明实施例合成雷迪帕韦的路线图。
具体实施方式
下面结合实施例和附图对本发明进一步说明。
本发明提供了一种雷迪帕韦关键中间体的制备方法，包括以下步骤：
(1)在碱性物质的作用下，将具有式I所示结构的化合物和2-(三甲基硅烷基)乙氧甲基氯在非质子有机溶剂中进行咪唑环保护反应，得到具有式Ⅱ所示结构的化合物；
Figure PCTCN2017093057-appb-000008
(2)在有机胺盐的作用下，将2-溴-7-氯-9H-芴与N-氟代双苯磺酰胺在醚类溶剂中进行氟代反应，得到2-溴-7-氯-9,9-二氟-9H-芴；
(3)在碱性物质、钯催化剂和有机磷配体的作用下，将所述具有式Ⅱ所示结构的化合物和所述2-溴-7-氯-9,9-二氟-9H-芴在极性溶剂中进行碳-氢活化偶联反应，得到具有式Ⅴ所示结构的化合物；
Figure PCTCN2017093057-appb-000009
(4)在碱性物质、钯催化剂和有机磷配体的作用下，将所述具有式Ⅴ所示结构的化合物和具有式Ⅵ所示结构的化合物在极性溶剂中进行 Suzuki偶联反应，得到具有式Ⅶ所示结构的化合物；
Figure PCTCN2017093057-appb-000010
(5)将所述具有式Ⅶ所示结构的化合物和酸性物质在非质子极性溶剂中进行脱保护基反应，得到雷迪帕韦关键中间体，具有式Ⅷ所示结构；
Figure PCTCN2017093057-appb-000011
所述步骤(1)和步骤(2)之间没有时间顺序限制。
本发明在碱性物质的作用下，将具有式I所示结构的化合物((S)-6-(1H-咪唑-2-基)-5-螺杂环[2.4]庚烷-5-羧酸叔丁酯)和2-(三甲基硅烷基)乙氧甲基氯在非质子有机溶剂中进行咪唑环保护反应，得到具有式Ⅱ所示结构的化合物((S)-6-[1-((2-(三甲基硅基)乙氧基)甲基-1H-咪唑-2-基]-5-螺杂环[2.4]庚烷-5-羧酸叔丁酯)。在本发明中，所述咪唑环保护反应用的碱性物质优选氢化钠、叔丁醇钾、叔丁醇钠、双(三甲基硅烷基)氨基锂、双(三甲基硅烷基)氨基钠和双(三甲基硅烷基)氨基钾中的一种或几种的混合物；所述咪唑环保护反应用的非质子有机溶剂优选为四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚和N,N-二甲基甲酰胺中的一种或几种的混合物。
在本发明中，所述具有式I所示结构的化合物、碱性物质和2-(三甲基硅烷基)乙氧甲基氯的物质的量比优选为1:1～4:1～3，更优选为1:2～3:1.5～2.5；所述具有式I所示结构的化合物的质量与非质子有机溶剂的体积比优选为1g：15～25ml，更优选为1g：20ml。
在本发明中，所述咪唑环保护反应的温度优选为室温；所述咪唑环保护反应的时间优选为1.5～3h，更优选为2h。本发明优选在搅拌的条件下进行咪唑环保护反应；所述搅拌的速率优选为300～500r/min，更优选为350～450r/min。
在本发明的部分具体实施例中，可以将具有式I所示结构的化合物和非质子有机溶剂混合，得到具有式I所示结构的化合物溶液；在0～5℃条件下将碱性物质和具有式I所示结构的化合物溶液混合，搅拌0.5～1h，得到第一混合溶液；将2-(三甲基硅烷基)乙氧甲基氯滴加至第一混合溶液中，控制滴加过程中第一混合液的温度为0～5℃，得到第二混合溶液；将第二混合溶液自然升温至室温进行咪唑环保护反应，所述反应时间自升温至室温时开始计算。在本发明中，滴加过程中控制混合溶液的温度优选为0～5℃；所述滴加的速度优选为1～5滴/秒，更优选为2～3滴/秒。
所述咪唑环保护反应完成后，本发明优选将得到咪唑环保护反应液进行后处理，得到具有式Ⅱ所示结构的化合物。在本发明中，咪唑环保护反应液的后处理过程优选包括：将咪唑环保护反应淬灭，依次对得到的反应液进行萃取、洗涤、浓缩和纯化，得到式Ⅱ所示结构的化合物。
在本发明中，所述淬灭反应用淬灭剂优选为水；本发明优选使用薄层色谱法检测反应历程，薄层色谱法检测显示反应结束时，将反应淬灭。在本发明中，所述萃取用萃取剂优选为乙酸乙酯；所述萃取的次数优选为2～5次，更优选为3～4次；本发明将所述萃取得到有机相洗涤，所述洗涤的洗涤剂优选为饱和氯化钠溶液；所述洗涤的次数优选为1～3次。在本发明中，所述浓缩优选为减压浓缩；本发明优选将所述洗涤产物浓缩至干。在本发明中，所述纯化优选为硅胶柱纯化；所述硅胶柱纯化用展开剂优选为乙酸乙酯和石油醚的混合物；所述乙酸乙酯和石油醚的混合物中乙酸乙酯和石油醚的体积比优选为1:1～5，更优选为1:2～4。
本发明对式Ⅰ所示化合物的来源没有特殊要求，使用市售商品或使用本领域常规方法进行合成均可。
本发明在有机胺盐的作用下，将2-溴-7-氯-9H-芴(式Ⅲ)与N-氟代双苯磺酰胺在醚类溶剂中进行氟代反应，得到2-溴-7-氯-9,9-二氟-9H-芴(式Ⅳ)。在本发明中，所述氟代反应用有机胺盐优选为双(三甲基硅烷基) 氨基钾、双(三甲基硅烷基)氨基锂、双(三甲基硅烷基)氨基钠和二异丙基氨基锂中的一种或几种的混合物；所述氟代反应用醚类溶剂优选为四氢呋喃、2-甲基四氢呋喃、异丙醚和甲基叔丁基醚中的一种或几种的混合物。
在本发明中，所述2-溴-7-氯-9H-芴、有机胺盐与N-氟代双苯磺酰胺的物质的量比优选为1:2.5～4.5:2～5，更优选为1:3.0～4.0:2.5～3.0；所述2-溴-7-氯-9H-芴的质量与醚类溶剂的体积比优选为1g：20～25ml，更优选为1g：21～23ml。
本发明对2-溴-7-氯-9H-芴的来源没有特殊要求，使用本领域常规方法进行合成或直接使用市售的商品均可。
在本发明中，所述氟代反应的温度优选为-60～-100℃，更优选为-70～-80℃；所述氟代反应的时间优选为1.5～3h，更优选为2h；本发明优选在惰性气体保护下进行氟代反应。
