WO2022246929A1 - 一种abt-737关键中间体的制备方法以及abt-737的制备方法 - Google Patents

一种abt-737关键中间体的制备方法以及abt-737的制备方法 Download PDF

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WO2022246929A1
WO2022246929A1 PCT/CN2021/100636 CN2021100636W WO2022246929A1 WO 2022246929 A1 WO2022246929 A1 WO 2022246929A1 CN 2021100636 W CN2021100636 W CN 2021100636W WO 2022246929 A1 WO2022246929 A1 WO 2022246929A1
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顾艳飞
何瑶
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苏州正永生物医药有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the technical field of drug synthesis, in particular to a method for preparing a key intermediate of ABT-737 and a method for preparing ABT-737.
  • Benzamide compound ABT-737 (chemical name: 4-[4-[(4'-chloro[1,1'-biphenyl]-2-yl]methyl]-1-piperazinyl]-N- [[4-[[((R)-3-(Dimethylamino))-1-[(((phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]- Benzoyl; CASNo.852808-04-9) is a new type of effective BCL-2 family protein inhibitor, which has high affinity for BCL-XL, BCL-2 and BCL-w, and relatively homologous Low BCL-B, MCL-1 and A1 have no affinity, and BCL-2 family proteins are crucial to the survival and overexpression of cells in many tumor cells.
  • ABT-737 has anti-lymphoma in vitro and in vivo, Single-drug activity in small cell lung cancer and myeloma. Recent studies have shown that ABT-737 can effectively kill acute myeloid leukemia cells, progenitor cells and stem cells while retaining intact hematopoietic cells. ABT-737 can disrupt BCL- 2/BAX complex, and activate the intrinsic apoptotic pathway in a BAK-dependent, but not BIM-dependent manner.
  • the key intermediate of ABT-737 is usually prepared first, and then ABT-737 is obtained through condensation reaction.
  • the common method for preparing the key intermediate of ABT-737 is as follows: taking N-fluorenylmethoxycarbonyl-D-aspartic acid-4-tert-butyl ester as the starting material, reducing by sodium borohydride, thiophenol sulfuration, alkali Remove the FMOC protection under neutral conditions, then condense the deprotected product with 3-nitro-4-fluorobenzenesulfonamide, aminate after hydrolysis of lithium hydroxide, and finally reduce to obtain the key intermediate of ABT-737, the specific route is shown in Figure 1 shown.
  • N-fluorenylmethoxycarbonyl is used as the protecting group, and the intermediate with N-fluorenylmethoxycarbonyl protecting group has poor stability, is difficult to synthesize in large quantities, and the product yield is low.
  • the object of the present invention is to provide a preparation method of the key intermediate of ABT-737 and the preparation method of ABT-737.
  • the invention synthesizes the key intermediate of ABT-737 by using the starting material containing the tert-butoxycarbonyl protecting group, the reaction intermediate is stable, easy to be synthesized in large quantities, and the product yield is high.
  • a preparation method of ABT-737 key intermediate comprising the following steps:
  • vulcanizing agent comprises thiophenol metal salt and diphenyl disulfide one or more of them;
  • R is an alkyl group or a cycloalkyl group
  • the activator includes N-hydroxysuccinimide and/or isobutyl chloroformate; the molar ratio of the compound having the structure shown in formula I to the activator is 1:(1 ⁇ 1.2);
  • the temperature of the esterification reaction is -20-0° C., and the time is 20-25 hours.
  • the esterification reaction is carried out under the catalysis of a catalyst, and the catalyst is an organic amine; the molar ratio of the compound having the structure shown in formula I to the catalyst is 1:(1.05-1.5).
  • the first reducing agent is a boron reducing agent; the molar ratio of the active ester to the first reducing agent is 1:(1.5 ⁇ 2);
  • the reduction reaction is carried out in a mixed solvent, and the mixed solvent includes one or more of tetrahydrofuran-water mixed solvent, tetrahydrofuran-methanol mixed solvent and methanol-water mixed solvent;
  • the temperature of the reduction reaction is -5-20° C., and the time is 5-20 minutes.
  • the molar ratio of the compound having the structure shown in formula II to the vulcanizing agent is 1:(1.2 ⁇ 2);
  • the organic phosphine includes one or more of tributylphosphine, triphenylphosphine and tricarboxyethylphosphine; the molar ratio of the compound with the structure shown in formula II to the organic phosphine is 1:(1.2 ⁇ 2);
  • the temperature of the vulcanization reaction is 70-85° C., and the time is 15-20 hours.
  • the alkaline condition is provided by an inorganic base
  • the molar ratio of the compound having the structure shown in formula III to the inorganic base is 1:(2 ⁇ 4);
  • the temperature of the hydrolysis reaction is room temperature, and the time is 20-24 hours.
  • the amination reaction is carried out under the conditions of a condensing agent and a catalyst
  • the condensing agent includes dicyclohexylcarbodiimide and/or 1-ethyl-3 (3-dimethylpropylamine) carbodiimide Hydrochloride
  • the catalyst includes 4-dimethylaminopyridine and/or N,N-diisopropylethylamine
  • the molar ratio of the hydrolyzate, condensation agent and catalyst is 1:(1.8 ⁇ 2.5):(2 ⁇ 2.2);
  • the molar ratio of the hydrolyzate to dimethylamine is 1: (1.5-2.5);
  • the temperature of the amination reaction is room temperature, and the time is 20-30 hours.
  • the deprotection reagent is one or more of hydrochloric acid aqueous solution, hydrogen chloride methanol solution, hydrogen chloride ethyl acetate solution and trifluoroacetic acid;
  • the temperature of the deprotection reaction is room temperature, and the time is 2-5 hours.
  • the molar ratio of the deprotected product to 3-nitro-4-halobenzenesulfonamide is 1:(1.05 ⁇ 1.3);
  • the temperature of the condensation reaction is 20-30°C, and the time is 20-30h.
  • the second reducing agent is a boron reducing agent
  • the acidic condition is provided by an acidic reagent
  • the acidic reagent includes hydrochloric acid and/or trifluoroacetic acid
  • the carbonyl reduction reaction specifically includes: mixing a compound having a structure shown in formula V and a boron reducing agent for a complex reaction to obtain a boron complex; mixing the boron complex with an acidic reagent for a hydrolysis reaction to obtain A compound of the structure shown in formula VI.
  • step (4) is replaced by step (4'), and step (5) is replaced by (5'):
  • the present invention also provides a preparation method of ABT-737, comprising the following steps:
  • ABT-737 key intermediate is mixed with 4-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid Condensation reaction to obtain ABT-737, the structural formula is as shown in formula VII;
  • the ABT-737 key intermediate and 4-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid The molar ratio is 1:(1.05 ⁇ 1.1).
  • the condensation reaction is carried out under the action of a condensing agent and a catalyst
  • the condensing agent is dicyclohexylcarbodiimide and/or 1-ethyl-3 (3-dimethylpropylamine) carbodiimide salt salt
  • the catalyst is 4-dimethylaminopyridine and/or N,N-diisopropylethylamine.
  • the molar ratio of the ABT-737 key intermediate, condensing agent and catalyst is preferably 1:(2-2.5):(2-2.5), more preferably 1:2.1:2.1.
  • the temperature of the condensation reaction is room temperature, and the time is 40-60 hours.
  • the present invention provides a preparation method of ABT-737 key intermediate.
  • the present invention uses the compound having the structure shown in formula I as the starting material, first reducing the carboxyl group in the compound shown in formula I to hydroxyl, and then combining with The vulcanizing agent undergoes vulcanization reaction, and then through amination, deprotection, condensation and carbonyl reduction, the key intermediate of ABT-737 with the structure shown in formula VI is obtained.
  • the compound with the structure shown in formula I uses tert-butoxycarbonyl as the protecting group, and the subsequent obtained intermediate containing the tert-butoxycarbonyl protecting group is stable and easy to deprotect, easy to synthesize in large quantities, and the yield of the key intermediate of ABT-737 high.
  • Diphenyl disulfide is a vulcanizing reagent, all of which are low-toxic reagents and are stable at normal temperature and pressure. Compared with traditional methods, the present invention can avoid the use of toxic and harmful reagents, and the operation is simpler, greatly reducing production costs. Good prospects for industrialization.
  • the yield of the carboxylic acid reduction step is twice that of the FMOC protecting group, and the raw material 3-nitro-4 -
  • the halobenzenesulfonamide group is very polar, and column chromatography after the reaction is difficult, so it is selected to be used in the last step or the last two steps, which can greatly reduce the amount of solvent used in column chromatography and reduce the cost.
  • the preparation method of the present invention can also first reduce the carbonyl group in the amination product, and then perform deprotection and condensation reactions, the synthesis route is more flexible, easy to operate, and can further increase the product yield.
  • the preparation method provided by the invention has mild reaction conditions and low cost of reagents used.
  • the present invention also provides a method for preparing ABT-737.
  • the key intermediate of ABT-737 is prepared by the method described in the above scheme, and then ABT-737 is prepared by condensation reaction.
  • the structural formula is shown in formula VII. The results of the examples show that the purity of the product prepared by the method of the present invention is above 99.1%, and the yield is above 55%.
  • Figure 1 is a synthetic route diagram for the synthesis of key intermediates of ABT-737 in the prior art.
  • the present invention provides a kind of preparation method of ABT-737 key intermediate, comprises the following steps:
  • vulcanizing agent comprises thiophenol metal salt and diphenyl disulfide one or more of them;
  • R is an alkyl group or a cycloalkyl group, and the number of C atoms in the alkyl group is preferably no more than 8, more preferably 1 to 6, and specifically preferably methyl, ethyl or iso Butyl; the number of carbon atoms of the cycloalkyl group is preferably 5 to 8, and the cycloalkyl group is specifically preferably cyclopentylmethyl, cyclohexylmethyl;
  • the compound having the structure shown in formula I is subjected to an esterification reaction with an activator to obtain an active ester.
  • the activator preferably includes N-hydroxysuccinimide and/or isobutyl chloroformate, and the molar ratio of the compound with the structure shown in formula I and the activator is preferably 1:(1 ⁇ 1.2), more preferably 1:1.1;
  • the catalyst for the esterification reaction is preferably an organic amine, more preferably one of dicyclohexylcarbodiimide, triethylamine and N,N-diisopropylethylamine one or more;
  • the molar ratio of the compound having the structure shown in formula I to the catalyst is preferably 1:(1.05-1.5), more preferably 1:(1.1-1.2).
  • the solvent for the esterification reaction is preferably one or more of ethyl acetate, dichloromethane and tetrahydrofuran; the present invention has no special requirements on the amount of the solvent for the esterification reaction, and can make the esterification reaction The chemical reaction can proceed smoothly.
  • the present invention has no special requirements on the source of the compound with the structure shown in formula I, and it can be prepared by using commercially available products or methods well known to those skilled in the art.
  • the compound with formula I The compounds with the structures shown were purchased from Shanghai Bi De Pharmaceutical Reagent Co., Ltd.
  • the temperature of the esterification reaction is preferably -20-0°C, more preferably -5-0°C, and the time of the esterification reaction is preferably 20-25h, more preferably 22-24h.
  • Reducing the carboxyl group to an alcohol group requires a strong reducing agent. If it is directly reduced, it is easy to reduce the ester group at the other end of the compound of the structure shown in formula I.
  • the present invention makes the compound of the structure shown in formula I generate Active esters, followed by a reduction reaction, enable the reduction reaction to proceed rapidly while reducing the impact on the ester group.
  • the solvent used in the catalyst solution is preferably the same as the solvent used in the esterification reaction, and will not be repeated here.
  • the concentration of the catalyst solution is preferably 0.19 to 0.3 g/mL; the time of the esterification reaction starts to be counted since the catalyst solution is added dropwise.
  • the reaction can be considered complete;
  • the reagent used in the TLC detection is preferably a mixed reagent of dichloromethane, methanol and acetic acid, and the dichloromethane, methanol
  • the volume ratio with acetic acid is preferably 4:0.2:0.1.
  • the post-treatment method is preferably: filtering the resulting product material, washing and layering the filtrate and saturated sodium carbonate solution successively to obtain a water layer; extracting the water layer with an organic solvent, and The organic phase obtained is washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain the active ester; the organic solvent for extraction is preferably ethyl acetate.
  • the active ester is subjected to a reduction reaction with a first reducing agent to obtain a compound having the structure shown in formula II.
