WO2020119345A1 - 用于制备软海绵素类化合物的中间体及其制备方法 - Google Patents

用于制备软海绵素类化合物的中间体及其制备方法 Download PDF

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WO2020119345A1
WO2020119345A1 PCT/CN2019/116349 CN2019116349W WO2020119345A1 WO 2020119345 A1 WO2020119345 A1 WO 2020119345A1 CN 2019116349 W CN2019116349 W CN 2019116349W WO 2020119345 A1 WO2020119345 A1 WO 2020119345A1
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formula
compound
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徐为平
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北京天一绿甫医药科技有限公司
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Priority to JP2020523997A priority Critical patent/JP2022510740A/ja
Priority to US16/768,943 priority patent/US11713329B2/en
Priority to EP19861292.1A priority patent/EP3686208B1/en
Publication of WO2020119345A1 publication Critical patent/WO2020119345A1/zh

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    • 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 Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • 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 Table
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/16—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four 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 Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888

Definitions

  • the present invention relates to intermediate compounds that can be used to prepare soft sponge sponge or its analogs, especially iribulin, and methods for preparing these intermediate compounds, and belongs to the technical field of organic synthesis.
  • Soft sponge sponge (Halichondrin, hereinafter referred to as HB) is a type of natural product that exists in the sponge body and has a polyether macrolide structure. Such substances have strong antitumor effects and broad medical prospects. Based on their structural differences, such natural products are divided into the following categories: norhalichondrin (norhalichondrin), soft sponge (Halichondrin), high soft sponge (homohalichondrin), etc., and each category has a series of representative sub Type, the subtype and the specific structure are known in the art and are disclosed in detail in WO2016003975A1, the prior art document is fully incorporated herein; Eribulin (hereinafter referred to as EB) is a soft sponge The structure of the analog is simplified, and it has been used clinically to treat advanced breast cancer and liposarcoma.
  • EB Eribulin
  • HB and EB cannot be obtained in large quantities from natural sources and can only rely on artificial synthesis. Since these compounds have similar structures, especially the C1-C29 parts have the same structure, suitable intermediate compounds can be used to synthesize such compounds.
  • the intermediates represented by the following Formula 1a and Formula 4 can be used to construct the fragment part of C20-C35 of Eribulin.
  • the intermediate portions represented by the following formula 1b and formula 6 can be used to construct the fragment part of C20-C35 of iribrin.
  • the preparation method of the compound of formula 4 or formula 6 has many defects, for example, the synthetic route is too long, the optical purity of the starting material is difficult to control, and the highly toxic and expensive n-Bu 3 S n H reagent is involved , Poor stereo selectivity, etc. These defects will bring about a series of production problems such as cost control, environmental and labor protection, and product quality. Therefore, there is an urgent need to develop intermediates or synthetic methods that can improve synthesis efficiency, improve production costs, facilitate industrial mass production, increase selectivity, yield and purity, and are environmentally friendly to improve the preparation method of soft sponge-like pharmaceutical compounds .
  • the present invention provides the following intermediates for constructing soft sponge sponge and its analogs, especially the C20-C26 structural fragment of iribulin and preparation methods thereof.
  • a method for preparing a compound of formula (8) is provided.
  • the formula (8) is defined as follows:
  • R 1 is selected from hydroxyl protecting groups
  • R 2 and R 3 are the same or different, and are independently selected from H and OR a , and R a is independently selected from H, C 1-10 alkyl, and R b SO 2 , where R b is C 1-10 alkyl; Or both R 2 and R 3 are OR a , and the two R a bond chains form C 1-6 alkylene; or R 2 and R 3 together with the carbon of their bond chain form a carbonyl group;
  • X is selected from halogen and sulfonyloxy.
  • R 1 is selected from silyl hydroxyl protecting groups, such as TMS, TES, TBDMS, TBDPS, DIPS, DPS, TIPDS, and the like.
  • R 2, R 3 a is selected from H, the other is selected from OR a, and R a is H or i-PrSO 2; or R 2 and R 3 are OR a, R a and two The bond chain forms n-propylene; or R 2 and R 3 together with the carbon of the bond chain form a carbonyl group;
  • X is selected from chlorine, bromine, iodine and the like.
  • the method includes the following steps:
  • R 5 in formula (2) is selected from silyl groups, such as TMS, TES, TBDMS, TBDPS, DIPS, DPS, TIPDS, etc.; the oxazolidinone moiety in formula (1), formula (2) is An oxazolidinone chiral prosthetic group, for example: R 4 is a C 1-10 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl 2-oxooxazolidinone.
  • the R 4 is isopropyl, unsubstituted or hydroxy, nitro, dimethylamino mono- or poly-substituted phenyl or benzyl.
  • the step of recrystallizing formula (2) once, twice or more times is also included.
  • the formula (2) is obtained by reacting the formula (1) with the Grignard reagent R 6 MgX or R 6 Li, where R 6 is
  • the reaction is in the presence of a cuprous salt, such as cuprous chloride, cuprous bromide, cuprous iodide (CuI) or cuprous cyanide, in an inert atmosphere at -50°C to 0°C and In a solvent.
  • a cuprous salt such as cuprous chloride, cuprous bromide, cuprous iodide (CuI) or cuprous cyanide
  • the solvent may be tetrahydrofuran or anhydrous ether, and the amount (mass) of the cuprous salt is about 10-25% of the reactant formula (1), preferably 15-20%.
  • the content of optical isomers can be controlled and reduced by recrystallization of formula (2).
  • the solvent for recrystallization is any solvent that dissolves formula (2) at room temperature or slightly above room temperature and can crystallize at a lower temperature (for example, -10 to -30°C), such as a non-polar organic solvent, preferably Alkanes, examples of which may be n-pentane, n-hexane, n-heptane, isooctane, or mixed solvents thereof, such as petroleum ether.
  • the recrystallization can be repeated multiple times.
  • the isomer content of formula (2) of the present invention can be controlled to 1% or less, and the isomer content of two recrystallizations can be controlled to 1 ⁇ or less.
  • the isomer content Can be controlled in a lower range.
  • the preparation method of the Grignard reagent includes the following steps:
  • the acid binding agent may be an organic weak base or an inorganic weak base, such as diethylamine, ethylenediamine, triethylamine, diisopropylamine, pyridine, potassium carbonate, sodium carbonate, cesium carbonate, and the like.
  • the above halogenated vinyl silane reacts with metal magnesium or metal lithium in an aprotic solvent to generate the corresponding Grignard reagent or lithium reagent.
  • the aprotic solvent may be an ether solvent, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclohexyl methyl ether, tetrahydrofuran, dioxane, etc., or a hydrocarbon solvent, such as n-pentane, n-hex Alkane, n-heptane, benzene, toluene, xylene, etc.
  • the above halogenated vinyl silane can also be combined with other readily available Grignard reagents, such as methyl, ethyl, n-propyl, isopropyl Grignard reagents, etc., or easily obtainable lithium alkyl reagents in the solvent as described above , Such as methyl, n-butyl, sec-butyl, tert-butyl lithium, metal-halogen exchange reaction to generate the corresponding Grignard reagent or lithium reagent.
  • other readily available Grignard reagents such as methyl, ethyl, n-propyl, isopropyl Grignard reagents, etc.
  • lithium alkyl reagents such as methyl, n-butyl, sec-butyl, tert-butyl lithium, metal-halogen exchange reaction to generate the corresponding Grignard reagent or lithium reagent.
  • the method for preparing the compound of formula (8) according to the present invention further includes the following steps from formula (2) to formula (3):
  • X in formula (3) is halogen or sulfonyloxy.
  • the reaction is a halogenation reaction known to those skilled in the art, which is carried out in a suitable solvent at a mild reaction temperature, for example, from 0°C to room temperature.
  • the halogenated reagent used may be X 2 , RCO 2 X, R n SiX 4-n , where X is selected from halogens of chlorine, bromine, and iodine, and two X in X 2 may be different, and R is selected from C 1-10 Alkyl or fluorinated C 1-10 alkyl, n is an integer of 1-3.
  • the halogenated reagent may be elemental substances of chlorine, bromine, and iodine, BrCl, ICl, TMSCl, TMSI, CF 3 CO 2 I, and the like.
  • the preparation method of the present invention further includes further converting the compound of formula (3) where X is halogen into a compound of formula (3) where X is sulfonyloxy according to a substitution reaction known in the art.
  • the method for preparing the compound of formula (8) according to the present invention further includes the following steps:
  • the reaction is performed under alkaline and low temperature conditions (-80°C to -20°C), and the reaction may optionally use a catalytic amount of lithium chloride and a solvent.
  • the base is selected from organic bases, inorganic bases or mixtures thereof, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, triethylamine, pyridine, piperidine, n- One or more of butyl lithium (n-BuLi).
  • the solvent is, for example, tetrahydrofuran, N,N-dimethylformamide (DMF), dichloroethane, diethyl ether, carbon tetrachloride, toluene, etc.; the acyl compound may be an ester, carboxylic acid, acid halide, or anhydride .
  • the oxazolidinone chiral prosthetic group reacts with the acid halide in the presence of -80 ⁇ -60°C, tetrahydrofuran as a solvent, argon protection and n-butyl lithium.
  • the mass amount of the base lithium is about 30-50% of the oxazolidinone; or the oxazolidinone chiral prosthetic group and anhydride at -30 ⁇ -20°C, tetrahydrofuran as the solvent, lithium chloride and triethylamine In the reaction in the presence of, the mass amount of lithium chloride is about 35%-55% of oxazolidinone.
  • the method for preparing the compound of formula (8) according to the present invention further includes the following steps: preparing formula (4) from formula (3):
  • the reaction is carried out under the condition of removing and isolating the chiral prosthetic group of oxazolidinone, preferably hydrolyzed and removed under alkaline conditions.
  • the reaction is carried out in -15 to 5°C, alkaline conditions and solvent medium, and optionally hydrogen peroxide.
  • the reaction temperature may be -10 to 0°C, preferably -5 to 0°C.