在本发明的部分具体实施例中，可以将具有式Ⅲ所示结构的化合物、N-氟代双苯磺酰胺和第一部分醚类溶剂混合，得到混合溶液；将碱性化合物溶解于第二部分醚类溶剂中，得到碱溶液；将所述碱溶液滴加到混合溶液中，进行氟代反应。在本发明中，滴加过程中控制混合溶液的温度为-70～-80℃；所述滴加的速度优选为1～5滴/秒，更优选为2～3滴/秒；所述第一部分醚类溶剂和第二部分醚类溶剂的总体积符合上述比例，在此不再赘述；所述第一部分醚类溶剂和第二部分醚类溶剂的体积比优选为1:0.9～1.2，更优选为1:1～1.1；本发明的反应时间自碱溶液滴加完毕开始计算。
所述氟代反应完成后，本发明优选将得到的氟代反应液进行后处理，得到2-溴-7-氯-9,9-二氟-9H-芴。在本发明中，所述后处理优选包括以下步骤：
将氟代反应液自然升温至-10～-20℃，向反应液中加入水后浓缩，得到浓缩物；
将所述浓缩物过滤，得到第一滤饼，将所述第一滤饼与甲醇混合，在30～50℃下搅拌0.5～1h，过滤得到第二滤饼；
将所述第二滤饼与甲苯混合，在80～95℃下搅拌1～1.5h，趁热过滤，滤液旋干得到第三滤饼；
将所述第三滤饼与异丙醇混合，在0～5℃下搅拌1～1.5h，过滤，得到第四滤饼；
将所述第四滤饼用异丙醇洗涤后干燥，得到2-溴-7-氯-9,9-二氟-9H-芴。
在本发明中，所述水的加入量优选为反应液体积的0.5～2.0倍，更优选为1.0～1.5倍；所述浓缩优选为减压浓缩；本发明优选将反应液浓缩至原体积的1/5～1/3；
在本发明中，所述甲醇的体积和第一滤饼的重量比优选为2～5ml：1g，更优选为3～4ml:1g；所述搅拌的转速优选为300～500r/min，更优选为350～450r/min；
在本发明中，所述甲苯的体积和第二滤饼的重量比优选为2～5ml：1g，更优选为3～4ml:1g；
在本发明中，所述异丙醇的体积和第三滤饼的重量比优选为4～7ml:1g，更优选为5～6ml:1g；
在本发明中，所述使用异丙醇洗涤的次数优选为2～5次，更优选为3～4次；所述干燥的温度优选为40～60℃，更优选为50℃，干燥至恒重即可；
在上述后处理过程中，所述各步骤中搅拌的转速独立的优选为300～500r/min，更优选为350～450r/min。
得到具有式Ⅱ所示结构的化合物和2-溴-7-氯-9,9-二氟-9H-芴后，本发明在碱性物质、钯催化剂和有机磷配体的作用下，将所述具有式Ⅱ所示结构的化合物和所述2-溴-7-氯-9,9-二氟-9H-芴在极性溶剂中进行碳-氢活化偶联反应，得到具有式Ⅴ所示结构的化合物((S)-6-(4-(7-氯-9,9-二氟-9H-芴-2-基)-1-[(2-(三甲基硅基)乙氧基)甲基-1H-咪唑-2-基]-5-螺杂环[2.4]庚烷-5-羧酸叔丁酯)。
在本发明中，所述碳-氢活化偶联反应用碱性物质优选为碳酸钾、叔丁醇钾、碳酸铯和醋酸铯中的一种或几种的混合物；所述碳-氢活化偶联反应用钯催化剂优选为Pd(OAc)2、Pd2(dba)3、Pd(PPh3)4和Pd(PPh3)2Cl2中的一种或几种的混合物；所述碳-氢活化偶联反应用有机磷配体优选为2-二环己基膦-2′,6′-二甲氧基-联苯(SPhos)、正丁基二(1-金刚烷基)膦 (P(n-Bu)Ad2)和2-二环己基磷-2,4,6-三异丙基联苯(XPhos)中的一种或几种的混合物；所述碳-氢活化偶联反应用极性溶剂的极性值优选为4.5～7.5，更优选为5.0～7.0；所述极性溶剂具体的优选为二氧六环、N,N-二甲基乙酰胺、N-甲基吡咯烷酮和乙二醇二甲醚中的一种或几种的混合物。
在本发明中，所述具有式Ⅱ所示结构的化合物、2-溴-7-氯-9,9-二氟-9H-芴、碱性物质、钯催化剂和有机磷配体的物质的量比优选为1:1～1.5:2～3：0.005～0.1:0.01～0.2，和更优选为1:1.2～1.3:2.3～2.5：0.01～0.05:0.05～0.15；所述具有式Ⅱ所示结构的化合物的质量与极性溶剂的体积比优选为1:10～20ml，更优选为1:13～16ml。
在本发明中，所述碳-氢活化偶联反应的温度优选为110～130℃，更优选为115～125℃，最优选为120℃；所述碳-氢活化偶联反应的时间优选为11～13h，最优选为12h。
所述碳-氢活化偶联反应后，本发明优选将得到的碳-氢活化偶联反应液过滤，向得到的滤液中加水淬灭反应，再依次对所述淬灭后的滤液进行萃取、洗涤和浓缩，得到具有式Ⅴ所示结构的化合物的粗产品，粗产品可直接应用于下一步的制备。在本发明中，所述萃取用萃取剂优选为乙酸乙酯；所述萃取剂与滤液的体积比优选为1.5～3.5:1，更优选为2～3:1；所述萃取的次数优选为2～5次，更优选为3～4次。本发明优选将萃取得到的有机相合并，进行洗涤；所述洗涤的洗涤剂优选为饱和氯化钠溶液；所述洗涤的次数优选为1～3次。在本发明中，所述浓缩优选为减压浓缩；本发明对减压浓缩的具体操作方法没有特殊要求，使用本领域常规的减压浓缩方法即可，本发明优选浓缩至干，得到粗产品。