  • the first reducing agent is preferably a boron reducing agent
  • the boron reducing agent preferably includes one or more of sodium borohydride, potassium borohydride, borane and borane derivative solutions, and the boron reducing agent
  • the alkane derivative solution is preferably a borane tetrahydrofuran solution, and the concentration of the borane tetrahydrofuran solution is preferably 1mol/L; the present invention has no special requirements on the source of the borane tetrahydrofuran solution, and commercially available products can be used.
  • the molar ratio of the active ester to the first reducing agent is preferably 1:(1.5-2); when the first reducing agent is a borane derivative solution, the molar amount of the first reducing agent Measured in moles of solute in solution.
  • the reduction reaction is carried out in a mixed solvent
  • the mixed solvent preferably includes one or more of tetrahydrofuran-water mixed solvent, tetrahydrofuran-methanol mixed solvent and methanol-water mixed solvent, more preferably tetrahydrofuran -Water mixed solvent, the volume ratio of tetrahydrofuran and water in the tetrahydrofuran-water mixed solvent is preferably (5-8):1, more preferably (7-7.5):1.
  • the present invention has no special requirements on the amount of the mixed solvent, as long as the reduction reaction can proceed smoothly.
  • the temperature of the reduction reaction is preferably -5-20°C, more preferably 0-10°C, and the time of the reduction reaction is preferably 5-20 minutes, more preferably 5-10 minutes.
  • the first reducing agent is added to the solvent for the reduction reaction to obtain a first reducing agent solution, and the active ester is dissolved in an organic solvent to obtain an active ester solution , then the active ester solution is added dropwise to the first reducing agent solution, and the reaction is carried out at the reduction reaction temperature;
  • the organic solvent for dissolving the active ester is preferably tetrahydrofuran;
  • the time of the reduction reaction is from the active ester solution
  • the present invention preferably uses TLC to detect and confirm that the active ester reaction ends, and the reagent used in the TLC detection is preferably dichloromethane-methanol mixed reagent or dichloromethane-ethyl acetate mixed reagent; the dichloromethane -The volume ratio of dichloromethane and methanol in the methanol mixed reagent is preferably 20:1, and the volume ratio of dichloromethane and eth
  • the obtained product feed solution is preferably post-treated to obtain the compound having the structure shown in formula II.
  • the post-treatment preferably includes the following steps: adding saturated ammonium chloride aqueous solution to the reduction reaction solution, quenching the reaction, extracting the obtained product material liquid with ethyl acetate, and subjecting the obtained organic phase to saturated table salt successively.
  • the reagent used is preferably a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether and ethyl acetate in the mixed solvent is preferably 3:1.
  • the present invention performs a sulfurization reaction on the compound having the structure shown in formula II, a vulcanizing agent and an organic phosphine to obtain the compound having the structure shown in formula III.
  • the vulcanizing agent includes one or more of thiophenol metal salt and diphenyl disulfide, and the thiophenol metal salt preferably includes lithium thiophenate, potassium thiophenate and thiophenate
  • the thiophenol metal salt preferably includes lithium thiophenate, potassium thiophenate and thiophenate
  • One or more in sodium phenate, in specific embodiments of the present invention, described vulcanizing agent is most preferably diphenyl disulfide;
  • the mol ratio of described compound with structure shown in formula II and vulcanizing agent preferably 1 : (1.2 ⁇ 2);
  • Described organophosphine preferably comprises one or more in tributylphosphine, triphenylphosphine and tricarboxyethyl
  • the temperature of the vulcanization reaction is preferably 70-85°C, more preferably 78-82°C, and the time of the vulcanization reaction is preferably 15-20h, more preferably 18-20h.
  • the vulcanization reaction is preferably carried out under airtight conditions.
  • the present invention preferably adopts TLC detection to confirm that the vulcanization reaction is complete, and the reagent used in the TLC detection is preferably a dichloromethane-methanol mixed solvent, and the volume ratio of dichloromethane and methanol in the mixed solvent is preferably 20:1.
  • the obtained product feed solution is preferably post-treated to obtain a compound having a structure represented by formula III.
  • the post-treatment preferably includes the following steps: concentrating the obtained product feed liquid to remove the solvent, and subjecting the concentrated product to column chromatography to obtain a compound having a structure shown in formula III; the column chromatography reagent is preferably A mixed solvent of petroleum ether and ethyl acetate, the volume ratio of petroleum ether and ethyl acetate in the described mixed solvent is preferably 10:1.
  • the present invention performs hydrolysis reaction on the compound having the structure shown in formula III under basic conditions to obtain the hydrolyzed product.
  • the alkaline condition is provided by an inorganic base, and the inorganic base is preferably one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide and potassium carbonate.
  • the lithium hydroxide is preferably lithium hydroxide monohydrate; the molar ratio of the compound having the structure shown in formula III to the inorganic base is preferably 1:(2 ⁇ 4), more preferably 1:3;
  • the solvent for the hydrolysis reaction is preferably methanol; in the present invention, there is no special requirement on the amount of the solvent for the hydrolysis reaction, as long as the hydrolysis reaction can proceed smoothly.
  • the temperature of the hydrolysis reaction is preferably room temperature, and the time is preferably 20-24 hours, more preferably 22-23 hours.
  • the compound having the structure represented by formula III is dissolved in a solvent for the hydrolysis reaction, and then an inorganic base is added to the obtained solution to carry out the hydrolysis reaction.
  • the obtained product feed liquid is preferably post-treated to obtain a hydrolyzed product.
  • the post-treatment preferably includes the following steps: mixing the resulting product feed liquid with a weakly acidic solution, and extracting the resulting mixed solution with ethyl acetate to obtain an organic phase; sequentially subjecting the organic phase to saturated saline Washing, drying with anhydrous sodium sulfate and spinning to obtain the hydrolyzate.
  • the weakly acidic solution is preferably 0.1mol/L dilute hydrochloric acid aqueous solution, saturated sodium dihydrogen phosphate aqueous solution, 0.5mol/L acetic acid aqueous solution or saturated potassium dihydrogen phosphate aqueous solution;
  • the remaining alkali in the hydrolysis reaction is neutralized, and the loss of the protective group in the hydrolyzed product is avoided by controlling the acidity of the solution; in the present invention, the number of extractions is preferably 3 times, and the organic phases obtained from the three extractions are combined.
  • the present invention performs an amination reaction on the hydrolyzate and dimethylamine to obtain a compound having the structure shown in formula IV.
  • the amination reaction is preferably carried out under the conditions of a condensing agent and a catalyst, and the condensing agent preferably includes dicyclohexylcarbodiimide and/or 1-ethyl-3 (3-dimethylpropylamine) Carbodiimide hydrochloride;
  • the catalyst preferably includes 4-dimethylaminopyridine and/or N,N-diisopropylethylamine;
  • the molar ratio of the hydrolyzate, condensation agent and catalyst is preferably 1:( 1.8 ⁇ 2.5):(2 ⁇ 2.2), more preferably 1:2:2.
  • the molar ratio of the hydrolyzate and dimethylamine is preferably 1:(1.5 ⁇ 2.5);
  • the solvent for the amination reaction is preferably dichloromethane; the present invention uses a solvent for the amination reaction
  • the temperature of the amination reaction is preferably room temperature, and the time is preferably 20-30 hours, more preferably 24-25 hours.
  • the solvent of the dimethylamine solution is preferably tetrahydrofuran
  • the present invention preferably adopts TLC monitoring to raw material reaction completely, and described TLC monitoring reagent is preferably the mixed solvent of dichloromethane, methyl alcohol and acetic acid, and the volume ratio of dichloromethane, methyl alcohol and acetic acid in the described mixed solvent is preferably 4: 0.2:0.1.
  • the obtained product feed solution is preferably post-treated to obtain the compound having the structure shown in formula IV.
  • the post-treatment preferably includes the following steps: washing the obtained product feed liquid with hydrochloric acid aqueous solution and saturated brine successively, drying the washed feed liquid with anhydrous sodium sulfate, and then successively filtering, concentrating and column layering analysis, to obtain the compound with the structure shown in formula IV;
  • the concentration of the aqueous hydrochloric acid solution is preferably 1mol/L;
  • the reagent for the column chromatography is preferably a mixed solvent of sherwood oil and ethyl acetate, and in the mixed solvent, sherwood oil and The volume ratio of ethyl acetate is preferably 2:1.
  • the present invention performs a deprotection reaction on the compound with the structure shown in formula IV and a deprotection reagent to obtain a deprotected product.
  • the deprotection reagent is preferably one or more of hydrochloric acid aqueous solution, hydrogen chloride methanol solution, hydrogen chloride ethyl acetate solution and trifluoroacetic acid; the concentration of the hydrochloric acid aqueous solution is preferably 4 to 10mol/L, More preferably 4-5 mol/L; the concentration of the hydrogen chloride methanol solution is preferably 2 mol/L; the concentration of the hydrogen chloride ethyl acetate solution is preferably 2 mol/L.
  • the molar ratio of the compound having the structure shown in formula IV to the deprotecting reagent is preferably 1:(30-35), and the molar amount of the deprotecting reagent is calculated by the molar amount of the solute.
  • the solvent for the deprotection reaction is preferably one or more of dioxane, tetrahydrofuran and N,N-dimethylformamide; Requirements, the deprotection reaction can be carried out smoothly.
  • the temperature of the deprotection reaction is preferably room temperature, and the time is preferably 2-5 hours, more preferably 2-3 hours.
  • the obtained product feed liquid is preferably post-treated to obtain the deprotected product.
  • the post-treatment preferably includes the following steps: mixing the obtained product feed liquid with a saturated aqueous solution of sodium carbonate, extracting the obtained mixed solution with ethyl acetate, washing the obtained organic phase with saturated brine, anhydrous Drying over sodium sulfate, filtering and spin-drying to obtain the crude product of the deprotected product, which is directly used in the next step without further purification; Accurate;
  • the extraction is preferably carried out multiple times, and the specific number of extractions is determined by TLC until there is no product in the aqueous phase, and the organic phases obtained from multiple extractions are combined.
  • the deprotected product is condensed with 3-nitro-4-halogenated benzenesulfonamide to obtain the compound having the structure shown in formula V.
  • the 3-nitro-4-halobenzenesulfonamide is preferably 3-nitro-4-fluorobenzenesulfonamide; the deprotection product and 3-nitro-4-halobenzenesulfonamide
  • the molar ratio of amides is preferably 1:(1.05-1.3), more preferably 1:1.2.
  • the solvent for the condensation reaction is preferably one or more of dichloromethane, N,N-dimethylformamide and toluene, more preferably N,N-dimethylformamide;
  • the invention has no special requirements on the amount of solvent used for the condensation reaction, as long as the condensation reaction can proceed smoothly.
  • the condensation reaction is preferably carried out under the action of a basic reagent, and the basic reagent is preferably N,N-diisopropylethylamine and/or triethylamine; the deprotected product and basic
  • the molar ratio of the reagents is preferably 1:(2.2-2.5), more preferably 1:(2.3-2.4).
  • the present invention it is preferred to dissolve the crude product of the deprotected product obtained in the above scheme in a solvent for condensation reaction, and then add an alkaline reagent and 3-nitro-4-halogenated benzenesulfonamide for condensation reaction; the present invention
  • the completion of the reaction is preferably monitored by TLC, and the reagent for TLC monitoring is preferably ethyl acetate.
  • the obtained product feed liquid is preferably post-treated to obtain a compound having a structure represented by formula V.
  • the post-treatment preferably includes the following steps: mixing the obtained product feed liquid with water and then filtering to obtain a filter cake; washing the filter cake with water and spinning to obtain a dry solid; crushing the dry solid Afterwards, ethyl acetate was added to make a slurry, and the obtained slurry was filtered to collect the solid to obtain a compound having a structure represented by formula V.
  • the temperature of the beating is preferably room temperature, and the time is preferably 2 hours.
  • the present invention will carry out the carbonyl reduction reaction between the compound with the structure shown in formula V and the second reducing agent under acidic conditions to obtain the key intermediate of ABT-737, the structural formula is shown in formula VI .
  • the second reducing agent is preferably a boron reducing agent
  • the boron reducing agent is preferably sodium borohydride, potassium borohydride, boron trifluoride, boron trifluoride-sodium borohydride complex, borohydride
  • the concentration of the borane tetrahydrofuran solution is preferably 1mol/L
  • the borane is preferably a commercially available product or self-prepared, When preparing by yourself, it is preferably prepared by the following method: mix sodium borohydride and anhydrous tetrahydrofuran, add boron trifluoride tetrahydrofuran solution dropwise under the protection of nitrogen, and react for 30 minutes after the dropwise addition to obtain borane feed liquid, and the obtained borane
  • the feed liquid does not need any treatment and can be used directly.