  • the base may be selected from organic bases, inorganic bases or mixtures thereof, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, lithium hydroxide, lithium hydroxide hydrate, sodium hydroxide, hydroxide
  • the solvent is a mixed solvent of water and alcohols, ethers, such as tetrahydrofuran (THF) or dioxane, one or more of acetone, the ratio (volume ratio) of water to organic solvent in the mixed solvent can be It is about 1:1 to about 1:6, preferably about 1:2 to 1:3.
  • the reaction is carried out in the presence of -5 to 0°C in the presence of a mixed solvent of tetrahydrofuran and water, lithium hydroxide monohydrate, hydrogen peroxide, and the compound formula (3) and hydrogen peroxide
  • the mass ratio with lithium hydroxide monohydrate is 12-20:3-9:1-6.
  • the method for preparing the compound of formula (8) according to the present invention further includes the following steps: preparing formula (5) from formula (4):
  • the reaction is carried out in the presence of a coupling agent, which may be an EDCI/DMAP, EDC/DMAP, EDC/NHS, DCC/NHS system, the reaction is at 15-40°C, preferably Reaction at room temperature (20-25°C).
  • the reaction solvent may be dichloromethane (DCM), tetrahydrofuran (THF), dimethylformamide (DMF) and the like.
  • the method for preparing the compound of formula (8) according to the present invention further includes the following steps: preparing formula (6) from formula (5) and aldehyde:
  • the reaction is carried out in the presence of titanium tetrachloride (TiCl 4 ) and triethylamine (TEA), protected by an inert atmosphere, and the reaction is carried out at a lower temperature of -10 to 10°C, preferably 0°C.
  • the reaction solvent may be dichloromethane (DCM) or the like.
  • the preparation method of the above aldehyde includes the following steps:
  • X is selected from halogens of chlorine, bromine and iodine
  • R is selected from C 1-10 alkyl or fluorinated C 1-10 alkyl
  • n is an integer of 1-3.
  • Examples of the halogenated silane R n SiX 4-n may be TMSCl, TMSI, TBDPSCl, TBDPSI, etc.
  • the coupling agent may be an EDCI/DMAP, EDC/DMAP, EDC/NHS, DCC/NHS system, and the reaction is performed at 15-40°C, preferably at room temperature (20-25°C).
  • the reaction solvent may be dichloromethane (DCM), tetrahydrofuran (THF), dimethylformamide (DMF) and the like.
  • the oxidation is any method of oxidizing alcohol to aldehyde or ketone as described below.
  • the method for preparing the compound of formula (8) according to the present invention further includes the following steps: preparing formula (7) from formula (6):
  • the oxidation is any method known to those skilled in the art that can oxidize alcohols to aldehydes or ketones, such as swern oxidation, Pfitzner-Moffatt oxidation, Albright-Goldman oxidation.
  • the oxidation uses the Parikh-Doering oxidation method: dimethyl sulfoxide (DMSO) and sulfur trioxide-pyridine complex (SO 3 ⁇ py) at -15 to 25° C. under alkaline conditions Under the reaction with alcohol.
  • DMSO dimethyl sulfoxide
  • SO 3 ⁇ py sulfur trioxide-pyridine complex
  • the base may be triethylamine or N,N-diisopropylethylamine (DIPEA); the reaction temperature is preferably 0°C to room temperature (room temperature is 20-25°C); the reaction may be optionally added with a solvent This depends on the amount of DMSO added. A small amount of DMSO requires the use of more solvents, while more DMSO can be added with a small amount of solvent or no solvent, such as dichloromethane, tetrahydrofuran, chloroform, etc.
  • DIPEA N,N-diisopropylethylamine
  • the method further includes the following step: the above formula (7) is hydrolyzed to obtain the formula (8) wherein “R 2 and R 3 form a carbonyl group together with the carbon of their bond”.
  • the hydrolysis reaction is carried out at 15-40°C, alkaline conditions and solvent medium.
  • the reaction temperature may be room temperature (20-25°C)
  • the base may be selected from organic bases, inorganic bases or mixtures thereof, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, hydroxide
  • organic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, hydroxide
  • potassium carbonate sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate
  • hydroxide One or more of lithium, lithium hydroxide hydrate, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, sodium acetate, triethylamine, pyridine, piperidine.
  • the solvent may be a mixed solvent of water and alcohols, ethers, such as tetrahydrofuran (THF) and dioxane, one or more of acetone, the ratio of water to organic solvent in the mixed solvent (volume ratio) It may be about 1:1 to about 1:6, preferably about 1:4.
  • the hydrolysis reaction is carried out in the presence of a mixed solvent of tetrahydrofuran and water, and lithium hydroxide monohydrate at room temperature.
  • R 2 and R 3 are the same or different, and are independently selected from H and OR a , and R a is Step of formula (8) selected from H, C 1-10 alkyl, R b SO 2 , where R b is C 1-10 alkyl".
  • the reaction is a hydroxyalkylation or sulfonylation reaction known in the art.
  • R 2 and R 3 are both OR a from the formula (8) formed by "R 2 and R 3 together with the carbon of their bond chain” and the step of forming two R a bonding chain C 1-6 alkylene "in formula (8).
  • the reaction is a reaction known in the art for producing ketals.
  • ketones and corresponding diols such as ethylene glycol, propylene glycol, etc.
  • benzene or toluene as a water-carrying agent
  • the formula (8) is an intermediate for constructing C20-C26 structural fragments of soft sponge sponge, especially iribulin or a pharmaceutically acceptable salt thereof.
  • R 4 and R 5 are as described above.
  • the method for preparing the compound of formula (2) includes the above steps of preparing formula (2) from formula (1).
  • the method for preparing the compound of formula (2) further includes the step of recrystallizing once, twice or more times.
  • the method for preparing the compound of formula (2) further includes the step of preparing formula (1) from the oxazolidinone chiral prosthetic group and the corresponding acyl compound.
  • R 4 and X are as described above.
  • the method for preparing the compound of formula (3) includes the above steps of preparing formula (3) from formula (2).
  • the preparation method further includes the preparation method of the compound of formula (2).
  • the step of recrystallizing the compound of formula (2) above is further included.
  • it further comprises the step of preparing formula (1) from the oxazolidinone chiral prosthetic group and the corresponding acyl compound.
  • R 1 is selected from hydroxyl protecting groups
  • R 2 and R 3 are the same or different, and are independently selected from H and OR a , and R a is independently selected from H, C 1-10 alkyl, and R b SO 2 , where R b is C 1-10 alkyl; Or both R 2 and R 3 are OR a , and the two R a bond chains form C 1-6 alkylene; or R 2 and R 3 together with the carbon of their bond chain form a carbonyl group;
  • X is selected from halogen, sulfonyloxy.
  • R 1 is selected from silyl hydroxyl protecting groups, such as TMS, TES, TBDMS, TBDPS, DIPS, DPS, TIPDS and the like.
  • R 2 and R 3 is selected from H, the other is selected from OR a , and R a is H or i-PrSO 2 ; or R 2 and R 3 are both OR a , and the two R a bond chains form a sub N-propane; or R 2 and R 3 together with the carbon of their bond to form a carbonyl;
  • X is selected from chlorine, bromine, iodine and the like.
  • the preparation method of the compound of formula (7) includes the following steps:
  • R 2 and R 3 form a carbonyl group together with the carbon of their bond chain from the oxidation of formula (7) where R 2 and R 3 are H and OH, respectively:
  • the oxidation is any method known to those skilled in the art that can oxidize alcohols to aldehydes or ketones, such as swern oxidation, Pfitzner-Moffatt oxidation, Albright-Goldman oxidation.
  • the oxidation uses the Parikh-Doering oxidation method: dimethyl sulfoxide (DMSO) and sulfur trioxide-pyridine complex (SO3 ⁇ py) at -15 to 25°C under alkaline conditions Reacts with alcohol.
  • DMSO dimethyl sulfoxide
  • SO3 ⁇ py sulfur trioxide-pyridine complex
  • the base may be triethylamine or N,N-diisopropylethylamine (DIPEA); the reaction temperature is preferably 0°C to room temperature (20-25°C); the reaction may optionally be added with a solvent, which Depending on the amount of DMSO added, a small amount of DMSO requires more solvent, while more DMSO can add a small amount of solvent or no solvent, such as dichloromethane, tetrahydrofuran, chloroform, etc.
  • DIPEA N,N-diisopropylethylamine
  • the reaction is carried out in the presence of titanium tetrachloride (TiCl 4 ) and triethylamine (TEA), protected by an inert atmosphere, and the reaction is carried out at a lower temperature of -10 to 10°C, preferably 0°C.
  • the reaction solvent may be dichloromethane (DCM) or the like.
  • R 2 and R 3 are other defined compounds, then R 2 and R 3 can form a carbonyl group or R 2 and R 3 together with the carbon of the bond chain by conventional methods known in the art such as substitution or condensation.
  • the compounds of formula (7) which are H and OH are prepared.
  • the use of compounds of formula (2), formula (3), and formula (7) which are used to prepare soft sponges, especially eribulin, its pharmaceutically acceptable salts and the like .
  • the compounds of formula (2), formula (3), and formula (7) are used to prepare compounds of formula (8).
  • the formula (8) is used to construct soft sponge sponge, especially C20- Intermediate of C26 structural fragment.
  • the following formula is further included: the oxidation reaction of formula (7) wherein R 2 and R 3 are H and OH, respectively, to obtain formula (7) wherein R 2 and R 3 form a carbonyl group together with the carbon of their bond chain:
  • the step of recrystallizing formula (2) once, twice or more times is also included;
  • the step of the above-mentioned oxazolidinone chiral prosthetic group to the compound of formula (1) is also included.
  • a seventh aspect of the present invention there is provided a method for preparing soft sponge sponge, eribulin, its analogues or pharmaceutically acceptable salts thereof, or their C20-C26 parts, including using the above-mentioned oxazolidinone chiral auxiliary Radical, any compound of formula (1) to formula (7), and/or one or more methods for preparing formula (1) to formula (8) described above.