得到具有式Ⅴ所示结构的化合物后，本发明在碱性物质、钯催化剂和有机磷配体的作用下，将所述具有式Ⅴ所示结构的化合物和具有式Ⅵ所示结构的化合物((1R,3S,4S)-3-[6-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-苯并咪唑-2-基]-2-氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯)在极性溶剂中进行Suzuki偶联反应，得到具有式Ⅶ所示结构的化合物((S)-6-(4-(7-(2-((1R,3S,4S)-2-(叔丁氧羰基)-2-氮杂双环[2.2.1]庚烷-3-基)-1H-苯并[d]咪唑-6-剂)-9,9-二氟-9H-芴-2-基)-1-[(2-(三甲基硅基)乙氧 基)甲基-1H-咪唑-2-基]-5-螺杂环[2.4]庚烷-5-羧酸叔丁酯)。在本发明中，所述Suzuki偶联反应用碱性物质优选为碳酸钾、碳酸钠、碳酸铯和碳酸氢钠中的一种或几种的混合物；所述Suzuki偶联反应用钯催化剂不能为Pd(PPh3)2Cl2，其余和步骤(3)中使用的钯催化剂种类相同，且还可以为Pd(dppf)Cl2；所述Suzuki偶联反应用有机磷配体优选为2-二环己基膦-2′,6′-二甲氧基-联苯(SPhos)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(XantePhos)和2-二环己基磷-2,4,6-三异丙基联苯(XPhos)中的一种或几种的混合物；所述Suzuki偶联反应用极性溶剂的极性值优选为4.5～7.2，更优选为5～6.5；所述极性溶剂具体的优选为二氧六环、N,N-二甲基乙酰胺、N-甲基吡咯烷酮和乙二醇二甲醚中的一种或几种的混合物。
在本发明中，所述具有式Ⅴ所示结构的化合物、具有式Ⅵ所示结构的化合物、碱性物质、钯催化剂和有机磷配体的物质的量比优选为1:1～1.5:2～3:0.005～0.1:0.001～0.2，更优选为1:1.2～1.3:2.3～2.5:0.01～0.05:0.005～0.1；所述具有式Ⅴ所示结构的化合物的质量和极性溶剂的体积优选为1g:20～30ml，更优选为1g：25ml。
本发明对具有式Ⅵ所示结构的化合物的来源没有特殊要求，使用本领域方法进行合成或直接使用市售的商品均可。
在本发明中，所述Suzuki偶联反应的温度优选为100～110℃，更优选为103～105℃；所述Suzuki偶联反应的时间优选为6～8h，更优选为7h。
本发明还提供了一种通过“一锅法”实现碳-氢活化偶联反应和Suzuki偶联反应的方法，即当步骤(3)和步骤(4)中使用的碱性物质和有机磷配体的种类一致时，所述步骤(3)的反应完成后，将步骤(3)的反应液与具有式Ⅵ所示结构的化合物和钯催化剂混合进行Suzuki偶联反应；步骤(3)中得到的具有式Ⅴ所示结构的化合物无需进行分离和纯化处理；此处所用的钯催化剂与上述方案步骤(4)中的钯催化剂一致，在此不再赘述。
本发明提供的制备方法通过“一锅法”来实现具有式Ⅶ所示结构的化合物的合成，将步骤(3)和步骤(4)综合到一个反应器中，无需进行中间产物的分离和纯化，进一步简化了制备步骤，降低了生产成本。
所述Suzuki偶联反应完成后，本发明优选将反应淬灭，依次对反应 液进行萃取、洗涤、浓缩和纯化，得到式Ⅶ所示结构的化合物。在本发明中，所述萃取、洗涤、浓缩和纯化的方法与分离咪唑环保护反应产物时的方法一致，在此不再赘述。
得到具有式Ⅶ所示结构的化合物后，本发明将所述具有式Ⅶ所示结构的化合物和酸性物质在非质子极性溶剂中进行脱保护基反应，得到雷迪帕韦关键中间体，具有式Ⅷ所示结构。在本发明中，所述酸性物质优选为盐酸、氢溴酸、甲磺酸、对甲苯磺酸和三氟醋酸中的一种或几种的混合物；所述盐酸优选为质量浓度为36～38％的浓盐酸；所述氢溴酸优选为质量浓度为47.5％的浓氢溴酸；所述甲磺酸优选为纯度大于98％的甲磺酸；所述对甲苯磺酸优选为纯度大于96％的对甲苯磺酸；所述三氟醋酸优选为纯度大于99％的浓三氟醋酸；所述脱保护基反应用非质子极性溶剂的极性值优选为4.5～7.2，更优选为5～6.5；所述非质子极性溶剂具体的优选为乙二醇二甲醚、丙酮和乙腈中的一种或几种的混合物。
在本发明中，所述具有式Ⅶ所示结构的化合物和酸性物质的摩尔比优选为1:4.0～6.0，更优选为1:4.3～5.0；所述具有式Ⅶ所示结构的化合物的质量和非质子极性溶剂的体积比优选为1g：15～25ml，更优选为1g：20ml。
在本发明中，所述脱保护基反应的温度优选为70～90℃，更优选为75～85℃，最优选为80℃；所述脱保护基反应的时间优选为5～7h，更优选为5.5～6.5h，最优选为6h；本发明优选在加热回流的条件下进行所述脱保护基反应。
在本发明的部分具体实施例中，可以将具有式Ⅶ所示结构的化合物和非质子极性溶剂混合，得到具有式Ⅶ所示结构的化合物的溶液；将酸性物质滴加至具有式Ⅶ所示结构的化合物的溶液中进行脱保护剂反应，得到具有式VIII所示结构的化合物。在本发明中，所述滴加速度优选为1～5滴/秒，更优选为2～3滴/秒；本发明的反应时间自酸性物质滴加完毕开始计算。
所述脱保护基反应完成后，本发明优选将脱保护基反应液进行后处理，得到雷迪帕韦关键中间体。在本发明中，所述脱保护基反应液后处理的方法优选具体为：将反应液过滤，得到滤饼；将所述滤饼用乙酸乙酯洗涤后浓缩去除残留溶剂。
本发明提供了一种利用上述方案所述制备方法制备的关键中间体制备雷迪帕韦的方法，包括以下步骤：
在碱性物质和缩合剂的作用下，将所述雷迪帕韦关键中间体与Moc-L-缬氨酸在极性溶剂中进行缩合反应，得到雷迪帕韦。
在本发明中，所述缩合反应用碱性物质优选为有机碱；更优选为N-甲基吗啉、三乙胺和二异丙基乙胺中的一种或几种的混合物；所述缩合剂优选为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC.HCl)和1-羟基苯并三唑(HOBt)或2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)中的一种或几种的混合物；所述缩合反应用极性溶剂的极性值优选为4.5～7.2，更优选为5.0～6.5；所述极性溶剂具体的优选为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮和二氯甲烷中的一种或几种的混合物。