  • the borane tetrahydrofuran solution is preferably a commercially available product.
  • the molar ratio of the compound having the structure represented by formula V to the second reducing agent is preferably 1:(1.5-2), more preferably 1:(1.7-1.8).
  • the acidic condition is provided by an acidic reagent
  • the acidic reagent preferably includes hydrochloric acid and/or trifluoroacetic acid
  • the acid concentration of the acidic reagent is preferably 4-10 mol/L, more preferably 6-10 mol/L
  • the amount of the acidic reagent and the compound having the structure represented by formula V are preferably (2-3):1.
  • the carbonyl reduction reaction specifically includes: mixing the compound having the structure shown in formula V and a boron reducing agent to perform a complex reaction to obtain a boron complex; mixing the boron complex with an acidic reagent to carry out A hydrolysis reaction to obtain a compound having a structure shown in formula VI;
  • the temperature of the complexation reaction is preferably room temperature, and the time is preferably 20 to 24 hours;
  • the temperature of the hydrolysis reaction is preferably 70 to 90°C, more preferably 80°C, The time is preferably 3 to 5 hours, more preferably 4 hours.
  • methanol is preferably added to quench the complexation reaction, and then hydrochloric acid is added for hydrolysis; during the complexation reaction, the compound having the structure shown in formula V and
  • the boron reducing agent carries out coordinate bonding to obtain a boronyl radical intermediate, and then under acidic conditions, hydrogen ions are obtained, and the boronyl group is removed to obtain an amine compound, thereby realizing the reduction of the amide carbonyl group.
  • the present invention preferably performs post-treatment on the obtained product feed liquid to obtain the key intermediate of ABT-737 (referred to as intermediate A).
  • the post-treatment preferably includes the following steps: after cooling the obtained product feed liquid to room temperature, adding saturated sodium carbonate solution to adjust the pH value of the obtained product feed liquid to 9-10, and then extracting with ethyl acetate, The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, spin-dried and column chromatography to obtain the key intermediate of ABT-737; in the present invention, the number of extractions is preferably 2 times, and the The organic phases obtained from the two extractions are combined; the column chromatography reagent is preferably a mixed solvent of dichloromethane and methanol, and the volume ratio of dichloromethane and methanol in the mixed solvent is preferably 20:1.
  • the present invention also provides another route for synthesizing the key intermediate of ABT-737.
  • Steps (1) to (3) are the same as the above-mentioned scheme. Only after obtaining the compound with the structure shown in formula IV, the carbonyl reduction reaction is carried out first. Carry out deprotection reaction and condensation reaction again, specifically for replacing above-mentioned step (4) with step (4'), step (5) is replaced with (5'):
  • the compound having the structure shown in formula IV is subjected to a carbonyl reduction reaction with a second reducing agent under acidic conditions to obtain the compound having the structure shown in formula V'.
  • the acidic condition is provided by an acidic reagent, the type of the second reducing reagent and the acidic reagent are consistent with the above-mentioned scheme, and will not be repeated here; the conditions and operation method of the carbonyl reduction reaction are consistent with the above-mentioned scheme , not repeat them here;
  • the molar ratio of the compound having the structure shown in formula IV to the second reducing agent is preferably 1:(1.5 ⁇ 2);
  • the molar ratio of the acidic reagent to the compound having the structure shown in formula IV is preferably For (2 ⁇ 3):1.
  • the present invention preferably carries out post-treatment to the resulting product feed liquid to obtain a compound having a structure shown in formula V'; the post-treatment method and the post-treatment method of the carbonyl reduction reaction in the above-mentioned scheme step (5) Consistent, no more details here.
  • the present invention performs deprotection reaction on the compound having the structure shown in formula V' and a deprotection reagent, and reacts the obtained deprotected product with 3-nitro-4-halogenated benzenesulfonate
  • the amide is subjected to condensation reaction to obtain the key intermediate of ABT-737.
  • the type of the deprotection reagent is consistent with the above-mentioned scheme, and will not be repeated here; the conditions and specific operation methods of the deprotection reaction are consistent with the above-mentioned scheme, and will not be repeated here;
  • the molar ratio of the compound with the structure shown in ' to the deprotection reagent is preferably 1:(30-35), and the molar amount of the deprotective reagent is based on the molar amount of the solute.
  • the present invention preferably carries out post-treatment to the resulting product material liquid to obtain the deprotected product; the post-treatment method is preferably consistent with the post-treatment method after the deprotection reaction is completed in the above-mentioned scheme step (4). This will not be repeated here.
  • the specific type of the 3-nitro-4-halogenated benzenesulfonamide is preferably consistent with the above-mentioned scheme, and will not be repeated here; the conditions and specific operation methods of the condensation reaction are consistent with the above-mentioned scheme. This will not go into details; the post-processing method after the condensation reaction is completed is consistent with the post-processing method after the condensation reaction in the above-mentioned scheme step (4), and will not be repeated here.