  • the present invention also provides the above-mentioned oxazolidinone chiral prosthetic group, any compound of formula (1) to formula (7) in the preparation of soft sponge, eribulin, its analogs or their C20-C26 part Use in.
  • number of 1 to 10 should be understood as not only describing each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least each of the integers and Sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
  • soft sponge should be understood as a substance having a polyether macrolide structure, which has a C20-C26 structural fragment of iribrin.
  • C 1-10 alkyl is understood to preferably mean a straight or branched chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Group, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-di
  • the group has 1, 2, 3, 4, 5, 6, carbon atoms ("C 1-6 alkyl”), such as methyl, ethyl, propyl, butyl, isopropyl , Isobutyl, sec-butyl, tert-butyl, more particularly, the group has 1, 2 or 3 carbon atoms ("C 1-3 alkyl”), such as methyl, ethyl, n-propyl Base or isopropyl.
  • C 1-3 alkyl such as methyl, ethyl, n-propyl Base or isopropyl.
  • C 1-6 alkylene is understood to preferably mean a linear or branched saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, for example methylene, ethylene, N-propylene, isopropylidene, etc.
  • hydroxyl protecting group means any group capable of protecting the oxygen atom to which it is attached from reaction or bonding. These hydroxyl protecting groups are known in the art. Exemplary hydroxyl protecting groups include, but are not limited to: acyl, ester, carbonate, urethane, sulfonate, and ether groups.
  • exemplary ether hydroxyl protecting groups include C 1-12 alkyl (eg, C 1-8 , C 1-6 , C 1-4 , C 2-7 , C 3-12, and C 3 -6 alkyl), and silyl groups (for example, tri(C 1-6 alkyl) silyl, tri(C 6-10 aryl or C 1-6 heteroaryl) silyl, di( C 6-10 aryl or C 1-6 heteroaryl) (C 1-6 alkyl) silyl and (C 6-10 aryl or C 1-6 heteroaryl) di(C 1-6 alkyl Radical) silyl).
  • silyl groups for example, tri(C 1-6 alkyl) silyl, tri(C 6-10 aryl or C 1-6 heteroaryl) silyl, di( C 6-10 aryl or C 1-6 heteroaryl) (C 1-6 alkyl) silyl and (C 6-10 aryl or C 1-6 heteroaryl) di(C 1-6 alkyl Radical) silyl).
  • alkyl group examples include methyl and t-butyl
  • silyl group examples include trimethylsilyl (TMS), triethylsilyl (TES), and t-butyldimethylsilyl ( TBS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS) and triphenylsilyl (TPS) ether groups, TBDMS, DIPS, DPS, TIPDS, etc.
  • the hydroxy protecting group as defined above can be deprotected using a remover.
  • the hydroxy protecting group removers are those reagents that can react with compounds having protected hydroxyl groups to provide compounds having deprotected hydroxyl groups.
  • the hydroxyl protecting group remover and deprotection reaction conditions may be those known in the art.
  • the hydroxyl group masked as the silyl ether can be unmasked by reaction with a fluoride source (eg, fluoride salt, such as KF or TBAF).
  • a fluoride source eg, fluoride salt, such as KF or TBAF
  • the hydroxyl group protected as TMS or TES ether can be deprotected by reaction with Bronsted acid (eg, carboxylic acid).
  • the hydroxyl group protected as an ester can be deprotected by reaction with a C 1-6 alkoxide (eg, an alkali metal C 1-6 alkoxide or an alkaline earth metal C 1-6 alkoxide) .
  • a C 1-6 alkoxide eg, an alkali metal C 1-6 alkoxide or an alkaline earth metal C 1-6 alkoxide
  • the hydroxyl group protected as an aryl alkyl ether eg, 1-arylalkyl-1-yl ether
  • a reduction reaction eg, with Pd/C and H 2 , or with Na/NH 3
  • the hydroxy group protected as an alkoxy-aryl alkyl ether eg, MPM ether
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • the hydroxy group protected as an alkoxyalkyl ether eg, 1-alkoxyalkyl-1-yl
  • THP ether can be deprotected by reaction with Bronsted acid .
  • Cyclic protected diols eg acetals or ketals (eg 2-alkyl-1,3-dioxolane, 2,2-dialkyl-1,3-dioxolane, 2- Alkyl-1,3-dioxane or 2,2-dialkyl-1,3-dioxane)
  • Bronsted acid eg, carboxylic acid
  • the sulfonyloxy group in the present invention may be an alkylsulfonyloxy group (for example, C 1-10 alkyl group), an alkenylsulfonyloxy group (for example, C 2-10 alkenyl group), and an arylsulfonyloxy group.
  • Examples include but are not limited to: methanesulfonyloxy, tosyloxy (eg p-toluenesulfonyloxy), trifluoromethanesulfonyloxy, nitrobenzenesulfonyloxy (o, p-nitro Benzenesulfonyloxy), bromobenzenesulfonyloxy (o, p-bromobenzenesulfonyloxy).
  • the silyl group in the present invention may be tri(C 1-6 alkyl) silyl group, tri(C 6-10 aryl group or C 6-10 heteroaryl group) silyl group, di(C 6-10 Aryl or C 6-10 heteroaryl) (C 1-6 alkyl) silyl and (C 6-10 aryl or C 6-10 heteroaryl) di(C 1-6 alkyl) monosilane base).
  • silyl examples include, but are not limited to, trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS), t-butyldiphenylmethyl Silyl (TBDPS), triisopropylsilyl (TIPS) and triphenylsilyl (TPS) ether, TBDMS, DIPS, DPS, TIPDS, etc.
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TSS t-butyldimethylsilyl
  • TDPS t-butyldiphenylmethyl Silyl
  • TIPDS triphenylsilyl
  • Suitable substituents on phenyl or benzyl in the present invention include, but are not limited to: halogen (fluorine, chlorine, bromine, iodine), C 1-10 alkyl, C 1-10 alkoxy, hydroxyl, nitrate Group, amino group, amino group substituted with one or two C 1-10 alkyl groups, SO 3 H, SO 3 C 1-10 alkyl group.
  • the base of the present invention may be an organic base, an inorganic base or a mixture thereof, for example, selected from alkali metal or alkaline earth metal carbonates or bicarbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, carbonic acid Sodium bicarbonate, potassium bicarbonate, calcium bicarbonate; alkali metal alkoxides, such as sodium tert-butoxide or potassium tert-butoxide; organic lithium such as butyllithium or phenyllithium; alkali metal hydrides, such as sodium hydride or potassium hydride; Amides, such as lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide or lithium diisopropylamide (LDA); organic amines, such as triethylamine, N-methyl Morpholine, piperidine, N-methylpiperidine, N,N-diisopropylethylamine, 1,5-diazabicyclo[4.3.0]
  • the acid according to the present invention may be an organic acid, an inorganic acid, or a mixture thereof, for example, one or more selected from the following: hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid; carboxylic acid, such as acetic acid or trifluoroacetic acid; sulfonic acid, for example Methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid; phosphonic acid; hydrochloric acid, sulfuric acid, phosphoric acid.
  • the acid also includes Lewis acid.
  • the Lewis acid may be selected from, for example, BF 3 ⁇ OEt 2 , MgCl 2 , MgBr 2 , ZnBr 2 , ZnI 2 , ZnCl 2 , ZnSO 4 , CuCl 2 , CuCl, Cu(O 3 SCF 3 ) 2 , CoCl 2 , CoI 2 , FeI 2 , FeCl 3 , FeCl 2 , FeCl 2 , SnCl 4 , TiCl 4 , TiCl 3 , MnCl 2 , ScCl 3 , AlCl 3 , (iC 4 H 9 ) 2 AlCl, (C 6 H 5 ) 2 AlCl, (C 6 H 5) AlCl 2, ReCl 5, ZrCl 4, NbCl 5, VCl 3, CrCl 2, MoCl 5, YCl 3, CdCl 2, LaCl 3, Er (O 3 SCF 3) 3, Yb (O 2 CCF 3 ) 3 , S
  • the solvent of the present invention may include one or a mixture of two or more selected from the following: water; ketone solvents, such as acetone and methyl ethyl ketone; ether solvents, including acyclic ethers and cyclic ethers, for example Diethyl ether, tetrahydrofuran, dioxane; ester solvents, such as ethyl acetate or butyl acetate; alkane solvents, such as n-hexane or n-heptane; halogenated alkane solvents, such as monochloromethane, methylene chloride, trichloromethane Methane, carbon tetrachloride, 1,2-dichloroethane; naphthenic solvents such as cyclohexane or cycloheptane; substituted or unsubstituted aromatic solvents such as benzene, toluene, xylene and chlorobenzene;
  • the solvent is selected from inert solvents that are inactive to the reaction substrate and catalyst.
  • the inert solvent may be selected from, for example, alcohol solvents (such as methanol, ethanol), ether solvents (such as diethyl ether, tetrahydrofuran, dioxane), halogenated alkane solvents (such as dichloromethane, chloroform, One or more of carbon tetrachloride, 1,2-dichloroethane), substituted or unsubstituted aromatic hydrocarbons (such as benzene, toluene, chlorobenzene).
  • alcohol solvents such as methanol, ethanol
  • ether solvents such as diethyl ether, tetrahydrofuran, dioxane
  • halogenated alkane solvents such as dichloromethane, chloroform, One or more of carbon tetrachloride, 1,2-dichloroethane
  • the solvent in the present invention is an anhydrous solvent.
  • the present invention provides intermediates that can be used to synthesize soft sponge sponge, eribulin or its analogues, especially its C20-C26 structural fragment, its preparation method and use.
  • the starting materials of the synthetic route of the present invention are cheap and readily available, and the compounds of formula (2) and formula (3) are both crystalline, which can improve the purity of the product by a simple recrystallization purification method.
  • the optical purity can be obtained higher than 99.9%, and the configuration of the chiral carbon atom linked to the ⁇ -position methyl group of the compound will not be changed in the subsequent steps , So as to ensure the optical purity of soft sponge, eribulin or the like in C20-C26.