在本发明中，所述雷迪帕韦关键中间体、缩合剂、碱性物质和Moc-L-缬氨酸的物质的量比优选为1:3～8:8～14:2～4，更优选为1:4～6:9～11:2.5～3.5；所述具有式Ⅷ所示结构的化合物的质量和极性溶剂的体积比优选为1g:8～12ml，更优选为1g:9～11ml，最优选为1g：10ml。
在本发明中，所述缩合反应的温度优选为0～40℃，更优选为10～30℃；所述缩合反应的时间优选为2～3h，更优选为2.5～2.8h。
在本发明的部分具体实施例中，优选将酸性物质、Moc-L-缬氨酸和极性溶剂混合并在0～40℃条件下搅拌0.5～1h，得到酸性物质和Moc-L-缬氨酸的混合溶液；将所述混合溶液温度降至0～5℃，向所述混合溶液中加入具有式Ⅷ所示结构的化合物，得到反应原液；将有机碱滴加至所述反应原液中，滴加完毕后将溶液温度升至2～30℃进行缩合反应，得到雷迪帕韦。在本发明中，所述滴加的速度优选为1～5滴/秒，更优选为2～3滴/秒；所述缩合反应的时间自升温至所需温度时开始计算；本发明步骤(6)中使用的有机碱均为液态物质，可以直接滴加，无需使用溶剂进行溶解。
所述缩合反应完成后，本发明优选将缩合反应产物分离，得到雷迪帕韦。在本发明中，所述分离缩合反应产物优选具体为：向反应液中加入乙酸乙酯和水，搅拌0.5～1h后静置分层，得到水相和第一有机相；将所述水相用乙酸乙酯萃取，得到第二有机相；将所述第二有机相和第一有机相 合并后与吸水性物质混合，再搅拌1～1.5h后过滤，得到滤液；将所述滤液浓缩，得到浓缩物；将所述浓缩物与丙酮混合，在5～15℃下搅拌12～24h后过滤和干燥，得到雷迪帕韦粗产品；将所述雷迪帕韦粗产品与乙酸乙酯混合后过滤、浓缩至干，得到浓缩固体；将所述浓缩固体用丙酮溶解至澄清后，搅拌10～12h，析出固体后过滤和干燥，得到雷迪帕韦纯品。
在本发明中，所述反应液中加入的乙酸乙酯和反应液的体积比优选为1.8～2.2:1，更优选为2:1；所述反应液中加入的乙酸乙酯和水的体积比优选为2～3:1，更优选为2.3～2.5:1；
在本发明中，所述萃取用乙酸乙酯与水相的体积比优选为1.5～3.5:1，更优选为2～3:1；所述萃取的次数优选为2～3次；
在本发明中，所述吸水性物质优选为无水硫酸钠和/或硅胶；所述吸水性物质的加入量优选为0.05～0.2g/ml，更优选为0.1～0.15g/ml；
在本发明中，所述浓缩滤液的温度优选为70～100℃，更优选为80～90℃；所述浓缩滤液的时间优选为1～3h，更优选为2h；本发明优选将滤液浓缩至原体积的1/5～1/3，更优选为浓缩至原体积的1/4；
在本发明中，所述丙酮与浓缩物的体积比优选为4～5:1，更优选为4.5:1；所述雷迪帕韦粗产品的干燥温度优选为70～90℃，更优选为75～85℃，干燥时间优选为1～3h，更优选为1.5～2.5h；
在本发明中，所述雷迪帕韦粗产品与乙酸乙酯的质量比优选为1:3～3.5，更优选为1:3.1～3.3；
在本发明中，所述浓缩得到浓缩固体的步骤中的浓缩的温度优选为70～100℃，更优选为80～90℃，本发明此处对浓缩时间没有特殊要求，浓缩至干即可；
在本发明中，所述浓缩固体与丙酮的质量比优选为1:10～12，更优选为1:11；
在本发明中，所述雷迪帕韦粗纯品的干燥温度和时间与雷迪帕韦粗产品的干燥温度和时间一致，在此不再赘述。
本发明的制备过程中合成了用于制备雷迪帕韦的新的中间体化合物，具有式XV所示结构：
Figure PCTCN2017093057-appb-000012
式XV中，R为H、
Figure PCTCN2017093057-appb-000013
该中间体化合物用于合成雷迪帕韦，能够减少合成步骤，提高合成效率。
下面结合实施例对本发明提供的雷迪帕韦的制备方法进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
实施例1
(1)在250mL的四口瓶中加入5.0g具有式Ⅰ所示结构的化合物和100mL四氢呋喃，降温至0℃，加入质量分数为60％的分散于石蜡油的氢化钠912mg，温度控制在0℃；氢化钠加入结束后，在0℃下搅拌反应30分钟。滴加3.3g 2-(三甲基硅烷基)乙氧甲基氯,滴加过程温度控制在0℃，滴加结束后自然升温至室温，搅拌反应2小时；反应完成后取样，TLC(PE:EA＝1：1)检测显示反应结束；
对产物进行分离提纯：缓慢滴加100mL水淬灭反应，用150mL乙酸乙酯萃取三次，合并有机相用40mL饱和食盐水洗涤一次，减压浓缩至干，浓缩物用快速硅胶柱纯化，展开剂为乙酸乙酯和石油醚混合物(PE:EA＝10：1到PE:EA＝3：1),收集含有产品的组分，浓缩得具有式Ⅱ所示结构的化合物5.2g，收率69.6％，纯度97％；
使用核磁共振对产物结构进行检测，可得1HNMR谱图数据为：1HNMR(400MHz CDCl3)δ6.99(s,1H),6.90(s,1H),5.78-5.73(m,0.5H),5.44–5.35(m,0.5H),5.20–5.13(m,1H),5.10–5.02(m,1H),3.80-3.64(m,1H),3.53–3.45(m,2H),3.33(d,1H,J＝10Hz),2.33–2.23(m,1H),2.10-1.95(m,1H),1.40(s,4.5H),1.22(s,4.5H),1.00-0.83(m,2H),0.78–0.66(m,1H),0.64–0.58(m,2H),0.57–0.52(m,1H)；
根据核磁共振结果可知，所得产物确实为具有式Ⅱ所示结构的化合物；
(2)在2.0L反应瓶中加入60g 2-溴-7-氯-9H-芴，186g N-氟代双苯磺酰胺和660mL四氢呋喃，在氮气保护下，反应液降温至-78℃，缓慢滴加690mL 1.0mol/L的双(三甲基硅烷基)氨基锂的四氢呋喃溶液，滴加时温度控制在-70℃，滴加结束后，在-70℃下搅拌反应2小时；取样送LC-MS检测显示反应结束；