  • the present invention also provides a preparation method of ABT-737, comprising the following steps:
  • ABT-737 key intermediate is mixed with 4-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid Condensation reaction to obtain ABT-737, the structural formula is as shown in formula VII;
  • the condensation reaction is preferably carried out under the action of a condensing agent and a catalyst
  • the condensing agent is preferably dicyclohexylcarbodiimide and/or 1-ethyl-3 (3-dimethylpropylamine) carbon Diimine hydrochloride
  • the catalyst is preferably 4-dimethylaminopyridine and/or N,N-diisopropylethylamine
  • the ABT-737 key intermediate (the compound with the structure shown in formula VI)
  • the molar ratio of the condensing agent and the catalyst is preferably 1:(2-2.5):(2-2.5), more preferably 1:2.1:2.1.
  • the molar ratio of benzoic acid is preferably 1:(1.05-1.1).
  • the solvent for the condensation reaction is preferably dichloromethane, 1,2 dichloroethane, N,N dimethylformamide, more preferably dichloromethane; the solvent for the condensation reaction is mixed with ABT-
  • the weight ratio of the 737 key intermediate is preferably (100-600):1, more preferably (300-500):1.
  • the temperature of the condensation reaction is preferably room temperature, and the time is preferably 40-60 hours, more preferably 48-50 hours.
  • the present invention preferably performs post-treatment on the obtained product feed liquid to obtain ABT-737.
  • the post-treatment preferably includes the following steps: mixing the obtained product feed liquid and saturated ammonium chloride solution and then layering, sequentially washing the obtained organic layer with saturated saline, drying over anhydrous sodium sulfate, filtering, Drying and column chromatography to obtain a crude product; the crude product was dissolved in dichloromethane, and the resulting solution was added dropwise to methyl tert-butyl ether to precipitate a solid product. The precipitated system was stirred for 30 minutes and then filtered, and the obtained solid product was dried , to get ABT-737.
  • reaction solution is poured in 2L saturated sodium dihydrogen phosphate aqueous solution, then Extract three times with 500 mL of ethyl acetate, combine the organic phases, wash the organic phase with 500 mL of saturated brine, dry over anhydrous sodium sulfate, and spin dry to obtain a hydrolyzate.
  • reaction solution was poured into 500L saturated aqueous sodium dihydrogen phosphate solution, extracted three times with 300mL ethyl acetate, the organic phase was combined, and the organic phase was washed with 300mL saturated saline Washed, dried over anhydrous sodium sulfate, and spin-dried to obtain a hydrolyzate.

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Abstract

涉及药物合成技术领域，提供了一种ABT-737关键中间体的制备方法以及ABT-737的制备方法。以具有式I所示结构的化合物为起始原料，首先将式I所示结构的化合物中的羧基还原为羟基，之后与硫化剂进行硫化反应，再通过胺化、脱保护、缩合和羰基还原，得到具有式VI所示结构的ABT-737关键中间体。具有式I所示结构的化合物以叔丁氧羰基为保护基，后续得到的含有叔丁氧羰基保护基的中间体稳定且易于脱保护，易于大批量合成，产物收率高，生产成本低，具有良好的工业化前景。

Description

一种ABT-737关键中间体的制备方法以及ABT-737的制备方法
本申请要求于2021年5月26日提交中国专利局、申请号为202110575439.7、发明名称为“一种ABT-737关键中间体的制备方法以及ABT-737的制备方法”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
本发明涉及药物合成技术领域，尤其涉及一种ABT-737关键中间体的制备方法以及ABT-737的制备方法。
背景技术
苯甲酰胺化合物ABT-737(化学名称为：4-[4-[(4'-氯[1,1'-联苯]-2-基]甲基]-1-哌嗪基]-N-[[4-[[((R)-3-(二甲基氨基))-1-[((苯硫基)甲基]丙基]氨基]-3-硝基苯基]磺酰基]-苯甲酰；CASNo.852808-04-9)是一种新型有效的BCL-2家族蛋白抑制剂，对BCL-XL、BCL-2和BCL-w有高亲和性，而对同源性较低的BCL-B、MCL-1及A1没有亲和性，BCL-2家族蛋白对许多肿瘤细胞中细胞的存活和过表达是至关重要的。ABT-737具有在体外和体内对抗淋巴瘤、小细胞肺癌和骨髓瘤的单药活性。最近的研究表明，ABT-737可以有效的杀死急性髓性白血病细胞、祖细胞和干细胞，而保留了完整的造血细胞。ABT-737可以扰乱BCL-2/BAX复合体，并以BAK依赖，而非BIM依赖的方式激活内在的凋亡途径。
目前，现有技术中通常先制备ABT-737的关键中间体，然后通过缩合反应得到ABT-737。制备ABT-737的关键中间体的常用方法如下：以N-芴甲氧羰基-D-天冬氨酸-4-叔丁酯为起始原料，通过硼氢化钠还原、苯硫酚硫化、碱性条件下脱去FMOC保护，然后将脱保护产物与3-硝基-4-氟苯磺酰胺缩合，氢氧化锂水解后胺化，最后还原得到ABT-737关键中间体，具体路线如图1所示。
上述方案中以N-芴甲氧羰基为保护基，带有N-芴甲氧羰基保护基的中间体稳定性差，难以大批量合成，产物收率低。
发明内容
有鉴于此，本发明的目的在于提供一种ABT-737关键中间体的制备方法以及ABT-737的制备方法。本发明以含有叔丁氧羰基保护基的起始原料合成ABT-737关键中间体，反应中间体稳定，易于大批量合成，产物收率高。
为了实现上述发明目的，本发明提供以下技术方案：
一种ABT-737关键中间体的制备方法，包括以下步骤：
(1)将具有式I所示结构的化合物与活化剂进行酯化反应，得到活 性酯；将所述活性酯与第一还原剂进行还原反应，得到具有式II所示结构的化合物；
Figure PCTCN2021100636-appb-000001
(2)将所述具有式II所示结构的化合物、硫化剂和有机膦进行硫化反应，得到具有式III所示结构的化合物；所述硫化剂包括苯硫酚金属盐和二苯二硫醚中的一种或几种；
Figure PCTCN2021100636-appb-000002
式I～式III中，R为链烷基或环烷基；
(3)将所述具有式III所示结构的化合物在碱性条件下进行水解反应，将水解产物和二甲胺进行胺化反应，得到具有式IV所示结构的化合物；
Figure PCTCN2021100636-appb-000003
(4)将所述具有式IV所示结构的化合物与脱保护试剂进行脱保护反应，将所得脱保护产物与3-硝基-4-卤代苯磺酰胺进行缩合反应，得到具有式V所示结构的化合物；
Figure PCTCN2021100636-appb-000004
(5)将具有式V所示结构的化合物和第二还原试剂在酸性条件下进行羰基还原反应，得到ABT-737关键中间体，结构式如式VI所示；
Figure PCTCN2021100636-appb-000005
优选的，所述活化剂包括N-羟基琥珀酰亚胺和/或氯甲酸异丁酯；所述具有式I所示结构的化合物和活化剂的摩尔比为1:(1～1.2)；
所述酯化反应的温度为-20～0℃，时间为20～25h。
优选的，所述酯化反应在催化剂的催化下进行，所述催化剂为有机胺；所述具有式I所示结构的化合物和催化剂的摩尔比为1:(1.05～1.5)。
优选的，所述步骤(1)中，第一还原试剂为硼还原剂；所述活性酯和第一还原试剂的摩尔比为1:(1.5～2)；
所述还原反应在混合溶剂中进行，所述混合溶剂包括四氢呋喃-水混合溶剂、四氢呋喃-甲醇混合溶剂和甲醇-水混合溶剂中的一种或几种；
所述还原反应的温度为-5～20℃，时间为5～20min。
优选的，所述具有式II所示结构的化合物与硫化剂的摩尔比为1:(1.2～2)；
所述有机膦包括三丁基膦、三苯基膦和三羧基乙基膦中的一种或几种；所述具有式II所示结构的化合物与有机膦的摩尔比为1:(1.2～2)；
所述硫化反应的温度为70～85℃，时间为15～20h。
优选的，所述步骤(3)中，所述碱性条件由无机碱提供；
所述具有式III所示结构的化合物和无机碱的摩尔比为1:(2～4)；
所述水解反应的温度为室温，时间为20～24h。
优选的，所述胺化反应在缩合剂和催化剂条件下进行，所述缩合剂包括二环己基碳二亚胺和/或1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐；所述催化剂包括4-二甲氨基吡啶和/或N,N-二异丙基乙胺；
所述水解产物、缩合剂和催化剂的摩尔比为1:(1.8～2.5):(2～2.2)；
所述水解产物和二甲胺的摩尔比为1：(1.5～2.5)；
所述胺化反应的温度为室温，时间为20～30h。
优选的，所述脱保护试剂为盐酸水溶液、氯化氢甲醇溶液、氯化氢乙酸乙酯溶液和三氟乙酸中的一种或几种；
所述脱保护反应的温度为室温，时间为2～5h。
优选的，所述脱保护产物和3-硝基-4-卤代苯磺酰胺的摩尔比为1:(1.05～1.3)；
所述缩合反应的温度为20～30℃，时间为20～30h。
优选的，所述步骤(5)中，第二还原试剂为硼还原剂；所述酸性条件由酸性试剂提供，所述酸性试剂包括盐酸和/或三氟乙酸；
所述羰基还原反应具体为：将具有式V所示结构的化合物和硼还原剂混合进行络合反应，得到硼络合物；将所述硼络合物和酸性试剂混合进行水解反应，得到具有式VI所示结构的化合物。
优选的，所述步骤(4)替换为步骤(4’)，步骤(5)替换为(5’)：
(4’)在第二还原试剂和酸性试剂的作用下，将所述具有式IV所示结构的化合物进行羰基还原反应，得到具有式V’所示结构的化合物；
Figure PCTCN2021100636-appb-000006
(5’)在脱保护试剂作用下，将具有式V’所示结构的化合物进行脱保护反应，将所得脱保护产物与3-硝基-4-卤代苯磺酰胺进行缩合反应，得到ABT-737关键中间体。
本发明还提供了一种ABT-737的制备方法，包括以下步骤：
按照上述方案所述的制备方法制备得到ABT-737关键中间体；
将所述ABT-737关键中间体与4-(4-((4’-氯-[1,1’-联苯]-2-基)甲基)哌嗪-1-基)苯甲酸混合进行缩合反应，得到ABT-737，结构式如式VII所示；