  • the method for constructing the chiral center of the C20-26 structural fragment of the present invention has high diastereoselectivity and yield, and its by-products only need to be removed by simple methods such as recrystallization. All the process steps are carried out under relatively mild reaction conditions, especially the step of preparing the compound of formula (8) by the compound of formula (7), which avoids the thermal decomposition loss of the product caused by high temperature heating; the whole set of preparation methods, especially The products in the front-end step are crystalline solids, which are easy to purify and refine. Based on the above advantages, the method of the present invention has low cost, high yield and purity, and simple refining and purification, so it is more suitable for industrial mass production.
  • FIG. 1 Synthesis circuit diagram of Embodiment 1 of the present invention.
  • the organic phase was sequentially saturated with sodium bicarbonate and saturated sodium chloride. Wash once, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate. Distillation under reduced pressure, collecting 80 g of fractions (38-42°C). The yield is 45%.
  • Mg particles (8.4g) and iodine particles (1-2 particles) were added to a three-necked bottle, and argon gas was changed and protected with argon gas.
  • Dissolve (1-bromovinyl)trimethylsilane (62.7g) in dry THF (159ml) add part of it (20ml) to the above three-necked flask at room temperature, heat the three-necked flask to the reaction flask Initiate the reaction, reflux, continue dropping, keep the reflux state, after the drop, move the reaction bottle to an oil bath and heat to reflux for 1h.
  • the Grignard reagent is prepared.
  • TLC monitored the disappearance of the compound at 1 o'clock, slowly added saturated ammonium chloride solution to quench, and vigorously stirred for 4-6h to obtain a clear two-phase, liquid separation, the aqueous phase was extracted twice with ethyl acetate, the organic phase was combined and saturated brine Washed twice, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 57g of crude product. Dissolve the crude product in 570ml of n-hexane at room temperature, place it in a -20°C refrigerator, and let it stand for crystallization. The next day, it was filtered while cold and washed with cold n-hexane to obtain 42 g of white solid. After the second recrystallization, the purity was 99.94%.
  • the raw material 3 (14.27g) was dissolved in a mixed solution of THF-H 2 O (148ml-37ml), and then the temperature was lowered to about -5°C, and hydrogen peroxide (35%, 15.8ml) was added in sequence.
  • Aqueous solution (3.1g/30ml H 2 O), after completion of the drop, keep the reaction at 0°C for 2h.
  • Step 1 Add 1,4-butanediol (100ml) to a 2000ml three-necked bottle at room temperature, then add DCM (1300ml), triethylamine (59ml) and DMAP (4.7g), then slowly add TBSCl. After the drop, the reaction was kept at room temperature overnight (about 17h). TLC monitoring showed that the raw material point of TBSCl disappeared, quenched by adding saturated ammonium chloride solution, liquid separation, the aqueous layer was extracted twice with DCM, the organic phases were combined and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated . Separated and purified by column chromatography to obtain 108g syrup-like product with a yield of 80%.
  • Step 2 Dissolve 4-((tert-butyldiphenylsilyl)oxy)butanol (11.6g) in dry DCM (71ml), then drop to 0°C, then add dry DMSO (12.6ml) and DIPEA (15.4ml), then add sulfur trioxide pyridine (11.3g) in batches, keeping the internal temperature ⁇ 10 °C. After the addition was completed, the temperature was raised to room temperature and the reaction was performed for 0.5-1h. TLC monitoring showed that the starting point disappeared. The reaction was quenched by adding water, and then washed once with 1N dilute hydrochloric acid. The aqueous layer was extracted once with DCM.
  • the starting material 7 (10.4g) was dissolved in a mixed solvent of THF and H 2 O (120ml / 30ml), the room temperature was added lithium hydroxide monohydrate (6.54 g), kept at room temperature the reaction was stirred for 6-8h. After the reaction was completed, water was added to separate the liquid. The aqueous phase was extracted with n-hexane. The THF layer was concentrated under reduced pressure and dissolved with n-hexane. The organic phases were combined and washed with saturated sodium dihydrogen phosphate, saturated brine, and dried over anhydrous sodium sulfate. Filter and concentrate. Column chromatography purification yielded 7.08g with a yield of 87%.

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Abstract