对产物进行分离提纯：将反应液自然升温至-20℃，滴加108mL水至澄清，减压浓缩至大量固体析出，分三批加入840mL水带蒸四氢呋喃，冷却至20℃，过滤；滤饼加入180g甲醇中，升温至40℃搅拌30分钟，降温至20℃搅拌30分钟，过滤；滤饼加入192g甲苯中，升温至90℃搅拌1小时；布氏漏斗中铺少量硅胶，趁热过滤；滤饼用热甲苯洗涤两次；减压浓缩大部分甲苯，滴加300g异丙醇，降温至5℃搅拌1小时，过滤，滤饼用异丙醇洗涤两次，滤饼在50℃下鼓风干燥得43.8g2-溴-7-氯-9,9-二氟-9H-芴；收率63.9％，纯度96.6％；
使用核磁共振对产物结构进行检测，可得1HNMR谱图数据为：1H NMR(400MHz,CDCl3)，δ：7.80–7.70(m,1H),7.70–7.56(m,2H),7.46(q,J＝8.4Hz,2H),7.50–7.36(m,1H)；
根据核磁共振结果可知，所得产物确实为具有式Ⅳ所示结构的化合物；
(3)在氮气保护下，向250mL单口瓶中加入6.2g具有式Ⅱ所示结构的化合物，4.1g 2-溴-7-氯-9,9-二氟-9H-芴，3.6g碳酸钾，147mg Pd(OAc)2，550mg SPhos和90mLN,N-二甲基乙酰胺，加完后，反应体系升温至120℃搅拌反应12小时；取样TLC(PE:EA＝3：1)检测显示反应结束；
将产物进行分离提纯：向反应液中加少量硅藻土，过滤除去黑色不溶物；向滤液中，加150mL水淬灭反应，用300mL乙酸乙酯萃取两次；合并有机相，用饱和食盐水洗涤两次，减压浓缩干；得到具有式Ⅴ所示结构的化合物的粗品，粗产品可直接用于下一步反应。
取样品，采用硅胶柱方法纯化，将得到的纯品进行质谱和核磁共振检测；所得数据为：MS＝628[M+H]+；1HNMR(400MHz CDCl3)δ7.80–7.70(m,1H),7.63–7.54(m,3H),7.52–7.48(m,1H),7.45–7.42(m,1H), 7.17–7.11(m,1H),5.70-5.60(m,0.5H),5.33–5.28(m,0.5H),5.20–5.13(m,2H),3.92-3.64(m,1H),3.53–3.45(m,2H),3.40–3.33(m,1H),2.12–2.07(m,1H),1.95-1.85(m,1H),1.40(s,4.5H),1.22(s,4.5H),0.97-0.92(m,2H),0.87–0.81(m,2H),0.68–0.62(m,1H),0.57–0.52(m,1H),0.00(s,9H)；
根据检测结果可知，所得产物确实为具有式Ⅴ所示结构的化合物；
(4)在250mL单口瓶中加入4.0g具有式Ⅴ所示结构的化合物，3.4g具有式Ⅵ所示结构的化合物，1.8g碳酸钾，143mg Pd(dppf)Cl2,526mg SPhos，80mL 1.4-二氧六环和20mL水；反应体系用氮气置换三次，升温至100℃回流7小时；取样送LC-MS检测显示反应结束；
将产物分离提纯：加少量硅藻土和50mL水淬灭反应，加100mL乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗涤两次，减压浓缩干；浓缩物用快速硅胶柱纯化，展开剂为乙酸乙酯和石油醚混合物(PE:EA＝10：1到PE:EA＝3：1),收集含有产品的组分，浓缩、干燥得具有式Ⅶ所示结构的化合物4.7g，纯度98％，收率为82％；
使用核磁共振对产物结构进行质谱和核磁共振检测，所得谱图数据为：MS＝453[M/2+1]；1HNMR(400MHz CDCl3)δ10.88–10.62(m,1H),7.90(s,1H),7.80–7.70(m,2H),7.63–7.54(m,2H),7.52–7.48(m,3H),7.18–7.10(m,1H),5.70-5.60(m,0.5H),5.33–5.28(m,0.5H),5.20–5.13(m,2H),4.58(s,1H),4.18(s,1H),3.82-3.64(m,1H),3.53–3.45(m,2H),3.40–3.33(m,1H),2.12–2.07(m,2H),1.78-1.70(m,3H),1.52(s,9H),1.45-1.38(m,4H),1.24(s,9H),0.97-0.92(m,2H),0.87–0.81(m,4H),0.68–0.62(m,2H),0.00(s,9H).
根据检测结果可知，所得产物确实为具有式Ⅶ所示结构的化合物。
(5)在250mL单口瓶中加入2.5g具有式Ⅶ所示结构的化合物和50mLDME，滴加1.3g浓盐酸，升温至80℃回流6小时；取样送LC-MS检测显示反应结束；
将产物分离提纯：将反应液过滤，滤饼用25mL乙酸乙酯洗涤两次，减压浓缩，除去残留的溶剂，得到雷迪帕韦关键中间体(具有式Ⅷ所示结构)1.87g，收率94％，纯度97％；
使用质谱和核磁共振对产物结构进行检测，可得谱图数据为：MS＝288[M/2+1]。1HNMR(400MHz CDCl3)δ10.88–10.62(m,1H),10.40–10.32(m,2H),8.37(s,1H),8.29–8.24(m,1H),8.12–7.93(m,5H),7.83–7.70(m,3H),5.32-5.23(m,1H),4.84(s,1H),4.20(s,2H),3.69-3.63(m,1H),3.19–3.11(m,2H),2.90–2.80(m,1H),2.29–2.21(m,1H),2.15–2.05(m,1H),2.04–1.92(m,1H),1.72–1.62(m,3H),0.88–0.82(m,2H),0.75-0.68(m,2H).