Figure PCTCN2021100636-appb-000007
优选的，所述ABT-737关键中间体与4-(4-((4’-氯-[1,1’-联苯]-2-基)甲基)哌嗪-1-基)苯甲酸的摩尔比为1:(1.05～1.1)。
优选的，所述缩合反应在缩合剂和催化剂作用下进行，所述缩合剂为二环己基碳二亚胺和/或1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐；所述催化剂为4-二甲氨基吡啶和/或N,N-二异丙基乙胺。
优选的，所述ABT-737关键中间体、缩合剂和催化剂的摩尔比优选为1:(2～2.5):(2～2.5)，更优选为1:2.1:2.1。
优选的，所述缩合反应的温度为室温，时间为40～60h。
本发明提供了一种ABT-737关键中间体的制备方法，本发明以具有式I所示结构的化合物为起始原料，首先将式I所示结构的化合物中的羧基还原为羟基，之后与硫化剂进行硫化反应，再通过胺化、脱保护、缩合和羰基还原，得到具有式VI所示结构的ABT-737关键中间体。具有式I所示结构的化合物以叔丁氧羰基为保护基，后续得到的含有叔丁氧羰基保护基的中间体稳定且易于脱保护，易于大批量合成，ABT-737关键中间体的收率高。
进一步的，传统方法制备ABT-737关键中间体时，在硫化反应中需要使用甲磺酰氯、苯硫酚等高毒试剂，操作难度大，而本发明在硫化过程中可以采用苯硫酚金属盐、二苯二硫醚为硫化试剂，均为低毒试剂，在常温常压下稳定，和传统方法相比，本发明能够避免有毒有害试剂的使用，操作更加简单，大大降低了生产成本，具有良好的工业化前景。
此外，传统方法中是在得到硫化产物后先进行脱保护，然后与3-硝基-4-卤代苯磺酰胺进行缩合，因为FMOC保护基在碱性条件下很容易脱去，所以需要优先生成稳定的产物，再进行胺化和羰基还原，而本发明所述方案中，选取了带BOC保护基的起始原料，BOC保护基在碱性条件下不敏感，先将原料进行还原和硫化，将硫化产物进行胺化，再进行脱保护、缩合和羰基还原，本发明通过合成路线的调整，在羧酸还原一步收率比 FMOC保护基提高了两倍，且原料3-硝基-4-卤代苯磺酰胺基团极性大，反应后柱层析较困难，所以选择在最后一步或最后二步用到，能够大大减少柱层析溶剂的使用量，降低成本。
进一步的，本发明所述的制备方法还可以先将胺化产物中的羰基还原，然后再进行脱保护和缩合反应，合成路线更加灵活，容易操作，还能够进一步提高产物收率。
进一步的，本发明提供的制备方法反应条件温和，使用的试剂成本低。
实施例结果表明，采用本发明的制备方法制备ABT-737关键中间体，由具有式I所示结构的化合物制备具有式II所示结构的化合物时，收率为61％以上，由具有式II所示结构的化合物制备具有式III所示结构的化合物时，收率为85％以上，由具有式III所示结构的化合物制备具有式IV所示结构的化合物和由具有式IV所示结构的化合物制备具有式V所示结构的化合物时，收率均为90％左右，由具有式V所示结构的化合物制备ABT-737关键中间体时，收率为68％以上；采用先还原羰基再进行脱保护和缩合的合成路线时，由具有式IV所示结构的化合物制备具有式V’所示结构的化合物时，收率为76％以上，由具有式V’所示结构的化合物制备ABT-737关键中间体时，收率为85％以上。
本发明还提供了一种ABT-737的制备方法，采用上述方案所述的方法制备得到ABT-737关键中间体，再通过缩合反应制备得到ABT-737，结构式如式VII所示。实施例结果表明，采用本发明的方法制备得到的产物纯度为99.1％以上，收率为55％以上。
说明书附图
图1为本领域现有技术中合成ABT-737关键中间体的合成路线图。
具体实施方式
本发明提供了一种ABT-737关键中间体的制备方法，包括以下步骤：
(1)将具有式I所示结构的化合物与活化剂进行酯化反应，得到活性酯；将所述活性酯与第一还原试剂进行还原反应，得到具有式II所示结构的化合物；
Figure PCTCN2021100636-appb-000008
(2)将所述具有式II所示结构的化合物、硫化剂和有机膦进行硫化反应，得到具有式III所示结构的化合物；所述硫化剂包括苯硫酚金属盐和二苯二硫醚中的一种或几种；
Figure PCTCN2021100636-appb-000009
式I～式III中，R为链烷基或环烷基，所述链烷基的C原子数优选不超过8个，更优选为1～6个，具体优选为甲基、乙基或异丁基；所述环烷基的碳原子数优选为5～8，所述环烷基具体优选为环戊基甲基、环己基甲基；
(3)将所述具有式III所示结构的化合物在碱性条件下进行水解反应，将水解产物和二甲胺进行胺化反应，得到具有式IV所示结构的化合物；
Figure PCTCN2021100636-appb-000010
(4)将所述具有式IV所示结构的化合物与脱保护试剂进行脱保护反应，将所得脱保护产物与3-硝基-4-卤代苯磺酰胺进行缩合反应，得到具有式V所示结构的化合物；
Figure PCTCN2021100636-appb-000011
(5)将具有式V所示结构的化合物和第二还原试剂在酸性条件下进行羰基还原反应，得到具有时VI所示结构的ABT-737关键中间体；
Figure PCTCN2021100636-appb-000012
本发明将具有式I所示结构的化合物与活化剂进行酯化反应，得到活性酯。在本发明中，所述活化剂优选包括N-羟基琥珀酰亚胺和/或氯甲酸异丁酯，所述具有式I所示结构的化合物和活化剂的摩尔比优选为1:(1～1.2)，更优选为1:1.1；所述酯化反应用催化剂优选为有机胺，更优选为二环己基碳二亚胺、三乙胺和N,N-二异丙基乙胺中的一种或几种；所述具有式I所示结构的化合物和催化剂的摩尔比优选为1:(1.05～1.5)，更优选为1:(1.1～1.2)。在本发明中，所述酯化反应用溶剂优选为乙酸乙酯、二氯甲烷和四氢呋喃中的一种或几种；本发明对所述酯化反应用溶剂的用量没有特殊要求，能够使酯化反应顺利进行即可。本发明对所述具有式I所示结构的化合物的来源没有特殊要求，采用市售产品或使用本领域技术人员熟知的方法制备均可，在本发明的具体实施例中，所述具有式I所示结构的化合物购买自上海毕得医药试剂公司。
在本发明中，所述酯化反应的温度优选为-20～0℃，更优选为-5～0℃，所述酯化反应的时间优选为20～25h，更优选为22～24h。
在本发明中，当所述活化剂为N-羟基琥珀酰亚胺时，所示活性酯的结构式如式i所示，当所述活化剂为氯甲酸异丁酯时，所述活性酯的结构式如式ii所示：
Figure PCTCN2021100636-appb-000013
将羧基还原为醇基需要强还原剂，若直接进行还原，容易使式I所示结构的化合物中另一端的酯基也被还原，本发明通过酯化反应使式I所示结构的化合物生成活性酯，然后再进行还原反应，能够使还原反应迅速进行，同时减小对酯基的影响。
在本发明的具体实施例中，优选先将具有式I所示结构的化合物溶解 于溶剂中，然后使用氮气置换，并将体系温度降至0℃以下，然后加入活性剂，之后将催化剂溶液滴加到反应体系中，在酯化反应温度下保温进行反应；所述催化剂溶液使用的溶剂优选为酯化反应使用的溶剂一致，在此不再赘述，所述催化剂溶液的浓度优选为0.19～0.3g/mL；所述酯化反应的时间自催化剂溶液滴加完毕开始计。在本发明的具体实施例中，优选通过TLC检测确认原料消失，即可认为反应完毕；所述TLC检测使用的试剂优选为二氯甲烷、甲醇和醋酸的混合试剂，所述二氯甲烷、甲醇和醋酸的体积比优选为4:0.2:0.1。
酯化反应完成后，本发明优选将所得产物料液进行后处理，得到活性酯。在本发明中，所述后处理的方法优选为：将所得产物料过滤，滤液和饱和碳酸钠溶液混合后依次进行洗涤和分层，得到水层；将所述水层用有机溶剂萃取，将所得有机相依次进行饱和食盐水洗涤、无水硫酸钠干燥、过滤和旋干，得到活性酯；所述萃取用有机溶剂优选为乙酸乙酯。
得到活性酯后，本发明将所述活性酯与第一还原试剂进行还原反应，得到具有式II所示结构的化合物。在本发明中，所述第一还原试剂优选为硼还原剂，所述硼还原剂优选包括硼氢化钠、硼氢化钾、硼烷和硼烷衍生溶液中的一种或几种，所述硼烷衍生溶液优选为硼烷四氢呋喃溶液，所述硼烷四氢呋喃溶液的浓度优选为1mol/L；本发明对所述硼烷四氢呋喃溶液的来源没有特殊要求，采用市售产品即可。在本发明中，所述活性酯和第一还原试剂的摩尔比优选为1:(1.5～2)；当所述第一还原试剂为硼烷衍生溶液时，所述第一还原剂的摩尔量以溶液中溶质的摩尔量计。
在本发明中，所述还原反应在混合溶剂中进行，所述混合溶剂优选包括四氢呋喃-水混合溶剂、四氢呋喃-甲醇混合溶剂和甲醇-水混合溶剂中的一种或几种，更优选为四氢呋喃-水混合溶剂，所述四氢呋喃-水混合溶剂中四氢呋喃和水的体积比优选为(5～8):1，更优选为(7～7.5):1。本发明对所述混合溶剂的用量没有特殊要求，能够使还原反应顺利进行即可。
在本发明中，所述还原反应的温度优选为-5～20℃，更优选为0～10℃，所述还原反应的时间优选为5～20min，更优选为5～10min。
在本发明的具体实施例中，优选在冰浴条件下，将第一还原试剂加入还原反应用溶剂中，得到第一还原剂溶液，将所述活性酯溶解于有机溶剂中，得到活性酯溶液，然后将所述活性酯溶液滴加到所述第一还原剂溶液中，在还原反应温度下进行反应；所述溶解活性酯用有机溶剂优选为四氢呋喃；所述还原反应的时间自活性酯溶液滴加完毕开始计；本发明优选使用TLC检测确认活性酯反应结束，所述TLC检测使用的试剂优选为二氯甲烷-甲醇混合试剂或二氯甲烷-乙酸乙酯混合试剂；所述二氯甲烷-甲醇混合试剂中二氯甲烷和甲醇的体积比优选为20:1，所述二氯甲烷-乙酸乙酯 混合试剂中二氯甲烷和乙酸乙酯的体积比优选为3:2。
还原反应完成后，本发明优选将所得产物料液进行后处理，得到具有式II所示结构的化合物。在本发明中，所述后处理优选包括以下步骤：将饱和氯化铵水溶液加入还原反应液中，将反应淬灭，将所得产物料液用乙酸乙酯萃取，将所得有机相依次进行饱和食盐水洗涤、无水硫酸钠干燥、旋干和柱层析，得到具有式II所示结构的化合物；所述萃取的次数优选为2次，将两次萃取所得有机相合并；所述柱层析用试剂优选为石油醚和乙酸乙酯的混合溶剂，所述混合溶剂中石油醚和乙酸乙酯的体积比优选为3:1。
得到具有式II所示结构的化合物后，本发明将所述具有式II所示结构的化合物、硫化剂和有机膦进行硫化反应，得到具有式III所示结构的化合物。在本发明中，所述硫化剂包括苯硫酚金属盐和二苯二硫醚中的一种或几种，所述苯硫酚金属盐优选包括苯硫酚锂、苯硫酚钾和苯硫酚钠中的一种或几种，在本发明的具体实施例中，所述硫化剂最优选为二苯二硫醚；所述具有式II所示结构的化合物与硫化剂的摩尔比优选1:(1.2～2)；所述有机膦优选包括三丁基膦、三苯基膦和三羧基乙基膦中的一种或几种；所述具有式II所示结构的化合物与有机膦的摩尔比优选为1:(1.2～2)，更优选为1:1.5；所述硫化反应用溶剂优选为甲苯、乙腈、二氧六环和N,N-二甲基甲酰胺中的一种或几种，更优选为甲苯。
在本发明中，所述硫化反应的温度优选为70～85℃，更优选为78～82℃，所述硫化反应的时间优选为15～20h，更优选为18～20h。
在本发明的具体实施例中，优选将具有式II所示结构的化合物溶解于硫化反应用溶剂中，然后依次加入二苯二硫醚和有机膦，氮气置换后在油浴条件下保温进行硫化反应；所述硫化反应优选在密闭条件下进行。本发明优选采用TLC检测确认硫化反应完全，所述TLC检测使用的试剂优选为二氯甲烷-甲醇混合溶剂，所述混合溶剂中二氯甲烷和甲醇的体积比优选为20:1。
硫化反应完成后，本发明优选将所得产物料液进行后处理，得到具有式III所示结构的化合物。在本发明中，所述后处理优选包括以下步骤：将所得产物料液浓缩去除溶剂，将浓缩产物进行柱层析，得到具有式III所示结构的化合物；所述柱层析用试剂优选为石油醚和乙酸乙酯的混合溶剂，所述混合溶剂中石油醚和乙酸乙酯的体积比优选为10:1。
得到具有式III所示结构的化合物后，本发明将所述具有式III所示结构的化合物在碱性条件下进行水解反应，将水解产物。在本发明中，所述碱性条件由无机碱提供，所述无机碱优选为氢氧化锂、氢氧化钠、氢氧化钾和碳酸钾中的一种或几种，在本发明的具体实施例中，所述氢氧化锂优 选为一水氢氧化锂；所述具有式III所示结构的化合物和无机碱的摩尔比优选为1:(2～4)，更优选为1:3；所述水解反应用溶剂优选为甲醇；本发明对所述水解反应用溶剂的用量没有特殊要求，能够使水解反应顺利进行即可。
在本发明中，所述水解反应的温度优选为室温，时间优选为20～24h，更优选为22～23h。
在本发明的具体实施例中，优选将具有式III所示结构的化合物溶解于水解反应用溶剂中，然后将无机碱加入所得溶液中进行水解反应。
水解反应完成后，本发明优选将所得产物料液进行后处理，得到水解产物。在本发明中，所述后处理优选包括以下步骤：将所得产物料液和弱酸性溶液混合，使用乙酸乙酯对所得混合溶液进行萃取，得到有机相；将所述有机相依次进行饱和食盐水洗涤、无水硫酸钠干燥和旋干，得到水解产物。在本发明中，所述弱酸性溶液优选为0.1mol/L的稀盐酸水溶液、饱和磷酸二氢钠水溶液、0.5mol/L的醋酸水溶液或饱和磷酸二氢钾水溶液；本发明利用弱酸性溶液将水解反应中剩余的碱中和，并且通过控制溶液的酸性避免水解产物中保护基的脱落；在本发明中，所述萃取的次数优选为3次，将三次萃取所得有机相合并。
得到水解产物后，本发明将所述水解产物和二甲胺进行胺化反应，得到具有式IV所示结构的化合物。在本发明中，所述胺化反应优选在缩合剂和催化剂条件下进行，所述缩合剂优选包括二环己基碳二亚胺和/或1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐；所述催化剂优选包括4-二甲氨基吡啶和/或N,N-二异丙基乙胺；所述水解产物、缩合剂和催化剂的摩尔比优选为1:(1.8～2.5):(2～2.2)，更优选为1:2:2。在本发明中，所述水解产物和二甲胺的摩尔比优选为1:(1.5～2.5)；所述胺化反应用溶剂优选为二氯甲烷；本发明对所述胺化反应用溶剂的用量没有特殊要求，能够使胺化反应顺利进行即可。