本发明涉及用于制备软海绵素类化合物的中间体及其制备方法和用途，尤其是涉及用于制备软海绵素、艾日布林或其类似物的中间体、其制备方法和用途。所述中间体、其制备方法和用途用于构建软海绵素类化合物的C20-C26结构片段。本发明合成路线的起始原料廉价易得，来源稳定且质量可靠；手性中心构建构方法的选择上充分利用了反应物本身的结构特点，切实提高了合成效率，降低了产品质量控制的难度和风险；并且避免使用高毒性且昂贵的有机锡催化剂，显著改善了成本和环境友好性。

Description

用于制备软海绵素类化合物的中间体及其制备方法
本申请要求2018年12月10日向中国国家知识产权局提交的专利申请号为2018115084811，发明名称为“用于制备软海绵素类化合物的中间体及其制备方法”的在先申请的优先权，该在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及可用于制备软海绵素或其类似物、特别是艾日布林的中间体化合物、以及这些中间体化合物的制备方法，属于有机合成技术领域。
背景技术
软海绵素(Halichondrin，以下简称HB)是一类存在于海绵体内、具有聚醚大环内酯结构的天然产物，这类物质具有强烈的抗肿瘤作用和广阔的药用前景。基于其结构差异，这类天然产物被分为以下几类：去甲软海绵素(norhalichondrin)、软海绵素(Halichondrin)、高软海绵素(homohalichondrin)等，且每一类都有一系列代表亚型，所述亚型和具体结构是本领域已知的，且详细公开于WO2016003975A1中，在此全文引入该现有技术文献；艾日布林(Eribulin，以下简称EB)是一种软海绵素的结构简化类似物，目前已在临床上用于治疗晚期乳腺癌和脂肪肉瘤。
Figure PCTCN2019116349-appb-000001
HB和EB均无法从天然来源大量获取，只能依赖于人工合成。由于这类化合物结构类似，特别是C1-C29部分具有完全相同的结构，为此可将适宜的中间体化合物用于合成此类化合物。例如，可将下式1a和式4所示的中间体用于构建艾日布林的C20-C35的片段部分。
Figure PCTCN2019116349-appb-000002
或者，可用下式1b和式6所示的中间体构建艾日布林的C20-C35的片段部分。
Figure PCTCN2019116349-appb-000003
然而，现有技术中，上述式4或式6化合物的制备方法存在诸多缺陷，例如，合成路线过于冗长，起始原料光学纯度难以控制，涉及高毒性且昂贵的n-Bu 3S nH试剂，立体选择性不佳等。这些缺陷会带来成本控制、环境和劳动保护、产品品质等一系列的生产问题。因此，亟需开发可改善合成效率、改善生产成本、易于工业化大规模生产、提高选择性、产率和纯度、且环境友好的中间体或合成方法，以改善软海绵素类药物化合物的制备方法。
发明内容
为改善上述问题，本发明提供如下的用于构建软海绵素及其类似物，尤其是艾日布林的C20-C26结构片段的中间体及其制备方法。
本发明第一方面，提供式(8)化合物的制备方法，所述式(8)如下定义：
Figure PCTCN2019116349-appb-000004
其中，R 1选自羟基保护基；
R 2、R 3相同或不同，彼此独立地选自H和OR a，R a独立的选自H、C 1-10烷基、R bSO 2，其中R b为C 1-10烷基；或者R 2和R 3均为OR a，且两个R a键链形成C 1-6亚烷基；或者R 2和R 3与其键链的碳一起形成羰基；
X选自卤素、磺酰氧基。
示例性的，R 1选自甲硅烷类羟基保护基，例如TMS、TES、TBDMS、TBDPS、DIPS、DPS、TIPDS等。
示例性的，R 2、R 3中的一个选自H，另一个选自OR a，且R a为H或i-PrSO 2；或者R 2和R 3均为OR a，且两个R a键链形成亚正丙烷基；或者R 2和R 3与其键链的碳一起形成羰基；
示例性的，X选自氯、溴、碘等。
所述方法包括如下步骤：
Figure PCTCN2019116349-appb-000005
其中，式(2)中的R 5选自甲硅烷基，例如TMS、TES、TBDMS、TBDPS、DIPS、DPS、TIPDS等；式(1)、式(2)中的噁唑烷酮结构部分为噁唑烷酮类手性辅基，例如：R 4为C 1-10烷基，取代或未取代的苯基，或取代或未取代的苄基的2-氧代噁唑烷酮。优选地，所述R 4是异丙基，未取代的或羟基、硝基、二甲氨基单取代或多取代的苯基或苄基。
优选地，还包括将式(2)重结晶一次、二次或多次的步骤。
根据本发明，所述式(2)由式(1)与格氏试剂R 6MgX或R 6Li反应得到，R 6为
Figure PCTCN2019116349-appb-000006
根据本发明，所述反应在亚铜盐，如氯化亚铜、溴化亚铜、碘化亚铜(CuI)或氰化亚铜等存在下，，惰性气氛，-50℃～0℃和溶剂中进行。所述溶剂可以是四氢呋喃或无水乙醚，亚铜盐的用量(质量)约为反应物式(1)的10-25％，优选地为15-20％。
根据本发明，由式(1)制备式(2)后，将式(2)重结晶即可控制降低其光学异构体的含量。所述重结晶的溶剂是那些在室温或略高于室温溶解式(2)、在较低温度下(例如-10～-30℃)可析晶的任何溶剂，例如非极性有机溶剂，优选烷烃，其实例可以是正戊烷、正己烷、正庚烷、异辛烷，或其混合溶剂，例如石油醚。
优选地，所述重结晶可多次反复进行。经过一次重结晶，本发明式(2)的异构体含量可控制在1％及以下，两次重结晶异构体含量可控制在1‰及以下，经过多次重结晶，异构体含量可控制在更低范围内。本领域技术人员可以理解，本发明式(2)中β-甲基所连接的手性碳原子的构型在后续的转化过程中不会再发生改变，因此与该手性碳的构型相关的纯度将得以保持。
根据本发明，所述格氏试剂的制备方法包括以下步骤：
乙烯基硅烷
Figure PCTCN2019116349-appb-000007
与卤代试剂在较低温度(例如-30～-10℃)下混合，室温下加入缚酸剂，回流反应得到卤代乙烯基硅烷。所述缚酸剂可以是有机弱碱或无机弱碱，例如是二乙胺，乙二胺，三乙胺，二异丙基胺，吡啶，碳酸钾，碳酸钠，碳酸铯等。
上述卤代乙烯基硅烷在非质子性溶剂中与金属镁或金属锂反应生成相应的格氏试剂或锂试剂。所述非质子性溶剂可以是醚类溶剂，如乙醚，二异丙醚，叔丁基甲基醚，环己基甲基醚，四氢呋喃，二氧六环等，或者烃类溶剂，如正戊烷，正己烷，正庚烷，苯，甲苯，二甲苯等。
或者，上述卤代乙烯基硅烷也可在如上所述溶剂中与其他易得格氏试剂，如甲基，乙基，正丙基，异丙基格氏试剂等，或易得烷基锂试剂，如甲基，正丁基，仲丁基，叔丁基锂，进行金属-卤素交换反应，生成相应的格氏试剂或锂试剂。
根据本发明上述式(8)化合物的制备方法，进一步包括由式(2)至式(3)的如下步骤：
Figure PCTCN2019116349-appb-000008
其中，式(3)的X为卤素或磺酰氧基。
根据本发明，所述反应是本领域技术人员已知的卤代反应，其在合适的溶剂中，温和的反应温度下，例如0℃至室温的条件下进行。所用卤代试剂可以是X 2、RCO 2X、R nSiX 4-n，其中X选自氯、溴、碘的卤素，且X 2中的两个X可不同，R选自C 1-10烷基或氟代C 1-10烷基，n为1～3的整数。所述卤代试剂的实例可以是氯、溴、碘的单质，BrCl，ICl，TMSCl，TMSI，CF 3CO 2I等。
或者，本发明的制备方法，还进一步包括将X为卤素的式(3)化合物根据本领域已知的取代反应进一步转化为X为磺酰氧基的式(3)化合物。
根据本发明上述式(8)化合物的制备方法，进一步包括如下步骤：
由噁唑烷酮类手性辅基与相应的酰基化合物制备式(1)化合物
Figure PCTCN2019116349-appb-000009
根据本发明，所述反应在碱性、低温条件下(-80℃～-20℃)进行，所述反应可选的使用催化量的氯化锂和溶剂。所述碱选自有机碱、无机碱或其混合物，例如碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、氢氧化钠、氢氧化钾、碳酸铯、三乙胺、吡啶、哌啶、 正丁基锂(n-BuLi)中的一种或多种。所述溶剂例如是四氢呋喃、N，N-二甲基甲酰胺(DMF)、二氯乙烷、乙醚、四氯化碳、甲苯等；所述酰基化合物可以是酯、羧酸、酰卤或酸酐。根据本发明的一个实施方式，所述噁唑烷酮类手性辅基与酰卤在-80～-60℃、四氢呋喃为溶剂、氩气保护和正丁基锂的存在下反应，所述正丁基锂的质量用量约为噁唑烷酮的30-50％；或者所述噁唑烷酮类手性辅基与酸酐在-30～-20℃、四氢呋喃为溶剂、氯化锂和三乙胺的存在下反应，所述氯化锂的质量用量约为噁唑烷酮的35％-55％。
根据本发明上述式(8)化合物的制备方法，进一步包括如下步骤：由式(3)制备式(4)：
Figure PCTCN2019116349-appb-000010
所述反应在脱除分离噁唑烷酮手性辅基的条件下进行，优选在碱性条件下水解去除。
根据本发明，所述反应在-15～5℃、碱性条件和溶剂介质，以及可选的过氧化氢中进行。所述反应温度可以是-10～0℃，优选-5～0℃。所述的碱可以选自有机碱、无机碱或其混合物，例如碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、碳酸铯、氢氧化锂、氢氧化锂水合物、氢氧化钠、氢氧化钾、氢氧化钙、氨水、醋酸钠、三乙胺、吡啶、哌啶中的一种或多种。所述溶剂是水与醇类，醚类，例如四氢呋喃(THF)或二氧六环，丙酮中的一种或多种形成的混合溶剂，混合溶剂中水与有机溶剂的比例(体积比)可以为约1:1～约1:6，优选为约1:2～1:3。作为本发明的一个实施方式，所述反应在-5～0℃、四氢呋喃与水的混合溶剂、一水合氢氧化锂、过氧化氢的存在下进行，所述化合物式(3)与过氧化氢与一水合氢氧化锂的质量比为12-20:3-9:1-6。
根据本发明上述式(8)化合物的制备方法，进一步包括如下步骤：由式(4)制备式(5)：
Figure PCTCN2019116349-appb-000011
根据本发明，所述反应在偶联剂的存在下进行，所述偶联剂可以是EDCI/DMAP，EDC/DMAP，EDC/NHS，DCC/NHS体系，所述反应在15-40℃，优选室温(20-25℃)下反应。反应溶剂可以是二氯甲烷(DCM)、四氢呋喃(THF)和二甲基甲酰胺(DMF)等。
根据本发明上述式(8)化合物的制备方法，进一步包括如下步骤：由式(5)和醛制备式(6)：
Figure PCTCN2019116349-appb-000012
根据本发明，所述反应在四氯化钛(TiCl 4)和三乙胺(TEA)的存在下，以惰性气氛保护，在较低温度-10～10℃，优选0℃，进行反应，所述反应溶剂可以是二氯甲烷(DCM)等。
根据本发明，上述醛的制备方法，包括如下步骤：
(I)丁二醇与R nSiX 4-n在偶联剂的存在下反应得到单羟基保护的产物；
其中X选自氯、溴、碘的卤素，R选自C 1-10烷基或氟代C 1-10烷基，n为1～3的整数。所述卤代硅烷R nSiX 4-n的实例可以是TMSCl，TMSI，TBDPSCl，TBDPSI等。