根据检测结果可知，所得产物确实为具有式Ⅷ所示结构的化合物。
(6)向2L反应瓶内加1000g DMF,87.8g的EDC.HCl,41.2g的HOBt,和80g MOC-L-valine，在25℃下搅拌30分钟，降温到0℃，加入100克具有式Ⅷ所示结构的化合物，在0℃下滴加100g的N-甲基吗啉，30分钟加完；加完后，升温到25℃反应2小时，送样检测HPLC，VIII的含量在0.3％以内为反应终点，否则继续反应到合格为止；
将产物分离提纯：反应结束后，将反应液转入5L反应瓶中，向反应液中加入2000g的乙酸乙酯和800g水，搅拌30分钟后，静置分层得有机相；水层用1440g的乙酸乙酯提取2次，将得到的有机相合并，用5％碳酸氢钠溶液2000g洗涤有机相一次，1000g的水洗涤有机相一次，1000g的饱和氯化钠溶液洗涤有机相一次；洗涤完成后向有机相中加入380g的元明粉和380g的硅胶，在25℃下搅拌1小时，过滤后浓缩滤液至无明显液滴(240克左右)；向浓缩物中慢慢滴加1120g的丙酮(1小时加完)，降温到10℃，搅拌24h，过滤后将产物在50℃下真空干燥至水分小于0.1％，得到雷迪帕韦粗品；粗品加入3倍重量的乙酸乙酯溶解后，过滤，在45℃下将滤液浓缩至干，加入11倍重量的丙酮溶解澄清后，搅拌10小时，慢慢析出固体，过滤得到产物雷迪帕韦，为白色粉末，收率为77.1％，纯度为99.5％。
使用质谱和核磁共振对产物结构进行检测，可得谱图数据为：ESI-MS m/z:889[M+H]+；1H NMR(400MHz,DMSO)δ12.19(s,1H),11.85(s,1H),8.08(s,1H),7.96(s,2H),7.92–7.75(m,4H),7.70(s,1H),7.64–7.48(m,2H),7.30(d,J＝8.3Hz,1H),7.21(d,J＝8.6Hz,1H),5.20(dd,J＝7.7,5.1Hz,1H),4.67(d,J＝5.9Hz,1H),4.55(s,1H),4.17(t,J＝7.9Hz,1H), 4.01(t,J＝8.2Hz,1H),3.82(d,J＝9.7Hz,1H),3.72(d,J＝9.7Hz,1H),3.55(d,J＝2.5Hz,6H),2.67(s,1H),2.41(d,J＝9.3Hz,1H),2.22(m,1H),2.10–1.69(m,7H),1.51(m,2H),0.95(dd,J＝15.5,6.5Hz,6H),0.90–0.75(m,7H),0.70(m,1H),0.66–0.46(m,3H).13C NMR(101MHz,CDCl3)δ170.50,170.00,156.93,155.37,149.42,143.86,143.14,141.84,138.30,137.98,137.74,137.49,136.25,135.95,134.64,133.97,133.26,131.18,127.95,125.77,123.35,121.86,121.30,120.96,119.31,116.77,113.60,111.74,109.43,60.82,58.08,57.86,56.24,54.97,54.43,51.52,51.49,30.99,30.14,29.84,27.10,21.16,19.32,19.09,18.45,18.19,10.77,9.59.
根据检测结果可知，所得产物确实为雷迪帕韦。
对整个反应过程中N-氟代双苯磺酰胺的利用率进行计算，可得N-氟代双苯磺酰胺的利用率为59.4％。
实施例2
(1)在1L的四口瓶中加入20.0g具有式Ⅰ所示结构的化合物和400mL四氢呋喃，降温至5℃，加入10.2g叔丁醇钾，滴加13.2g 2-(三甲基硅烷基)乙氧甲基氯,滴加过程温度控制在5℃，滴加结束后自然升温至室温，搅拌反应4小时；反应完成后取样，TLC(PE:EA＝1：1)检测显示反应结束；
按照实施例1中的方法对产物进行分离提纯，得到具有式Ⅱ所示结构的化合物23.3g，收率78％，纯度98％；
(2)在2.0L反应瓶中加入70g 2-溴-7-氯-9H-芴，190g N-氟代双苯磺酰胺和700mL四氢呋喃，在氮气保护下，反应液降温至-60℃，缓慢滴加700mL 1.0mol/L的双(三甲基硅烷基)氨基锂的四氢呋喃溶液，滴加时温度控制在-60℃，滴加结束后，在-60℃下搅拌反应1.5小时；取样送LC-MS检测显示反应结束；
按照实施例1中的方法对产物进行分离提纯，得到得51.5g 2-溴-7-氯-9,9-二氟-9H-芴；收率65.2％，纯度98.6％；
(3)在氮气保护下，向500mL单口瓶中加入12.2g具有式Ⅱ所示结构的化合物，8.1g 2-溴-7-氯-9,9-二氟-9H-芴，16.7g碳酸铯，290mg Pd(pph3)4，1100mg SPhos和200mLN-甲基吡咯烷酮，加完后，反应体系 升温至130℃搅拌反应11小时；取样TLC(PE:EA＝3：1)检测显示反应结束；
按照实施例1中的方法将产物进行分离提纯，得到具有式Ⅴ所示结构的化合物的粗品，粗产品可直接用于下一步反应。
(4)在500mL单口瓶中加入8.0g具有式Ⅴ所示结构的化合物，6.5g具有式Ⅵ所示结构的化合物，2.1g碳酸氢钠，290mg Pd(dppf)Cl2,1050mg SPhos，200mL乙二醇二甲醚；反应体系用氮气置换三次，升温至回流，反应6小时；取样送LC-MS检测显示反应结束；
按照实施例1中的方法将产物分离提纯，得到具有式Ⅶ所示结构的化合物10.3g，收率89.5％，产物纯度98％；
(5)在250mL单口瓶中加入5g具有式Ⅶ所示结构的化合物和100mL丙酮，滴加3.8g氢溴酸，升温至70℃回流5小时；取样送LC-MS检测显示反应结束；