在本发明中，所述胺化反应的温度优选为室温，时间优选为20～30h，更优选为24～25h。
在本发明的具体实施例中，优选将所得水解产物和二甲胺溶液混合，然后依次加入缩合剂、催化剂和胺化反应用溶剂进行胺化反应；所述二甲胺溶液的溶剂优选为四氢呋喃；本发明优选采用TLC监测至原料反应完全，所述TLC监测用试剂优选为二氯甲烷、甲醇和醋酸的混合溶剂，所述混合溶剂中二氯甲烷、甲醇和醋酸的体积比优选为4:0.2:0.1。
胺化反应完成后，本发明优选将所得产物料液进行后处理，得到具有式IV所示结构的化合物。在本发明中，所述后处理优选包括以下步骤：将所得产物料液依次用盐酸水溶液和饱和食盐水洗涤，将洗涤后的料液用 无水硫酸钠干燥后依次进行过滤、浓缩和柱层析，得到具有式IV所示结构的化合物；所述盐酸水溶液的浓度优选为1mol/L；所述柱层析用试剂优选为石油醚和乙酸乙酯的混合溶剂，所述混合溶剂中石油醚和乙酸乙酯的体积比优选为2:1。
得到具有式IV所示结构的化合物后，本发明将所述具有式IV所示结构的化合物和脱保护试剂进行脱保护反应，得到脱保护产物。在本发明中，所述脱保护试剂优选为盐酸水溶液、氯化氢甲醇溶液、氯化氢乙酸乙酯溶液和三氟乙酸中的一种或几种；所述盐酸水溶液的浓度优选为4～10mol/L，更优选为4～5mol/L；所述氯化氢甲醇溶液的浓度优选为2mol/L；所述氯化氢乙酸乙酯溶液的浓度优选为2mol/L。所述具有式IV所示结构的化合物和脱保护试剂的摩尔比优选为1:(30～35)，所述脱保护试剂的摩尔量以溶质的摩尔量计。
在本发明中，所述脱保护反应用溶剂优选为二氧六环、四氢呋喃和N,N-二甲基甲酰胺中的一种或几种；本发明对脱保护反应用溶剂的用量没有特殊要求，能够使脱保护反应顺利进行即可。
在本发明中，所述脱保护反应的温度优选为室温，时间优选为2～5h，更优选为2～3h。
在本发明的具体实施例中，优选直接将具有式IV所示结构的化合物、脱保护反应用溶剂以及脱保护试剂混合进行脱保护反应。
脱保护反应完成后，本发明优选将所得产物料液进行后处理，得到脱保护产物。在本发明中，所述后处理优选包括以下步骤：将所得产物料液和饱和碳酸钠水溶液混合，使用乙酸乙酯对所得混合溶液进行萃取，将所得有机相依次进行饱和食盐水洗涤、无水硫酸钠干燥、过滤和旋干，得到脱保护产物粗品，所得粗品无需进行进一步提纯，直接用于下一步反应；所述饱和碳酸钠水溶液的用量以使所得混合溶液的pH值为9～10为准；所述萃取优选进行多次，具体的萃取次数以TLC确认水相中无产物为止，将多次萃取所得有机相合并。
得到脱保护产物后，本发明将所述脱保护产物与3-硝基-4-卤代苯磺酰胺进行缩合反应，得到具有式V所示结构的化合物。在本发明中，所述3-硝基-4-卤代苯磺酰胺优选为3-硝基-4-氟苯磺酰胺；所述脱保护产物和3-硝基-4-卤代苯磺酰胺的摩尔比优选为1:(1.05～1.3)，更优选为1:1.2。
在本发明中，所述缩合反应用溶剂优选为二氯甲烷、N,N-二甲基甲酰胺和甲苯中的一种或几种，更优选为N,N-二甲基甲酰胺；本发明对所述缩合反应用溶剂的用量没有特殊要求，能够使缩合反应顺利进行即可。
在本发明中，所述缩合反应优选在碱性试剂作用下进行，所述碱性试剂优选为N,N-二异丙基乙胺和/或三乙胺；所述脱保护产物和碱性试剂的 摩尔比优选为1:(2.2～2.5)，更优选为1:(2.3～2.4)。
在本发明的具体实施例中，优选将上述方案所得脱保护产物粗品溶解于缩合反应用溶剂中，然后加入碱性试剂和3-硝基-4-卤代苯磺酰胺进行缩合反应；本发明优选采用TLC监测反应完全，所述TLC监测用试剂优选为乙酸乙酯。
缩合反应完成后，本发明优选将所得产物料液进行后处理，得到具有式V所示结构的化合物。在本发明中，所述后处理优选包括以下步骤：将所得产物料液和水混合后过滤，得到滤饼；将所述滤饼水洗后旋干，得到干燥固体；将所述干燥固体碾碎后加入乙酸乙酯打浆，将所得浆料过滤，收集固体，得到具有式V所示结构的化合物。在本发明中，所述打浆的温度优选为室温，时间优选为2h。
得到具有式V所示结构的化合物后，本发明将具有式V所示结构的化合物和第二还原试剂在酸性条件下进行羰基还原反应，得到ABT-737关键中间体，结构式如式VI所示。在本发明中，所述第二还原试剂优选为硼还原剂，所述硼还原剂优选为硼氢化钠、硼氢化钾、三氟化硼、三氟化硼-硼氢化钠络合物、硼烷二甲硫醚和硼烷四氢呋喃溶液中的一种或几种，所述硼烷四氢呋喃溶液的浓度优选为1mol/L；在本发明中，所述硼烷优选为市售产品或自行制备，当自行制备时，优选通过以下方法制备：将硼氢化钠和无水四氢呋喃混合，在氮气保护下滴加三氟化硼四氢呋喃溶液，滴加结束后反应30min，得到硼烷料液，所得硼烷料液无需进行任何处理，直接使用即可。在本发明中，所述硼烷四氢呋喃溶液优选为市售产品。在本发明中，所述具有式V所示结构的化合物和第二还原试剂的摩尔比优选为1:(1.5～2)，更优选为1:(1.7～1.8)。
在本发明中，酸性条件由酸性试剂提供，所述酸性试剂优选包括盐酸和/或三氟乙酸，所述酸性试剂的酸浓度优选为4～10mol/L，更优选为6～10mol/L；所述酸性试剂的用量与所述具有式V所示结构的化合物优选为(2～3):1。
在本发明中，所述羰基还原反应具体为：将具有式V所示结构的化合物和硼还原剂混合进行络合反应，得到硼络合物；将所述硼络合物和酸性试剂混合进行水解反应，得到具有式VI所示结构的化合物；所述络合反应的温度优选为室温，时间优选为20～24h；所述水解反应的温度优选为70～90℃，更优选为80℃，时间优选为3～5h，更优选为4h。在本发明的具体实施例中，在络合反应结束后，优选加入甲醇将络合反应淬灭，然后再加入盐酸进行水解反应；在络合反应过程中，具有式V所示结构的化合物和硼还原剂进行配位键结合，得到硼氧烷基自由基中间体，然后在酸性条件下，得到氢离子，离去硼氧基团得到胺化合物，从而实现酰胺羰 基还原。
羰基还原反应完成后，本发明优选将所得产物料液进行后处理，得到ABT-737关键中间体(记为中间体A)。在本发明中，所述后处理优选包括以下步骤：将所得产物料液冷却至室温后，加入饱和碳酸钠溶液将所得产物料液的pH值调节至9～10，之后采用乙酸乙酯萃取，将所得有机相依次进行饱和食盐水洗涤、无水硫酸钠干燥、过滤、旋干和柱层析，得到ABT-737关键中间体；在本发明中，所述萃取的次数优选为2次，将两次萃取所得有机相合并；所述柱层析用试剂优选为二氯甲烷和甲醇的混合溶剂，所述混合溶剂中二氯甲烷和甲醇的体积比优选为20:1。
本发明还提供了另一种合成ABT-737关键中间体的路线，步骤(1)～(3)和上述方案相同，仅在得到具有式IV所示结构的化合物后，先进行羰基还原反应，再进行脱保护反应和缩合反应，具体为将上述步骤(4)替换为步骤(4’)，步骤(5)替换为(5’)：
(4’)将所述具有式IV所示结构的化合物与第二还原试剂在酸性条件下进行羰基还原反应，得到具有式V’所示结构的化合物；
Figure PCTCN2021100636-appb-000014
(5’)将具有式V’所示结构的化合物和脱保护试剂进行脱保护反应，将所得脱保护产物与3-硝基-4-卤代苯磺酰胺进行缩合反应，得到具有式VI所示结构的ABT-737关键中间体。
本发明将所述具有式IV所示结构的化合物与第二还原试剂在酸性条件下进行羰基还原反应，得到具有式V’所示结构的化合物。在本发明中，所述酸性条件由酸性试剂提供，所述第二还原试剂和酸性试剂的种类和上述方案一致，在此不再赘述；所述羰基还原反应的条件和操作方法和上述方案一致，在此不再赘述；所述具有式IV所示结构的化合物和第二还原剂的摩尔比优选为1:(1.5～2)；所述酸性试剂与式IV所示结构的化合物摩尔比优选为(2～3):1。
羰基还原反应完成后，本发明优选将所得产物料液进行后处理，得到 具有式V’所示结构的化合物；所述后处理的方法和上述方案步骤(5)中羰基还原反应的后处理方法一致，在此不再赘述。
得到具有式V’所示结构的化合物后，本发明将具有式V’所示结构的化合物和脱保护试剂进行脱保护反应，将所得脱保护产物与3-硝基-4-卤代苯磺酰胺进行缩合反应，得到ABT-737关键中间体。在本发明中，所述脱保护试剂的种类和上述方案一致，在此不再赘述；所述脱保护反应的条件以及具体操作方法和上述方案一致，在此不再赘述；所述具有式V’所示结构的化合物和脱保护试剂的摩尔比优选为1:(30～35)，所述脱保护试剂的摩尔量以溶质的摩尔量计。
脱保护反应完成后，本发明优选将所得产物料液进行后处理，得到脱保护产物；所述后处理的方法优选和上述方案步骤(4)中脱保护反应完成后的后处理方法一致，在此不再赘述。
在本发明中，所述3-硝基-4-卤代苯磺酰胺的具体种类优选和上述方案一致，在此不再赘述；所述缩合反应的条件以及具体操作方法和上述方案一致，在此不再赘述；缩合反应完成后的后处理方法和上述方案步骤(4)中缩合反应完成后的后处理方法一致，在此不再赘述。
本发明还提供了一种ABT-737的制备方法，包括以下步骤：
按照上述方案所述的制备方法制备得到ABT-737关键中间体；
将所述ABT-737关键中间体与4-(4-((4’-氯-[1,1’-联苯]-2-基)甲基)哌嗪-1-基)苯甲酸混合进行缩合反应，得到ABT-737，结构式如式VII所示；
Figure PCTCN2021100636-appb-000015
在本发明中，所述缩合反应优选在缩合剂和催化剂作用下进行，所述缩合剂优选为二环己基碳二亚胺和/或1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐；所述催化剂优选为4-二甲氨基吡啶和/或N,N-二异丙基乙胺；所述ABT-737关键中间体(具有式VI所示结构的化合物)、缩合剂和催化剂的摩尔比优选为1:(2～2.5):(2～2.5)，更优选为1:2.1:2.1。
在本发明中，所述ABT-737关键中间体与4-(4-((4’-氯-[1,1’-联苯]-2-基)甲基)哌嗪-1-基)苯甲酸的摩尔比优选为1:(1.05～1.1)。
在本发明中，所述缩合反应用溶剂优选为二氯甲烷、1，2二氯乙烷、N,N二甲基甲酰胺，更优选为二氯甲烷；所述缩合反应用溶剂与ABT-737关键中间体的重量比优选为(100～600):1，更优选为(300～500):1。
在本发明中，所述缩合反应的温度优选为室温，时间优选为40～60h，更优选为48～50h。
在本发明的具体实施例中，优选先将ABT-737关键中间体、4-(4-((4’-氯-[1,1’-联苯]-2-基)甲基)哌嗪-1-基)苯甲酸和溶剂混合，然后在搅拌条件下依次加入缩合剂和催化剂进行缩合反应。
缩合反应结束后，本发明优选将所得产物料液进行后处理，得到ABT-737。在本发明中，所述后处理优选包括以下步骤：将所得产物料液和饱和氯化铵溶液混合后进行分层，将所得有机层依次进行饱和食盐水洗涤、无水硫酸钠干燥、过滤、干燥和柱层析，得到粗品；将所述粗品用二氯甲烷溶解，将所得溶液滴加到甲基叔丁醚中，使固体产物析出，将析出体系搅拌30min后过滤，将所得固体产物干燥，得到ABT-737。
下面将结合本发明中的实施例，对本发明中的技术方案进行清楚、完整地描述。
下面将结合本发明中的实施例，对本发明中的技术方案进行清楚、完整地描述。
实施例1
以具有式I(R为-CH 3)所示结构的化合物为起始原料，具体合成步骤如下：
1)具有式II(R为-CH 3)所示结构化合物的制备
在三口瓶中加入81.7g(0.33mol)具有式I所示结构的化合物和1600mL乙酸乙酯进行溶解，氮气置换后将体系降至0℃以下，敞口加入N-羟基琥珀酰亚胺41.8g(0.363mol)，然后滴加二环己基碳二亚胺的乙酸乙酯溶液(75g(0.363mol)二环己基碳二亚胺溶于250mL乙酸乙酯中)，保持温度在-5～0℃，体系浑浊，室温反应24h，TLC确认原料消失(二氯甲烷:甲醇：醋酸＝4ml:0.2ml：0.1ml)；将所得产物料液用硅藻土过滤，滤液加入800mL饱和的碳酸钠水溶液洗涤，分层，水层用300mL乙酸乙酯萃取一次，将有机相用500mL饱和食盐水洗涤，无水硫酸钠干燥，过滤旋干，制得活性酯。
反应瓶中加入720mL四氢呋喃和96mL水，冰浴条件下，加入硼氢化钠20g(0.529mol)，搅拌，得到硼氢化钠溶液；将所得活性酯溶解于200mLTHF中，滴加到制得的硼氢化钠溶液中，控温0℃～10℃，滴加结 束后，反应5min，TLC(使用的试剂为二氯甲烷-甲醇混合溶剂，二氯甲烷和甲醇的体积比为20:1)确认活性酯反应结束后，加入300mL饱和氯化铵水溶液淬灭反应，然后使用500mL乙酸乙酯萃取产物料液二次，合并有机相，将有机相用300mL饱和食盐水洗涤，无水硫酸钠后旋干，柱层析(石油醚：乙酸乙酯＝3:1)得具有式II所示结构的化合物51g，收率66％。
2)具有式III所示结构化合物的制备
反应瓶中加入具有式II所示结构的化合物51g(0.219mol)和1.2L甲苯溶解，然后依次加入二苯二硫醚71.6g(0.329mol)和三丁基膦66g(0.329mol)，氮气置换，80℃油浴反应18h，密闭反应。TLC(使用的试剂为二氯甲烷-甲醇混合溶剂，二氯甲烷和甲醇的体积比为20:1)确认反应完全，浓缩掉甲苯，将浓缩产物进行柱层析(石油醚：乙酸乙酯＝10:1)纯化，得具有式III所示结构的化合物62g，收率87.7％。
3)具有式IV所示结构化合物的制备
反应瓶中依次加入式III化合物62g(0.191mol)，900mL四氢呋喃，300mL甲醇，300mL水，溶清后加入一水氢氧化锂32g(0.572mol)，室温搅拌24h。TLC(使用的试剂为石油醚-乙酸乙酯混合溶剂，石油醚和乙酸乙酯的体积比为2:1)确认反应结束后，将反应液倒入2L饱和的磷酸二氢钠水溶液中，然后使用500mL乙酸乙酯萃取三次，合并有机相，将有机相用500mL饱和食盐水洗涤，无水硫酸钠干燥，旋干得水解产物。