所述偶联剂可以是EDCI/DMAP，EDC/DMAP，EDC/NHS，DCC/NHS体系，所述反应在15-40℃，优选室温(20-25℃)下反应。反应溶剂可以是二氯甲烷(DCM)、四氢呋喃(THF)和二甲基甲酰胺(DMF)等。
(II)氧化步骤(I)的产物。
所述氧化是如下文所述的将醇氧化为醛或酮的任一方法。
根据本发明上述式(8)化合物的制备方法，进一步包括如下步骤：由式(6)制备式(7)：
Figure PCTCN2019116349-appb-000013
根据本发明，所述氧化是本领域技术人员已知的可实现将醇氧化为醛或酮的任何方法，例如swern氧化、Pfitzner-Moffatt氧化、Albright–Goldman氧化法。作为本发明的一个实施方式，所述氧化采用Parikh–Doering氧化法：二甲亚砜(DMSO)和三氧化硫-吡啶络合物(SO 3·py)在-15～25℃、碱性条件下与醇反应。所述碱可以是三乙胺或N,N-二异丙基乙胺(DIPEA)；所述反应温度优选为0℃至室温(室温为20-25℃)；所述反应可选的加入溶剂，这取决于DMSO的加入量，少量DMSO则需使用较多的溶剂，而较多的DMSO则可加入少量溶剂或不使用溶剂，所述溶剂例如是二氯甲烷、四氢呋喃、氯仿等。
根据本发明上述式(8)化合物的制备方法，进一步包括如下步骤：上述式(7)水解，得到“R 2和R 3与其键链的碳一起形成羰基”的式(8)。
根据本发明，所述水解反应，其在15-40℃、碱性条件和溶剂介质中进行。所述反 应温度可以是室温(20-25℃)，所述的碱可以选自有机碱、无机碱或其混合物，例如碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、碳酸铯、氢氧化锂、氢氧化锂水合物、氢氧化钠、氢氧化钾、氢氧化钙、氨水、醋酸钠、三乙胺、吡啶、哌啶中的一种或多种。所述溶剂可以是水与醇类，醚类，例如四氢呋喃(THF)和二氧六环，丙酮中的一种或多种形成的混合溶剂，混合溶剂中水与有机溶剂的比例(体积比)可以为约1:1-约1:6，优选为约1:4。作为本发明的一个实施方式，水解反应在室温、四氢呋喃与水的混合溶剂、一水合氢氧化锂存在下进行。
根据本发明上述式(8)化合物的制备方法，任选地，包括由式(6)化合物进一步得到“R 2、R 3相同或不同，彼此独立地选自H和OR a，R a独立的选自H、C 1-10烷基、R bSO 2，其中R b为C 1-10烷基”的式(8)的步骤。所述反应是本领域所公知的羟基烷基化或磺酰化反应。
根据本发明上述式(8)化合物的制备方法，任选地，包括由“R 2和R 3与其键链的碳一起形成羰基”的式(8)形成“R 2和R 3均为OR a，且两个R a键链形成C 1-6亚烷基”的式(8)的步骤。所述反应是本领域公知的生产缩酮的反应，例如，酮与相应的二醇，例如乙二醇，丙二醇等，在对甲苯磺酸催化下，用苯或甲苯做带水剂，可得到所述缩酮。
根据本发明，所述式(8)是构建软海绵素，尤其是艾日布林或其可药用盐的C20-C26结构片段的中间体。
本发明第二方面，提供下式(2)所示的化合物及其制备方法：
Figure PCTCN2019116349-appb-000014
其中R 4、R 5的定义如上所述。
式(2)化合物的制备方法，包括上述的由式(1)制备式(2)的步骤。
根据本发明，所述式(2)化合物的制备方法，还进一步包括上述的重结晶一次、两次或多次的步骤。
根据本发明，所述式(2)化合物的制备方法，还进一步包括由噁唑烷酮类手性辅基与相应的酰基化合物制备式(1)的步骤。
本发明第三方面，提供下式(3)所示的化合物及其制备方法：
Figure PCTCN2019116349-appb-000015
其中，R 4、X的定义如上所述。
式(3)化合物的制备方法，包括上述由式(2)制备式(3)的步骤。
根据本发明，所述制备方法还进一步包括上述式(2)化合物的制备方法。优选地，还进一步包括上述的式(2)化合物一次、两次或多次重结晶的步骤。
优选地，还进一步包括由噁唑烷酮类手性辅基与相应的酰基化合物制备式(1)的步骤。
本发明第四方面，提供下式(7)所示的化合物及其制备方法：
Figure PCTCN2019116349-appb-000016
其中，R 1选自羟基保护基；
R 2、R 3相同或不同，彼此独立地选自H和OR a，R a独立的选自H、C 1-10烷基、R bSO 2，其中R b为C 1-10烷基；或者R 2和R 3均为OR a，且两个R a键链形成C 1-6亚烷基；或者R 2和R 3与其键链的碳一起形成羰基；
X选自、卤素、磺酰氧基。
优选地，R 1选自甲硅烷类羟基保护基，例如TMS、TES、TBDMS、TBDPS、DIPS、DPS、TIPDS等。
R 2、R 3中的一个选自H，另一个选自OR a，且R a为H或i-PrSO 2；或者R 2和R 3均为OR a，且两个R a键链形成亚正丙烷基；或者R 2和R 3与其键链的碳一起形成羰基；
X选自氯、溴、碘等。
所述式(7)化合物的制备方法，包括以下步骤：
方法一：R 2和R 3与其键链的碳一起形成羰基的式(7)由R 2、R 3分别为H和OH的式(7)氧化得到：
Figure PCTCN2019116349-appb-000017
根据本发明，所述氧化是本领域技术人员已知的可实现将醇氧化为醛或酮的任何方法，例如swern氧化、Pfitzner-Moffatt氧化、Albright–Goldman氧化法。作为本发明的一个实施方式，所述氧化采用Parikh–Doering氧化法：二甲亚砜(DMSO)和三氧化硫-吡啶络合物(SO3·py)在-15～25℃、碱性条件下与醇反应。所述碱可以是三乙胺或N,N-二异丙基乙胺(DIPEA)；所述反应温度优选为0℃至室温(20-25℃)；所述 反应可选的加入溶剂，这取决于DMSO的加入量，少量DMSO则需使用较多的溶剂，而较多的DMSO则可加入少量溶剂或不使用溶剂，所述溶剂例如是二氯甲烷、四氢呋喃、氯仿等。
方法二：R 2、R 3分别为H和OH的式(7)由下式化合物(5)制备得到：
Figure PCTCN2019116349-appb-000018
根据本发明，所述反应在四氯化钛(TiCl 4)和三乙胺(TEA)的存在下，以惰性气氛保护，在较低温度-10～10℃，优选0℃，进行反应，所述反应溶剂可以是二氯甲烷(DCM)等。
式(7)中R 2和R 3为其他定义的化合物，则可通过本领域公知的取代或缩合等常规方法，由R 2和R 3与其键链的碳一起形成羰基或者R 2、R 3分别为H和OH的式(7)化合物制备得到。
本发明第五方面，还提供化合物式(2)、式(3)、式(7)的用途，其用于制备软海绵素、尤其是艾日布林，其可药用盐及其类似物。具体的，所述式(2)、式(3)、式(7)化合物用于制备式(8)化合物，所述式(8)是构建软海绵素，尤其是艾日布林的C20-C26结构片段的中间体。
本发明第六方面，提供上文式(8)化合物的制备方法，所述方法包括如下步骤：
Figure PCTCN2019116349-appb-000019
根据本发明式(8)化合物的制备方法，
优选地，还包括下式由R 2、R 3分别为H和OH的式(7)氧化反应得到R 2和R 3与其键链的碳一起形成羰基的式(7)的步骤：
Figure PCTCN2019116349-appb-000020
优选地，还包括下式的式(5)和式(6)制备R 2、R 3分别为H和OH的式(7)的步骤：
Figure PCTCN2019116349-appb-000021
优选地，还包括上文所述的由式(4)到式(5)化合物的步骤；
优选地，还包括上文所述的由式(3)到式(4)化合物的步骤；
优选地，还包括上文所述的由式(2)到式(3)化合物的步骤；
优选地，还包括上文所述的由式(1)到式(2)化合物的步骤；
优选地，还包括将式(2)重结晶一次、二次或多次的步骤；
优选地，还包括上文所述的噁唑烷酮类手性辅基到式(1)化合物的步骤。
本发明第七方面，提供一种制备软海绵素、艾日布林、其类似物或其可药用盐，或它们的C20-C26部分的方法，包括使用上述噁唑烷酮类手性辅基、式(1)至式(7)中的任一化合物，和/或使用上述一种或多种制备式(1)至式(8)的方法。
本发明还提供上述噁唑烷酮类手性辅基、式(1)至式(7)中的任一化合物在制备软海绵素、艾日布林、其类似物或它们的C20-C26部分中的用途。
本发明如上所描述的化合物符号、基团定义、反应条件，除有列外说明的，均与其前文具有相同定义或含义。
术语和定义
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文引用的所有专利、专利申请、公开材料的全文通过引用方式整体并入本文。
本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“0～10的整数”应当理解为记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数。当该数值范围被理解为“数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数以及该范围内的每一个小数。例如，“1～10的数”应当被理解为不仅记载了1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
术语“软海绵素、其类似物”应理解为具有聚醚大环内酯结构的物质，其具有艾日布林的C20-C26结构片段。例如艾日布林、去甲软海绵素A-C(norhalichondrin)、软海绵素B-C(Halichondrin)、高软海绵素A-C(homohalichondrin)，或其可药用盐，例如与药学上可接受的酸形成的盐，如甲磺酸盐，如艾日布林甲磺酸盐。
术语“C 1-10烷基”应理解为优选表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直连或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、 1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2、3、4、5、6、个碳原子(“C 1-6烷基”)，例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基，更特别地，所述基团具有1、2或3个碳原子(“C 1-3烷基”)，例如甲基、乙基、正丙基或异丙基。
术语“C 1-6亚烷基”应理解为优选表示具有1、2、3、4、5或6个碳原子的直链或支链饱和二价烃基，例如亚甲基、亚乙基、亚正丙基，亚异丙基等。
术语“羟基保护基”意指任何能够保护其连接的氧原子免于反应或成键的基团。这些羟基保护基是本领域已知的。示例性的羟基保护基包括但不限于：酰基、酯基、碳酸酯基、氨基甲酸酯基、磺酸酯基和醚基。