按照实施例1中的方法将产物分离提纯，得到雷迪帕韦关键中间体(具有式Ⅷ所示结构的氢溴酸盐)4.86g，收率98％，纯度98.5％；
(6)向2L反应釜内加1000g二氯甲烷，166g的HATU和165g MOC-L-valine，在20℃下搅拌30分钟，降温到0℃，加入200克具有式Ⅷ所示结构的氢溴酸盐，在0℃下滴加200g的三乙胺，30分钟加完；加完后，升温到20℃反应3小时，送样检测HPLC，有式Ⅷ所示结构的化合物的含量在0.3％以内为反应终点，否则继续反应到合格为止；
按照实施例1中的方法将产物分离提纯，得到产物雷迪帕韦，为白色粉末，收率为80.1％，纯度为99.4％。
对整个反应过程中N-氟代双苯磺酰胺的利用率进行计算，可得N-氟代双苯磺酰胺的利用率为70.0％。
实施例3
(1)在2L的四口瓶中加入30.0g具有式Ⅰ所示结构的化合物和600mL四氢呋喃，降温至3℃，加入15g叔丁醇钠，滴加19.8g 2-(三甲基硅烷基)乙氧甲基氯,滴加过程温度控制在3℃，滴加结束后自然升温至室温，搅拌反应3小时；反应完成后取样，TLC(PE:EA＝1：1)检测显示反应结束；
按照实施例1中的方法对产物进行分离提纯，得到具有式Ⅱ所示结构的化合物36.3g，收率81％，纯度98％；
(2)在2.0L反应瓶中加入50g 2-溴-7-氯-9H-芴，136g N-氟代双苯磺酰胺和500mL异丙醚，在氮气保护下，反应液降温至-65℃，缓慢滴加500mL 1.0mol/L的双(三甲基硅烷基)氨基钾的异丙醚溶液，滴加时温度控制在-65℃，滴加结束后，在-65℃下搅拌反应2.5小时；取样送LC-MS检测显示反应结束；
按照实施例1中的方法对产物进行分离提纯，得到得37.4g2-溴-7-氯-9,9-二氟-9H-芴；收率66.2％，纯度98.9％；
(3)在1000mL单口瓶中加入45.4g具有式Ⅱ所示结构的化合物，30g 2-溴-7-氯-9,9-二氟-9H-芴，26.3g碳酸钾，1.1gPd(OAc)2,4.0g SPhos和600mLN,N-二甲基乙酰胺，氮气置换三次，升温至120℃回流反应5小时，取样送LC-MS检测显示反应结束；
缓慢降温至20℃，向反应混合液中加入50.3g具有式Ⅵ所示结构的化合物和3.5g Pd(dppf)Cl2，氮气置换三次，升温至120℃回流7小时，取样送LC-MS检测显示反应结束；
按照实施例1中的方法将产物分离提纯，得到具有式Ⅶ所示结构的化合物53.3g，收率62％，产物纯度98％；
(4)在500mL单口瓶中加入10g具有式Ⅶ所示结构的化合物和200mL丙酮，滴加7.6g氢溴酸，升温至75℃回流6小时；取样送LC-MS检测显示反应结束；
按照实施例1中的方法将产物分离提纯，得到雷迪帕韦关键中间体(具有式Ⅷ所示结构的氢溴酸盐)7.0g，收率98.5％，纯度98.9％；
(5)向2L反应釜内加1000g二氯甲烷，200g的HATU和200g MOC-L-valine，在20℃下搅拌30分钟，降温到0℃，加入250克具有式Ⅷ所示结构的氢溴酸盐，在0℃下滴加250g的三乙胺，30分钟加完；加完后，升温到20℃反应3小时，送样检测HPLC，具有式Ⅷ所示结构的化合物的含量在0.3％以内为反应终点，否则继续反应到合格为止；
按照实施例1中的方法将产物分离提纯，得到产物雷迪帕韦253.3g，为白色粉末，收率为82.1％，纯度为99.5％。
对整个反应过程中N-氟代双苯磺酰胺的利用率进行计算，可得N-氟代双苯磺酰胺的利用率为50.0％。
由以上实施例可知，本发明提供的制备方法简单、步骤少，关键化合物2-溴-7-氯-9,9-二氟-9H-芴(式Ⅳ)仅需经过碳-氢活化偶联反应、Suzuki偶联反应和去保护基反应，三步即可得到制备雷迪帕韦的关键中间体VIII，且可以通过“一锅法”实现碳-氢活化反应和Suzuki偶联反应，提高了氟化合物的利用率，降低了制备成本。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。对这些实施例的多种修改对本领域的专业技术人员来说是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。

Claims (24)

  1. 一种雷迪帕韦关键中间体的制备方法，其特征在于，包括以下步骤：
    (1)在碱性物质的作用下，将具有式I所示结构的化合物和2-(三甲基硅烷基)乙氧甲基氯在非质子有机溶剂中进行咪唑环保护反应，得到具有式Ⅱ所示结构的化合物；
    Figure PCTCN2017093057-appb-100001
    (2)在有机胺盐的作用下，将2-溴-7-氯-9H-芴与N-氟代双苯磺酰胺在醚类溶剂中进行氟代反应，得到2-溴-7-氯-9,9-二氟-9H-芴；
    (3)在碱性物质、钯催化剂和有机磷配体的作用下，将所述具有式Ⅱ所示结构的化合物和2-溴-7-氯-9,9-二氟-9H-芴在极性溶剂中进行碳-氢活化偶联反应，得到具有式Ⅴ所示结构的化合物；
    Figure PCTCN2017093057-appb-100002
    (4)在碱性物质、钯催化剂和有机磷配体的作用下，将所述具有式Ⅴ所示结构的化合物和具有式Ⅵ所示结构的化合物在极性溶剂中进行进行Suzuki偶联反应，得到具有式Ⅶ所示结构的化合物；
    Figure PCTCN2017093057-appb-100003
    (5)将所述具有式Ⅶ所示结构的化合物和酸性物质在非质子极性溶 剂中进行脱保护基反应，得到雷迪帕韦关键中间体，具有式Ⅷ所示结构；
    Figure PCTCN2017093057-appb-100004
    所述步骤(1)和步骤(2)之间没有时间顺序限制。