向旋干的水解产物中加入2mol/L二甲胺四氢呋喃溶液170g(0.381mol)，再加入1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐73g(0.381mol)和4-二甲氨基吡啶23.3g(0.191mol)，然后加入二氯甲烷60mL，室温反应24h，TLC确认(二氯甲烷:甲醇：醋酸＝4ml:0.2ml：0.1ml)原料反应完全后，向产物料液中加入1mol/L的盐酸水溶液300mL(0.3mol)洗涤，再用300mL饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，将浓缩产物进行柱层析(石油醚：乙酸乙酯＝2：1)，得具有式IV所示结构的化合物60g，收率92.5％。
4)具有式V所示结构化合物的制备
在三口瓶中，加入具有式IV所示结构化合物60g(0.177mol)，1.5L二氧六环和1.5L4mol/L的盐酸，室温反应2h，确认原料反应完全后，将反应液倒入3L饱和的碳酸钠水溶液中，测得pH值为9～10的混合液，将混合液用1L乙酸乙酯萃取多次直至TLC确认水相中无产物，合并有机相，然后用2L饱和食盐水洗涤，无水硫酸钠干燥后，过滤旋干得粗品。
将制得的粗品加入500mLN,N-二甲基甲酰胺溶解，随后加入N,N-二异丙基乙胺57g(0.443mol)和3-硝基-4-氟苯磺酰胺46.8g(0.213mol)， 室温反应24h，TLC(乙酸乙酯)确认反应完全后，将反应液倒入3L的水中，过滤，水洗滤饼，收集固体，旋干，将得到的干燥固体碾碎后，加入300mL乙酸乙酯室温搅拌打浆2h，过滤，收集产品，得式V化合物68g，收率87.5％。
5)具有式VI所示结构化合物(中间体A)的制备
在反应瓶中加入硼氢化钠3.1g(0.082mol)，加入无水四氢呋喃100mL，氮气保护，滴加三氟化硼四氢呋喃溶液16g(0.114mol)，滴加结束后反应30min，再滴加具有式V所示结构的化合物的四氢呋喃的溶液(20g(0.046mol)具有式V所示结构的化合物溶于100mL四氢呋喃中)，过程产生大量气泡，而后将反应置于25℃油浴反应24h。原料反应完全后，加入30mL甲醇淬灭反应，，待无气泡后，加入30mL浓盐酸，升温至80℃回流4h，冷却至室温，加入200mL饱和碳酸钠调节pH值至9～10，然后使用200mL乙酸乙酯萃取二次，有机相用200mL饱和食盐水洗涤，无水硫酸钠干燥后依次进行过滤、旋干和柱层析(二氯甲烷：甲醇＝20：1)，收集产物(ABT-737关键中间体，具有式VI所示结构化合物)15g，收率77％。
6)具有式VII所示结构化合物的制备
反应瓶中加入具有式VI所示结构的化合物10g(23.6mmol)，4-(4-((4’-氯-[1,1’-联苯]-2-基)甲基)哌嗪-1-基)苯甲酸10.5g(25.8mmol)，然后加入二氯甲烷5000mL，搅拌条件下，加入4-二甲氨基吡啶6g(49.1mmol)，搅拌溶清后，再加入1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐9.48g(49.5mmol)，室温反应48h，反应结束后向体系加入1000mL饱和氯化铵洗涤，分层，1000mL饱和食盐水洗涤，无水硫酸钠干燥，过滤拉干，柱层析(二氯甲烷：甲醇＝20：1)，得粗品12g。
将所得粗品加入120mL二氯甲烷溶解，然后慢慢滴加到120mL甲基叔丁基醚中，固体析出，搅拌30min后，过滤，收集固体，干燥得到具有式VII所示结构的化合物10.5g，纯度99.1％，收率55％。
实施例2
以具有式I(R为-CH 3)所示结构的化合物为起始原料，具体合成步骤如下：
1)具有式II所示结构化合物的制备
三口瓶中，加入35g(0.121mol)具有式I所示结构的化合物和700mL乙酸乙酯溶解，氮气保护，降至0℃左右，然后加入N-羟基琥珀酰亚胺15.3g(0.133mol)，开始滴加二环己基碳二亚胺27.4g(0.133mol)溶于140mL乙酸乙酯的溶液，控温-5～0℃，撤掉冰浴，室温反应24h，TLC确认原料消失后，将所得产物料液用硅藻土过滤，滤饼乙酸乙酯淋洗，滤液 中加入300mL饱和的碳酸钠水溶液洗涤，200mL乙酸乙酯萃取一次，合并有机相，将有机相用200mL饱和食盐水洗涤，无水硫酸钠干燥后过滤旋干，制得活性酯粗品。
另取一反应瓶，加入300mL四氢呋喃和40mL水，冰浴条件下，加入硼氢化钠7.3g(0.194mol)，搅拌，得到硼氢化钠溶液；将制得的活性酯粗品溶解于100mL THF中，滴加到制得的硼氢化钠溶液中，滴加结束后，低温搅拌10min，确认活性酯反应结束后，加入100mL饱和氯化铵水溶液淬灭反应，然后使用200mL乙酸乙酯萃取二次，合并有机相，将有机相用200mL饱和食盐水洗涤，然后依次进行无水硫酸钠、旋干和柱层析(石油醚：乙酸乙酯＝3：1)，得到具有式II所示结构的化合物20.4g，收率61.2％。
2)具有式III所示结构的化合物的制备
在反应瓶中加入具有式II所示结构的化合物20g(0.073mol)和800mL甲苯溶解，然加入二苯二硫醚23.8g(0.109mol)，三丁基膦22g(0.109mol)，氮气置换，80℃油浴反应18h。TLC(二氯甲烷:甲醇＝20：1)确认反应完全，将所得产物料液浓缩，将所得浓缩产物进行柱层析(石油醚：乙酸乙酯＝10：1)，得具有式III所示结构的化合物22.8g，收率85.5％。
3)具有式IV所示结构的化合物的制备
在反应瓶中依次加入具有式III所示结构的化合物22g(0.06mol)，400mL乙醇，200mL水，溶清后加入氢氧化钠9.6g(0.24mol)，室温搅拌24h。反应结束后，将反应液倒入500L饱和的磷酸二氢钠水溶液中，使用300mL乙酸乙酯萃取三次，合并有机相，将有机相用200mL饱和食盐水洗涤，无水硫酸钠干燥，旋干得水解产物。
向旋干的水解产物中，加入2mol/L二甲胺四氢呋喃溶液60mL(0.12mol)，再加入1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐23g(0.12mol)和4-二甲氨基吡啶7.3g(0.06mol)，然后加入二氯甲烷20mL，室温反应24h，TLC确认(二氯甲烷:甲醇：醋酸的体积比为4:0.2：0.1)原料反应完全后，向产物料液中加入1mol/L的盐酸的水溶液100mL(0.1mol)洗涤，然后使用100mL饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，将浓缩产物进行柱层析(石油醚：乙酸乙酯＝2：1)，得具有式IV所示结构的化合物18.4g，收率90.8％。
4)具有式V所示结构化合物的制备
在三口瓶中，加入具有式IV所示结构的化合物15g(0.044mol)，375mL二氧六环和375mL 4mol/L的盐酸，室温反应2h，确认原料反应完全后，将反应液倒入800mL饱和的碳酸钠水溶液中，测得pH为9～10，使用300mL乙酸乙酯萃取多次直至TLC确认水相中无产物，将所得有机 相用800mL饱和食盐水洗涤，无水硫酸钠干燥，过滤旋干得粗品。
将以上制得的粗品加入130mL N,N-二甲基甲酰胺溶解，随后加入N,N-二异丙基乙胺14.2g(0.11mol)和3-硝基-4-氟苯磺酰胺11.7g(0.053mol)，室温反应24h，TLC(乙酸乙酯)确认反应完全后，将反应液倒入800mL的水中，过滤，水洗滤饼，收集固体，旋干，将得到的干燥固体碾碎后，加入100mL乙酸乙酯室温搅拌2h，过滤，收集产品，得具有式V所示结构的化合物17.2g，收率89％。
5)中间体A的制备
反应瓶中加入具有式V所示结构的化合物10g(0.023mol)，氮气保护，用针筒向体系内打入40mL 1mol/L的硼烷四氢呋喃溶液，而后将反应置于25℃油浴反应24h。原料反应完全后，加入15mL甲醇淬灭反应，待无气泡后，加入10mL浓盐酸，升温至80℃回流4h，冷却至室温，加入100mL饱和碳酸钠调节PH值至9-10，然后使用100mL乙酸乙酯萃取二次，100mL饱和食盐水洗涤，无水硫酸钠干燥后过滤旋干、柱层析(二氯甲烷：甲醇＝20：1)收集产物(ABT-737关键中间体，具有式VI所示结构化合物)，6.58g，收率68％。
6)具有式VII所示结构化合物的制备
反应瓶中加入具有式VI所示结构的化合物5.6g(13.2mmol)，4-(4-((4’-氯-[1,1’-联苯]-2-基)甲基)哌嗪-1-基)苯甲酸5.9g(14.5mmol)，然后加入二氯甲烷2800mL，搅拌条件下，加入4-二甲氨基吡啶3.38g(27.7mmol)，搅拌溶清后，再加入1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐5.31g(27.7mmol)，室温反应48h，反应结束后向体系加入800mL饱和氯化铵洗涤，分层，800mL饱和食盐水洗涤，无水硫酸钠干燥，过滤拉干，柱层析(二氯甲烷：甲醇＝20：1)，得粗品6.5g。
将所得粗品加入70mL二氯甲烷溶解，然后慢慢滴加到70mL甲基叔丁基醚中，固体析出，搅拌30min后，过滤，收集固体，干燥得式(VII)所示化合物6.2g，纯度99.2％，收率58％。
实施例3
以具有式I(R为-CH 3)所示结构的化合物为起始原料，具体合成步骤如下：
1)具有式II(R为-CH 3)所示结构化合物的制备
三口瓶中，加入55g(0.22mol)具有式I所示结构的化合物和1000mL乙酸乙酯溶解，氮气置换，体系降至0℃以下，敞口加入N-羟基琥珀酰亚胺27.9g(0.242mol)，然后滴加二环己基碳二亚胺50g(0.242mol)溶于160mL乙酸乙酯的溶液，保持温度在-5～0℃，体系浑浊，结束后室温反应24h，TLC确认原料消失(二氯甲烷:甲醇：醋酸＝4:0.2：0.1)，将 所得产物料液用硅藻土过滤，滤液加入500mL饱和的碳酸钠水溶液洗涤，200mL乙酸乙酯萃取一次，合并有机相，将有机相用400mL饱和食盐水洗涤，无水硫酸钠干燥，过滤旋干，制得活性酯。
反应瓶中加入480mL四氢呋喃和65mL水，冰浴条件下，加入硼氢化钠13.6g(0.36mol)，搅拌，将制得的活性酯溶解于150mL THF中，滴加到制得的硼氢化钠溶液中，控温0℃～10℃，滴加结束后，反应5分钟，TLC(二氯甲烷：甲醇＝20：1或二氯甲烷:乙酸乙酯＝3:2)确认中间态反应结束后，加入200mL饱和氯化铵水溶液淬灭，然后300mL乙酸乙酯萃取二次，合并有机相，将有机相用200mL饱和食盐水洗涤，无水硫酸钠，旋干，柱层析，得到具有式II所示结构的化合物33.7g，收率65％。
2)具有式III所示结构化合物的制备
反应瓶中加入具有式II所示结构的化合物30g(0.129mol)和750mL甲苯溶解，然后依次加入二苯二硫醚42g(0.193mol)和三丁基膦39g(0.193mol)，氮气置换，80℃油浴反应18h，尽量密闭反应。TLC(二氯甲烷:甲醇＝20：1)确认反应完全，浓缩掉甲苯，然后柱层析纯化，得到具有式III所示结构的化合物37.2g，收率89％。
3)具有式IV所示结构化合物的制备
反应瓶中依次加入具有式III所示结构的化合物31g(0.095mol)，450mL四氢呋喃，150mL甲醇，150mL水，溶清后加入一水氢氧化锂16g(0.286mol)，室温搅拌24h。TLC(石油醚:乙酸乙酯＝2:1)反应结束后，反应液倒入500L饱和的磷酸二氢钠水溶液中，300mL乙酸乙酯萃取三次，合并有机相，将有机相用300mL饱和食盐水洗涤，无水硫酸钠干燥，旋干得水解产物。
向旋干的水解产物中，加入2mol/L二甲胺四氢呋喃溶液85g(0.191mol)，再加入1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐36.5g(0.191mol)和4-二甲氨基吡啶11.6g(0.095mol)，然后加入二氯甲烷30mL，室温反应24h，TLC确认(二氯甲烷:甲醇：醋酸＝4:0.2：0.1)原料反应完全后，然后加入1mol/L的盐酸水溶液150mL(0.3mol)洗涤，200mL饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，柱层析得式IV化合物29.3g，收率91％。
4)具有式V’所示结构化合物的制备
反应瓶中加入硼氢化钠5g(0.133mol)，加入无水四氢呋喃200mL，氮气保护，开始滴加三氟化硼四氢呋喃溶液25.9g(0.185mol)，滴加结束后反应30min，再滴加具有式IV所示结构的化合物25g(0.074mol)溶于100mL四氢呋喃的溶液，过程产生大量气泡，而后将反应置于25℃油浴反应24h。原料反应完全后，加入40mL甲醇淬灭反应，待无气泡后，加 入40mL浓盐酸，升温至80℃回流4h，冷却至室温，加入300mL饱和碳酸钠调节pH值至9～10，然后使用300mL乙酸乙酯萃取二次，有机相合并，用300mL饱和食盐水洗涤，无水硫酸钠干燥，过滤旋干，柱层析收集具有式V’所示结构化合物18.8g，收率78.5％。
5)具有式VI所示结构化合物的制备
三口瓶中，加入具有式V’所示结构的化合物18.8g(0.058mol)，470mL二氧六环和470mL 4mol/L的盐酸，室温反应2h，确认原料反应完全后，将反应液倒入700mL饱和的碳酸钠水溶液中，测得pH为9～10，将产物料液用300mL乙酸乙酯萃取多次直至TLC确认水相中无产物，将有机相用800mL饱和食盐水洗涤，无水硫酸钠干燥，过滤旋干得粗品。
将以上制得的粗品氨加入170mLN,N-二甲基甲酰胺溶解，随后加入N,N-二异丙基乙胺18.7g(0.145mol)和3-硝基-4-氟苯磺酰胺15.4g(0.07mol)，室温反应24h，TLC(乙酸乙酯)确认反应完全后，将反应液倒入700mL的水中，300mL乙酸乙酯萃取产品两次，300mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，拉干柱层析，得到具有式VI所示结构的化合物(中间体A)21.1g，收率85.8％。