如本文所定义，示例性的醚基羟基保护基包括C 1-12烷基(例如，C 1-8、C 1-6、C 1-4、C 2-7、C 3-12和C 3-6烷基)、和甲硅烷基类(例如，三(C 1-6烷基)甲硅烷基、三(C 6-10芳基或C 1-6杂芳基)甲硅烷基、二(C 6-10芳基或C 1-6杂芳基)(C 1-6烷基)甲硅烷基和(C 6-10芳基或C 1-6杂芳基)二(C 1-6烷基)甲硅烷基)。烷基的具体实例包括甲基和叔丁基，甲硅烷基的具体实例包括三甲基甲硅烷基(TMS)、三乙基甲硅烷基(TES)、叔丁基二甲基甲硅烷基(TBS)、叔丁基二苯基甲硅烷基(TBDPS)、三异丙基甲硅烷基(TIPS)和三苯基甲硅烷基(TPS)醚基、TBDMS、DIPS、DPS、TIPDS等。
如上文所定义的羟基保护基，可使用去除剂脱保护。所述羟基保护基去除剂是可以与具有被保护的羟基的化合物反应以提供具有去保护的羟基的化合物的那些试剂。羟基保护基去除剂和去保护反应条件可以是本领域已知的那些。在一个非限制性实例中，被掩蔽为甲硅烷基醚的羟基可以通过与氟化物源(例如，氟化物盐，例如KF或TBAF)的反应来去掩蔽。备选地，被保护为TMS或TES醚的羟基可以通过与布朗斯台德酸(例如，羧酸)的反应来去保护。在另一个非限制性实例中，被保护为酯的羟基可以通过与C 1-6醇盐(例如，碱金属C 1-6醇盐或碱土金属C 1-6醇盐)的反应来去保护。在又一个非限制性实例中，被保护为芳基烷基醚(例如，1-芳基烷-1-基醚)的羟基可以利用还原反应(例如，与Pd/C和H 2，或与Na/NH 3)来去保护。备选地，被保护为烷氧基-芳基烷基醚(例如，MPM醚)的羟基可以通过与2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)的反应来去保护。在又一个非限制性实例中，被保护为烷氧基烷基醚(例如，1-烷氧基烷-1-基)或THP醚的羟基可以通过与布朗斯台德酸的反应来去保护。环状被保护的二醇(例如缩醛或缩酮(例如，2-烷基-1,3-二氧戊烷、2,2-二烷基-1,3-二氧戊烷、2-烷基-1,3-二噁烷或2,2-二烷基-1,3-二噁烷))可以通过与布朗斯台德酸(例如，羧酸)反应来去保护。
本发明所述的磺酰氧基可以是烷基磺酰氧基(例如C 1-10烷基)，烯基磺酰氧基(例如C 2-10烯基)，芳基磺酰氧基。所述实例包括但不限于：甲磺酰氧基、甲苯磺酰氧基(例如对甲苯磺酰氧基)、三氟甲磺酰氧基、硝基苯磺酰氧基(邻、对硝基苯磺酰氧基)、溴苯磺酰氧基(邻、对溴基苯磺酰氧基)。
本发明所述的甲硅烷基可以是三(C 1-6烷基)甲硅烷基、三(C 6-10芳基或C 6-10杂芳基) 甲硅烷基、二(C 6-10芳基或C 6-10杂芳基)(C 1-6烷基)甲硅烷基和(C 6-10芳基或C 6-10杂芳基)二(C 1-6烷基)甲硅烷基)。甲硅烷基的具体实例包括但不限于三甲基甲硅烷基(TMS)、三乙基甲硅烷基(TES)、叔丁基二甲基甲硅烷基(TBS)、叔丁基二苯基甲硅烷基(TBDPS)、三异丙基甲硅烷基(TIPS)和三苯基甲硅烷基(TPS)醚基、TBDMS、DIPS、DPS、TIPDS等。
本发明所述的合适的苯基或苄基上的取代基包括但不限于：卤素(氟、氯、溴、碘)，C 1-10烷基，C 1-10烷氧基，羟基，硝基，氨基，被一或二C 1-10烷基取代的氨基，SO 3H,SO 3C 1-10烷基。
本发明所述的碱可以为有机碱、无机碱或其混合物，例如选自碱金属或者碱土金属碳酸盐或碳酸氢盐，例如碳酸锂、碳酸钠、碳酸钾、碳酸钙、碳酸铯、碳酸氢钠、碳酸氢钾、碳酸氢钙；碱金属醇盐，例如叔丁醇钠或者叔丁醇钾；有机锂如丁基锂或苯基锂；碱金属氢化物，例如氢化钠或者氢化钾；氨化物，例如双(三甲基甲硅烷基)氨基锂、双(三甲基甲硅烷基)氨基钾或者二异丙基氨基锂(LDA)；有机胺，例如三乙胺、N-甲基吗啉、哌啶、N-甲基哌啶、N,N-二异丙基乙胺、1,5-二氮杂双环[4.3.0]壬-5-烯(DBN)、1,8-二氮杂双环[5.4.0]癸-7-烯(DBU)、吡啶或者4-二甲氨基吡啶(DMAP)。
本发明所述的酸可以为有机酸、无机酸或其混合物，例如选自下列的一种或多种：盐酸，硫酸，磷酸，硝酸；羧酸，如乙酸或者三氟乙酸；磺酸，例如甲磺酸、三氟甲磺酸或者对甲苯磺酸；膦酸；盐酸、硫酸、磷酸。所述酸还包括路易斯酸。所述的路易斯酸可以为选自例如BF 3·OEt 2、MgCl 2、MgBr 2、ZnBr 2、ZnI 2、ZnCl 2、ZnSO 4、CuCl 2、CuCl、Cu(O 3SCF 3) 2、CoCl 2、CoI 2、FeI 2、FeCl 3、FeCl 2、FeCl 2、SnCl 4、TiCl 4、TiCl 3、MnCl 2、ScCl 3、AlCl 3、(i-C 4H 9) 2AlCl、(C 6H 5) 2AlCl、(C 6H 5)AlCl 2、ReCl 5、ZrCl 4、NbCl 5、VCl 3、CrCl 2、MoCl 5、YCl 3、CdCl 2、LaCl 3、Er(O 3SCF 3) 3、Yb(O 2CCF 3) 3、SmCl 3、B(C 6H 5) 3、TaCl 5或三甲基三氟甲磺酸硅的一种或多种，其具体实例可以为选自BF 3·OEt 2、MgCl 2、ZnCl 2、MgBr 2、ZnBr 2、AlCl 3、SnCl 4、TiCl 4或三甲基三氟甲磺酸硅的一种或多种。
本发明所述的溶剂可包括选自例如下列的一种或两种以上的混合物：水；酮类溶剂，例如丙酮和甲基乙基酮；醚类溶剂，包括无环醚和环醚，例如乙醚、四氢呋喃、二氧六环；酯类溶剂，例如乙酸乙酯或者乙酸丁酯；烷烃类溶剂，例如正己烷或正庚烷；卤代烷烃类溶剂，例如一氯甲烷、二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷；环烷烃类溶剂，例如环己烷或环庚烷；取代或未取代的芳烃类溶剂，例如苯、甲苯、二甲苯、氯苯；醇类溶剂，例如甲醇、乙醇、正-丙醇、异丙醇，正丁醇或者叔丁醇；或者其它的溶剂，例如N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、乙腈或者吡啶。优选地，所述溶剂为选自对反应底物及催化剂无反应活性的惰性溶剂。作为实例，所述惰性溶剂可以选自例如醇类溶剂(如甲醇、乙醇)、醚类溶剂(如乙醚、四氢呋喃、二氧六环)、卤代烷烃类溶剂(如二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷)、取代或未取代的芳烃(如苯、甲苯、氯苯)中的一种或多种。
除非另有说明，本发明中的溶剂为无水溶剂。
有益效果
本发明提供了可用于合成软海绵素、艾日布林或其类似物，特别是其C20-C26结构片段部分的中间体、其制备方法和用途。本发明的合成路线的起始原料廉价易得，且式(2)、式(3)化合物均为结晶体，其通过简单重结晶纯化方式即可提高产物纯度。尤其是式(2)化合物在2次重结晶后，即可获得高于99.9％的光学纯度，而且该化合物β位甲基连接的手性碳原子的构型在后续步骤中不会再发生改变，从而保证了软海绵素、艾日布林或其类似物在C20-C26的光学纯度。因此本发明的构建C20-26结构片段手性中心的方法，具有较高的非对映选择性和产率，其副产物仅需重结晶等简单方法除去。所有方法步骤均在较低温和温和的反应条件下进行，尤其是式(7)化合物制备式(8)化合物的步骤，避免了因高温加热带来的产物热分解损失；整套制备方法，尤其是前端步骤的产物均为结晶状固体，易于纯化和精制。基于以上优势，本发明的方法成本低，产率和纯度高，精制纯化简单，因此更适于工业化大规模生产。
附图说明
图1：本发明实施例1的合成线路图。
具体实施方式
下文通过对本发明实施例的描述，更加详细地对本发明的上述及其他特性和优势进行解释和说明。应当理解，下列实施例旨在对本发明的技术方案进行示例性的说明，而并非旨在对由权利要求及其等价方案所限定的本发明保护范围进行任何限制。
除非另有说明，本文中的材料和试剂均为市售商品，或可由本领域技术人员根据现有技术制备。
本领域技术人员应当理解，下列实施例中的原料、试剂、中间体、目标化合物或反应式均为上文通式化合物或其反应的示例性技术方案，其中的一个或多个具体化合物或具体反应式均可与本发明上述概括性的技术方案结合，且该结合后的技术方案应当被理解为说明书记载的技术方案。
除非另有说明，下列实施例中的收率为以产品纯度为99.5％以上计。
实施例1：化合物8的制备方法一(参见附图1)
1.1 化合物1的制备
方法一：
将(s)-4-苯基-2-噁唑烷酮(15.6g)加入到500ml三口瓶中，加入干燥THF(200ml)溶解，换氩气并用氩气保护，然后将反应液降温至-78℃，滴加n-BuLi的THF溶液(2.5M,38ml)(保持内温≤-60℃)，滴毕，保持-78℃条件下反应15min，再滴加巴豆酰氯(10g)， 滴毕，保持-78℃反应30min，然后升至0℃反应1.5h。TLC检测反应完成后，缓慢加入氯化铵饱和溶液淬灭，充分搅拌至固体消失，可清晰分层。分液，水相用乙酸乙酯提取2次，合并有机相后，用饱和氯化钠溶液洗涤1次。有机相加入无水硫酸钠干燥，过滤，浓缩滤液。向所得浓缩物中加入乙酸乙酯(100ml)，加热回流溶解，再加入正己烷(500ml)，冷却，搅拌析晶。过滤得白色固体产品17.7g，收率80％。
方法二：
将(s)-4-苯基-2-噁唑烷酮(60g)加入到2000ml三口瓶中，加入普通(未经无水处理的试剂级别)THF(1200ml)溶解，室温条件下加入LiCl(26.4g)和TEA(91.2ml)，然后慢慢滴加巴豆酸酐(82.2ml)，保持内温≤25℃，滴毕，保持室温条件下反应3h。TLC监测至(s)-4-苯基-2-噁唑烷酮原料点消失，加水(800ml)，反应液中固体溶解，分液，水层用乙酸乙酯提取2次，合并有机相后，用饱和氯化钠溶液洗涤1次。有机相加入无水硫酸钠干燥，过滤，滤液浓缩。向所得浓缩物中加入乙酸乙酯(400ml)，加热回流溶解，再加入正己烷(2000ml)，冷却，搅拌析晶。过滤得白色固体产品72g，收率85％。
1H NMR(400MHz,)δ7.44–7.23(m,6H),7.21–6.96(m,1H),5.47(dd,J＝8.7,3.9Hz,1H),4.68(t,J＝8.8Hz,1H),4.26(dd,J＝8.9,3.9Hz,1H),1.92(dd,J＝6.9,1.6Hz,3H).
1.2 化合物2的制备
1)(1-溴乙烯基)三甲基硅烷的制备
将乙烯基三甲基硅烷(100g)加入到2000ml三口瓶中，然后降温至-35℃～-30℃，慢慢滴加溴水，滴加时剧烈放热，滴加过程保持内温在-30℃～-10℃之间(内温低于-30℃反应体系结成固体)，滴毕，自然升至室温，缓慢滴加二乙胺(676ml)，初始滴加放热，滴毕，加热回流反应1.2h。反应完成后将反应液降至室温，加入乙醚(1000ml)稀释，加水洗涤2-3次后用2N盐酸洗涤，洗至水层PH＝1，有机相依次用饱和碳酸氢钠，饱和氯化钠各洗涤一次，加无水硫酸钠干燥，过滤，滤液浓缩。减压蒸馏，收集馏分80g(38-42℃)。收率45％。
1H NMR(400MHz,Chloroform-d)δ6.27(s,1H),6.19(s,3H),0.20(s,9H).