  2. 根据权利要求1所述的制备方法，其特征在于，所述步骤(1)中的碱性物质为氢化钠、叔丁醇钾、叔丁醇钠、双(三甲基硅烷基)氨基锂、双(三甲基硅烷基)氨基钠和双(三甲基硅烷基)氨基钾中的一种或几种的混合物。
  3. 根据权利要求1所述的制备方法，其特征在于，所述步骤(1)中的非质子有机溶剂为四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚和N,N-二甲基甲酰胺中的一种或几种的混合物。
  4. 根据权利要求1所述的制备方法，其特征在于，所述步骤(1)中具有式I所示结构的化合物、碱性物质和2-(三甲基硅烷基)乙氧甲基氯的物质的量比优选为1:1～4:1～3。
  5. 根据权利要求1所述的制备方法，其特征在于，所述步骤(2)中的有机胺盐为双(三甲基硅烷基)氨基钾、双(三甲基硅烷基)氨基锂、双(三甲基硅烷基)氨基钠和二异丙基氨基锂中的一种或几种的混合物。
  6. 根据权利要求1所述的制备方法，其特征在于，所述步骤(2)中的醚类溶剂为四氢呋喃、2-甲基四氢呋喃、异丙醚和甲基叔丁基醚中的一种或几种的混合物。
  7. 根据权利要求1所述的制备方法，其特征在于，所述步骤(2)中2-溴-7-氯-9H-芴、有机胺盐和N-氟代双苯磺酰胺的质量比为1:2.5～4.5:2～5。
  8. 根据权利要求1所述的制备方法，其特征在于，所述步骤(2)中氟代反应的温度为-60～-100℃；氟代反应的时间为1.5～3h。
  9. 根据权利要求1所述的制备方法，其特征在于，所述步骤(3)中的碱性物质为碳酸钾、叔丁醇钾、碳酸铯和醋酸铯中的一种或几种的混 合物。
  10. 根据权利要求1所述的制备方法，其特征在于，所述步骤(3)中的钯催化剂为Pd(OAc)2、Pd2(dba)3、Pd(PPh3)4和Pd(PPh3)2Cl2中的一种或几种的混合物。
  11. 根据权利要求1所述的制备方法，其特征在于，所述步骤(3)中的有机磷配体为2-二环己基膦-2′,6′-二甲氧基-联苯、正丁基二(1-金刚烷基)膦和2-二环己基磷-2,4,6-三异丙基联苯中的一种或几种的混合物。
  12. 根据权利要求1所述的制备方法，其特征在于，所述步骤(3)中具有式Ⅱ所示结构的化合物、2-溴-7-氯-9,9-二氟-9H-芴、碱性物质、钯催化剂和有机磷配体的物质的量比为1:1～1.5:2～3：0.005～0.1:0.01～0.2。
  13. 根据权利要求1所述的制备方法，其特征在于，所述步骤(3)中碳-氢活化偶联反应的温度为110～130℃；碳-氢活化偶联反应的时间为11～13h。
  14. 根据权利要求1所述的制备方法，其特征在于，所述步骤(4)中的碱性物质为碳酸钾、碳酸钠、碳酸铯和碳酸氢钠中的一种或几种的混合物。
  15. 根据权利要求1所述的制备方法，其特征在于，所述步骤(4)中的钯催化剂为Pd(OAc)2、Pd(dppf)Cl2、Pd2(dba)3和Pd(PPh3)4中的一种或几种的混合物。
  16. 根据权利要求1所述的制备方法，其特征在于，所述步骤(4)中的有机磷配体为2-二环己基膦-2′,6′-二甲氧基-联苯、4,5-双二苯基膦-9,9-二甲基氧杂蒽和2-二环己基磷-2,4,6-三异丙基联苯中的一种或几种的混合物。
  17. 根据权利要求1所述的制备方法，其特征在于，所述步骤(4)中具有式Ⅴ所示结构的化合物、具有式Ⅵ所示结构的化合物、碱性物质、钯催化剂和有机磷配体的物质的量比为1:1～1.5:2～3:0.005～0.1:0.001～0.2。
  18. 根据权利要求1所述的制备方法，其特征在于，所述步骤(4)中Suzuki偶联反应的温度为100～110℃；Suzuki偶联反应的时间为6～8h。
  19. 根据权利要求1所述的制备方法，其特征在于，所述步骤(5)中的酸性物质为盐酸、氢溴酸、甲磺酸、对甲苯磺酸和三氟醋酸中的一种 或几种的混合物。
  20. 根据权利要求1所述的制备方法，其特征在于，所述步骤(5)中脱保护基反应的温度为70～90℃；脱保护基反应的时间为5～7h。
  21. 根据权利要求1～20任意一项所述的制备方法，其特征在于，当步骤(3)和步骤(4)中的碱和有机磷配体种类一致时，所述步骤(4)为：将所述步骤(3)得到的反应液与具有式Ⅵ所示结构的化合物和钯催化剂混合，进行Suzuki偶联反应，得到具有式Ⅶ所示结构的化合物。
  22. 利用权利要求1～21任意一项所述制备方法制备的关键中间体制备雷迪帕韦的方法，其特征在于，包括以下步骤：
    在碱性物质和缩合剂的作用下，将所述雷迪帕韦关键中间体与Moc-L-缬氨酸在极性溶剂中进行缩合反应，得到雷迪帕韦。
  23. 根据权利要求22所述的制备方法，其特征在于，所述缩合反应的温度为0～40℃；所述缩合反应的时间为2～3h。
  24. 用于制备雷迪帕韦的中间体化合物，具有式XV所示结构：
    Figure PCTCN2017093057-appb-100005
    式XV中，R为H、
    Figure PCTCN2017093057-appb-100006
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CN115010574A (zh) * 2022-06-06 2022-09-06 爱斯特（成都）生物制药股份有限公司 1-溴-2-氯-4-氟-2碘苯的合成方法
CN115010574B (zh) * 2022-06-06 2024-01-05 爱斯特（成都）生物制药股份有限公司 1-溴-2-氯-4-氟-2碘苯的合成方法

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