6)具有式VII所示结构化合物的制备
反应瓶中加入具有式VI所示结构的化合物20g(0.047mol)，4-(4-((4’-氯-[1,1’-联苯]-2-基)甲基)哌嗪-1-基)苯甲酸21g(0.052mol)，然后加入二氯甲烷1000mL，搅拌条件下，加入4-二甲氨基吡啶12g(0.098mol)，搅拌溶清后，再加入1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐19.2g(0.1mol)，室温反应48h，反应结束后向体系加入500mL饱和氯化铵洗涤，分层，500mL饱和食盐水洗涤，无水硫酸钠干燥，过滤拉干，柱层析，得粗品26g。
将所得粗品加入260mL二氯甲烷溶解，然后慢慢滴加260mL甲基叔丁基醚，固体析出，搅拌30min后，过滤，收集固体，干燥得具有式VII所示结构的化合物20g，纯度99.1％，收率52.3％。
实施例4
以具有式I(R为
Figure PCTCN2021100636-appb-000016
)所示结构的化合物为起始原料，具体合成步骤如下：
1)具有式II(R为
Figure PCTCN2021100636-appb-000017
)所示结构化合物的制备
三口瓶中加入5g(0.017mol)具有式I所示结构的化合物和100mL乙酸乙酯溶解，氮气保护，降至0℃左右，然后加入N-羟基琥珀酰亚胺2.2g(0.019mol)，滴加二环己基碳二亚胺3.9g(0.019mol)溶于20mL乙酸乙酯的溶液，控温-5～0℃，撤掉冰浴，室温反应24h，TLC确认原料消失后，硅藻土过滤，滤饼乙酸乙酯淋洗，然后往滤液加入50mL饱和的碳酸钠水溶液洗涤，50mL乙酸乙酯萃取一次，合并有机相，将有机相用50mL饱和食盐水洗涤，无水硫酸钠干燥，过滤旋干，制得活性酯粗品。
另取一反应瓶，加入45mL四氢呋喃和6mL水，冰浴条件下，加入硼氢化钠1.04g(0.028mol)，搅拌，得到硼氢化钠溶液；将制得的活性酯粗品溶解于15mL THF中，滴加到制得的硼氢化钠溶液中，滴加结束后，控温0℃～10℃，搅拌10min，确认活性酯反应结束后，加入20mL饱和氯化铵水溶液淬灭，然后50mL乙酸乙酯萃取二次，合并有机相，将有机相用50mL饱和食盐水洗涤，无水硫酸钠，旋干，柱层析，得到具有式II所示结构的化合物2.9g，收率63％。
2)具有式III所示结构化合物的制备
反应瓶中加入具有式II所示结构的化合物2g(0.0073mol)和80mL甲苯溶解，然加入二苯二硫醚2.4g(0.01mol)，三丁基膦2.2g(0.01mol)，氮气置换，80℃油浴反应18h；TLC(二氯甲烷:甲醇＝20：1)确认反应完全，浓缩，柱层析得具有式III所示结构的化合物2.2g，收率82％。
3)具有式IV所示结构化合物的制备
反应瓶中依次加入具有式III所示结构化合物2.2g(0.006mol)，40mL乙醇，20mL水，溶清后加入氢氧化钠0.96g(0.024mol)，室温搅拌24h。反应结束后，将反应液倒入50mL饱和的磷酸二氢钠水溶液中，30mL乙酸乙酯萃取三次，合并有机相，20mL饱和食盐水洗涤，无水硫酸钠干燥，旋干得中间体。
向旋干的中间体中，加入2mol/L二甲胺四氢呋喃溶液6mL(0.012mol)，再加入-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐2.3g(0.012mol)和4-二甲氨基吡啶0.73g(0.006mol)，然后加入二氯甲烷2mL，室温反应24h，TLC确认(二氯甲烷:甲醇：醋酸的体积比为4:0.2：0.1)原料反应完全后，然后加入1mol/L的盐酸水溶液10mL(0.01mol)洗涤，10mL饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，柱层析得式IV化合物1.77g，收率87.2％。
4)具有式V’所示结构化合物的制备
反应瓶中加入硼氢化钠0.3g(0.008mol)，加入无水四氢呋喃20mL，氮气保护，滴加三氟化硼四氢呋喃溶液1.68g(0.012mol)，滴加结束后反应30min，再滴加具有式IV所示结构的化合物1.56g(4.6mmol)溶于10mL四氢呋喃的溶液，过程产生大量气泡，而后将反应置于25℃油浴反应24h。原料反应完全后，加入2.5mL甲醇淬灭反应，待无气泡后，加入2.5mL浓盐酸，升温至80℃回流4h，冷却至室温，加入20mL饱和碳酸钠调节pH值至9～10，然后使用30mL乙酸乙酯萃取二次，30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤旋干，柱层析收集具有式V’所示结构的化合物1.13g，收率76％。
5)具有式VI所示结构化合物的制备
三口瓶中，加入具有式V’所示结构的化合物1g(3.1mmol)，25mL二氧六环和25mL4mol/L的盐酸，室温反应2h，确认原料反应完全后，将反应液倒入50mL饱和的碳酸钠水溶液中，测得pH为碱性(9～10)，30mL乙酸乙酯萃取多次直至TLC确认无产物，然后用50mL饱和食盐水洗涤，无水硫酸钠干燥，过滤旋干得粗品。
将以上制得的粗品氨加入10mL N,N-二甲基甲酰胺溶解，随后加入N,N-二异丙基乙胺1g(7.75mmol)和3-硝基-4-氟苯磺酰胺0.82g(3.72mol)，室温反应24h，TLC(乙酸乙酯)确认反应完全后，将反应液倒入50mL的水中，30mL乙酸乙酯萃取产品两次，30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，拉干柱层析，得到具有式VI所示结构的化合物(中间体A)1.16g，收率88％。
6)具有式VII所示结构化合物的制备
反应瓶中加入具有式VI所示结构的化合物1g(2.36mmol)，4-(4-((4’-氯-[1,1’-联苯]-2-基)甲基)哌嗪-1-基)苯甲酸1.04g(2.56mmol)，然后加入二氯甲烷50mL，搅拌条件下，加入4-二甲氨基吡啶0.6g(4.92mmol)，搅拌溶清后，再加入1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐0.94g(4.92mmol)，室温反应48h，反应结束后向体系加入20mL饱和氯化铵洗涤，分层，20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤拉干，过柱，得粗品1.3g。
将所得粗品加入15mL二氯甲烷溶解，然后慢慢滴加15mL甲基叔丁基醚，固体析出，搅拌30min后，过滤，收集固体，干燥，得到具有式VII所示结构的化合物1.1g，纯度99.2％，收率59％。
以上所述仅是本发明的优选实施方式，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，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (16)

  1. 一种ABT-737关键中间体的制备方法，其特征在于，包括以下步骤：
    (1)将具有式I所示结构的化合物与活化剂进行酯化反应，得到活性酯；将所述活性酯与第一还原剂进行还原反应，得到具有式II所示结构的化合物；
    Figure PCTCN2021100636-appb-100001
    (2)将所述具有式II所示结构的化合物、硫化剂和有机膦进行硫化反应，得到具有式III所示结构的化合物；所述硫化剂包括苯硫酚金属盐和二苯二硫醚中的一种或几种；
    Figure PCTCN2021100636-appb-100002
    式I～式III中，R为链烷基或环烷基；
    (3)将所述具有式III所示结构的化合物在碱性条件下进行水解反应，将水解产物和二甲胺进行胺化反应，得到具有式IV所示结构的化合物；
    Figure PCTCN2021100636-appb-100003
    (4)将所述具有式IV所示结构的化合物与脱保护试剂进行脱保护反应，将所得脱保护产物与3-硝基-4-卤代苯磺酰胺进行缩合反应，得到 具有式V所示结构的化合物；
    Figure PCTCN2021100636-appb-100004
    (5)将具有式V所示结构的化合物和第二还原试剂在酸性条件下进行羰基还原反应，得到ABT-737关键中间体，结构式如式VI所示；
    Figure PCTCN2021100636-appb-100005
  2. 根据权利要求1所示的制备方法，其特征在于，所述活化剂包括N-羟基琥珀酰亚胺和/或氯甲酸异丁酯；所述具有式I所示结构的化合物和活化剂的摩尔比为1:(1～1.2)；
    所述酯化反应的温度为-20～0℃，时间为20～25h。
  3. 根据权利要求1或2所示的制备方法，其特征在于，所述酯化反应在催化剂的催化下进行，所述催化剂为有机胺；所述具有式I所示结构的化合物和催化剂的摩尔比为1:(1.05～1.5)。
  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，第一还原试剂为硼还原剂；所述活性酯和第一还原试剂的摩尔比为1:(1.5～2)；
    所述还原反应在混合溶剂中进行，所述混合溶剂包括四氢呋喃-水混合溶剂、四氢呋喃-甲醇混合溶剂和甲醇-水混合溶剂中的一种或几种；
    所述还原反应的温度为-5～20℃，时间为5～20min。
  5. 根据权利要求1所述的制备方法，其特征在于，所述具有式II所示结构的化合物与硫化剂的摩尔比为1:(1.2～2)；
    所述有机膦包括三丁基膦、三苯基膦和三羧基乙基膦中的一种或几种；所述具有式II所示结构的化合物与有机膦的摩尔比为1:(1.2～2)；
    所述硫化反应的温度为70～85℃，时间为15～20h。
  6. 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， 所述碱性条件由无机碱提供；
    所述具有式III所示结构的化合物和无机碱的摩尔比为1:(2～4)；
    所述水解反应的温度为室温，时间为20～24h。
  7. 根据权利要求1所述的制备方法，其特征在于，所述胺化反应在缩合剂和催化剂条件下进行，所述缩合剂包括二环己基碳二亚胺和/或1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐；所述催化剂包括4-二甲氨基吡啶和/或N,N-二异丙基乙胺；
    所述水解产物、缩合剂和催化剂的摩尔比为1:(1.8～2.5):(2～2.2)；
    所述水解产物和二甲胺的摩尔比为1：(1.5～2.5)；
    所述胺化反应的温度为室温，时间为20～30h。
  8. 根据权利要求1所述的制备方法，其特征在于，所述脱保护试剂为盐酸水溶液、氯化氢甲醇溶液、氯化氢乙酸乙酯溶液和三氟乙酸中的一种或几种；
    所述脱保护反应的温度为室温，时间为2～5h。
  9. 根据权利要求1所述的制备方法，其特征在于，所述脱保护产物和3-硝基-4-卤代苯磺酰胺的摩尔比为1:(1.05～1.3)；
    所述缩合反应的温度为20～30℃，时间为20～30h。
  10. 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，第二还原试剂为硼还原剂；所述酸性条件由酸性试剂提供，所述酸性试剂包括盐酸和/或三氟乙酸；
    所述羰基还原反应具体为：将具有式V所示结构的化合物和硼还原剂混合进行络合反应，得到硼络合物；将所述硼络合物和酸性试剂混合进行水解反应，得到具有式VI所示结构的化合物。
  11. 根据权利要求1所述的制备方法，其特征在于，所述步骤(4)替换为步骤(4’)，步骤(5)替换为(5’)：
    (4’)在第二还原试剂和酸性试剂的作用下，将所述具有式IV所示结构的化合物进行羰基还原反应，得到具有式V’所示结构的化合物；
    Figure PCTCN2021100636-appb-100006
    (5’)在脱保护试剂作用下，将具有式V’所示结构的化合物进行脱保护反应，将所得脱保护产物与3-硝基-4-卤代苯磺酰胺进行缩合反应，得到ABT-737关键中间体。
  12. 一种ABT-737的制备方法，其特征在于，包括以下步骤：
    按照权利要求1～11任意一项所述的制备方法制备得到ABT-737关键中间体；
    将所述ABT-737关键中间体与4-(4-((4’-氯-[1,1’-联苯]-2-基)甲基)哌嗪-1-基)苯甲酸混合进行缩合反应，得到ABT-737，结构式如式VII所示；
    Figure PCTCN2021100636-appb-100007
  13. 根据权利要求12所述的制备方法，其特征在于，所述ABT-737关键中间体与4-(4-((4’-氯-[1,1’-联苯]-2-基)甲基)哌嗪-1-基)苯甲酸的摩尔比为1:(1.05～1.1)。
  14. 根据权利要求12所述的制备方法，其特征在于，所述缩合反应在缩合剂和催化剂作用下进行，所述缩合剂为二环己基碳二亚胺和/或1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐；所述催化剂为4-二甲氨基吡啶和/或N,N-二异丙基乙胺。
  15. 根据权利要求14所述的制备方法，其特征在于，所述ABT-737关键中间体、缩合剂和催化剂的摩尔比优选为1:(2～2.5):(2～2.5)，更优选为1:2.1:2.1。
  16. 根据权利要求12所述的制备方法，其特征在于，所述缩合反应的温度为室温，时间为40～60h。
PCT/CN2021/100636 2021-05-26 2021-06-17 一种abt-737关键中间体的制备方法以及abt-737的制备方法 WO2022246929A1 (zh)

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