2)化合物2的制备
将Mg粒(8.4g)和碘粒(1-2粒)加入到三口瓶中，换氩气并用氩气保护。将(1-溴乙烯基)三甲基硅烷(62.7g)溶于干燥THF(159ml)中，室温条件下将其部分(20ml)加入至上述三口瓶中，给三口瓶加热，至反应瓶中反应引发，回流，继续滴加，保持回流状态，滴毕，将反应瓶移至油浴中加热回流1h。制备得到格氏试剂。
将CuI(6.69g)加入到1000ml三口瓶中，加入THF，换氩气保护，然后将反应液降温至-40℃，滴加上述格氏试剂，保持内温≤-30℃，滴毕，保持-40℃反应0.5h后滴加化合物1的THF(40.45g/40ml THF)溶液，滴毕升至0℃反应2h。TLC监测化合物1点消失，慢慢加入饱和氯化铵溶液淬灭，剧烈搅拌4-6h，得澄清两相，分液，水相用 乙酸乙酯提取2次，有机相合并后用饱和食盐水洗涤2次，加入无水硫酸钠干燥，过滤，滤液浓缩得到粗品57g。将粗品常温溶于570ml正己烷中，放置-20℃冰箱，静置析晶。次日，趁冷过滤，用冷正己烷洗涤，得到42g白色固体。经过二次重结晶，纯度为99.94％。
1H NMR(500MHz,Chloroform-d)δ7.63–7.26(m,5H),5.74(d,J＝1.9Hz,1H),5.51(dd,J＝8.7,3.8Hz,1H),5.42(d,J＝2.2Hz,1H),4.76(t,J＝8.8Hz,1H),4.35(dd,J＝9.0,3.8Hz,1H),3.30(q,J＝9.4Hz,1H),3.08–2.84(m,2H),1.09(d,J＝6.2Hz,3H),0.12(s,9H).
1.3 化合物3的制备
将碘(43.2g)溶于DCM(752ml)中，0℃条件下分批加入原料2(18.8g)，加毕，升至室温反应约12-20h，TLC监测原料点基本消失，加入饱和亚硫酸钠溶液淬灭，剧烈搅拌至溶液紫色褪去，变为无色，分液，水层用DCM提取1次，有机相合并后加入无水硫酸钠干燥，过滤，浓缩得到粗品20g。柱层析分离得到15g产品。将产品加热溶于正己烷-乙酸乙酯混合溶剂(70ml)，冷却，搅拌析晶。过滤得到白色固体9.4g，收率43％。
1H NMR(500MHz,Chloroform-d)δ7.41–7.27(m,5H),6.09(d,J＝1.6Hz,1H),5.62(d,J＝1.6Hz,1H),5.43(dd,J＝8.8,4.0Hz,1H),4.70(t,J＝8.8Hz,1H),4.27(dd,J＝9.0,4.0Hz,1H),3.23(dd,J＝16.9,6.6Hz,1H),2.85(dd,J＝16.9,7.0Hz,1H),2.56(q,J＝6.8Hz,1H),1.04(d,J＝6.7Hz,3H).
1.4 化合物4的制备
将原料3(14.27g)溶于THF-H 2O的混合溶液(148ml-37ml)中，然后降温至约-5℃依次加入过氧化氢(35％，15.8ml)，一水合氢氧化锂的水溶液(3.1g/30ml H 2O)，滴毕，保持0℃反应2h。TLC监测显示原料点消失，将反应液升至室温，缓慢加入亚硫酸钠饱和溶液，至淀粉碘化钾试纸不变色，减压蒸馏去除THF，水相用DCM洗涤2-3次，至无(s)-4-苯基-2-噁唑烷酮。将水相加入到圆底烧瓶中，冷却至0℃，用10％稀盐酸溶液调节PH至1。然后用DCM萃取2-3次，干燥，过滤，浓缩得到化合物4。
1H NMR(400MHz,Chloroform-d)δ6.21(s,1H),5.90–5.59(m,1H),2.62–2.54(m,1H),2.54–2.46(m,1H),2.31(dd,J＝15.0,6.4Hz,1H),1.11(d,J＝6.5Hz,3H).
1.5 化合物5的制备
将上述所得化合物4溶于DCM(185ml)，室温条件下加入噻唑啉-2-硫酮(4.84g)，EDCI(8.86g)和DMAP(0.7g)。保持室温反应，4-6h，TLC监测原料点消失。加入饱和硫酸氢钠溶液淬灭，搅拌，分液，水相用DCM萃取2次，有机相合并，依次用饱和碳酸氢钠，饱和食盐水洗涤，然后加入无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化。得到黄色糖浆状产品10.06g(静置或冷冻会固化)，收率80％。
1H NMR(400MHz,Chloroform-d)δ6.22(dd,J＝1.6,0.9Hz,1H),5.76(d,J＝1.7Hz,1H),4.65–4.45(m,2H),3.47(dd,J＝17.1,7.3Hz,1H),3.35–3.22(m,2H),1.10(d,J＝6.7Hz,3H).
1.6 化合物6的制备
1)4-((叔丁基二苯基硅基)氧)丁醛的制备
第一步：室温条件下将1，4-丁二醇(100ml)加入到2000ml三口瓶中，然后加入DCM(1300ml)，三乙胺(59ml)和DMAP(4.7g)，再慢慢滴加TBSCl。滴毕，保持室温反应过夜(约17h)。TLC监测显示TBSCl原料点消失，加入饱和氯化铵溶液淬灭，分液，水层用DCM提取2次，有机相合并后用饱和食盐水洗涤1次，加入无水硫酸钠干燥，过滤，浓缩。柱层析分离纯化，得到108g糖浆状产品，收率80％。
1H NMR(400MHz,Chloroform-d)δ7.89–7.56(m,4H),7.53–7.35(m,6H),3.68(dt,J＝15.2,5.9Hz,4H),1.74–1.59(m,4H),1.05(s,9H).
第二步：将4-((叔丁基二苯基硅基)氧)丁醇(11.6g)溶于干燥DCM(71ml)中，然后降至0℃，依次加入干燥DMSO(12.6ml)和DIPEA(15.4ml)，再分批加入三氧化硫吡啶(11.3g)，保持内温≤10℃。加毕，升至室温反应0.5-1h，TLC监测显示原料点消失，加水淬灭反应，然后用1N稀盐酸洗涤1次，水层用DCM萃取1次，合并有机相后依次用饱和碳酸氢钠，饱和食盐水洗涤各一次，加入无水硫酸钠干燥，过滤，浓缩，得到糖浆状产品，直接用于下一步反应，故现做现用。
1H NMR(400MHz,Chloroform-d)δ9.79(s,1H),7.65(t,J＝7.6Hz,4H),7.52–7.30(m,6H),3.79–3.49(m,2H),2.55(d,J＝6.7Hz,2H),1.88(t,J＝8.3Hz,2H),1.04(s,9H).
2)将原料5(10.1g)加入到1000ml三口瓶中，加入干燥DCM溶解，换氩气保护，然后将反应液降温至0℃，滴加四氯化钛(3.4ml)，再快速加入三乙胺(3.58ml)，加毕保持0℃反应1h。滴加4-((叔丁基二苯基硅基)氧)丁醛的DCM溶液(11g/20ml)，滴毕，保持0℃反应4-6h，加入饱和食盐水淬灭反应，分液，水相用DCM提取2次，有机相合并后用饱和碳酸氢钠洗涤2次，用饱和食盐水洗涤1次，加入无水硫酸钠干燥，过滤，浓缩，色谱柱分离纯化。得到黄色糖浆状产品，13.1g，收率84％。
化合物6包含4个非对映异构体
异构体A：1H NMR(400MHz,Chloroform-d)δ7.65(ddd,J＝7.9,4.3,1.8Hz,4H),7.44–7.35(m,6H),6.37(dd,J＝1.3,0.6Hz,1H),5.84(d,J＝1.4Hz,1H),5.26(dd,J＝10.0,3.8Hz,1H),4.56(td,J＝7.4,5.8Hz,2H),3.69(t,J＝6.1Hz,3H),3.23–3.07(m,2H),2.85(d,J＝10.1Hz,1H),2.67(dd,J＝9.9,6.6Hz,1H),1.88–1.56(m,3H),1.07(d,J＝6.7Hz,3H),1.04(s,9H).
异构体B：1H NMR(400MHz,Chloroform-d)δ7.72–7.63(m,4H),7.45–7.34(m,6H),6.17(s,1H),5.76–5.73(m,1H),4.74(dd,J＝10.3,3.4Hz,1H),4.56(ddd,J＝11.9,7.5,2.1Hz,1H),4.38–4.26(m,1H),3.72–3.62(m,3H),3.41(ddd,J＝12.3,11.0,7.5Hz,1H),3.13(ddd,J＝10.9,7.3,2.1Hz,1H),2.87(d,J＝10.9Hz,1H),2.67(dd,J＝10.3,6.4Hz,1H),2.21–2.06(m,1H),1.97–1.72(m,2H),1.15(d,J＝5.7Hz,3H),1.04(s,9H).
异构体C的特征峰：1H NMR(400MHz,Chloroform-d)δ6.22(dt,J＝1.8,0.9Hz, 1H),5.72(d,J＝1.5Hz,1H),5.38(dd,J＝9.7,5.3Hz,1H).
异构体D的特征峰：1H NMR(400MHz,Chloroform-d)δ6.19–6.18(m,1H),5.76–5.75(m,1H),4.96(dd,J＝10.6,5.2Hz,1H).
1.7 化合物7的制备
将原料6(13.07g)溶于干燥DCM(40ml)中，然后降至0℃，依次加入干燥DMSO(6.95ml)和DIPEA(8.54ml)，再分批加入三氧化硫吡啶(6.23g)，保持内温≤10℃。加毕，升至室温反应0.5-1h，TLC监测显示原料点消失，加水淬灭反应，然后用1N稀盐酸洗涤1次，水层用DCM萃取1次，合并有机相后依次用饱和碳酸氢钠，饱和食盐水洗涤各一次，加入无水硫酸钠干燥，过滤，浓缩，得到糖浆状产品，柱层析纯化得到10.4g产品，收率80％。
1H NMR(400MHz,Chloroform-d)δ7.92–7.54(m,10H)(A/B),7.39(q,J＝7.8,7.1Hz,10H)(A/B),6.25(d,J＝8.5Hz,1H)(A),6.21(s,2H)(A/B),5.77(d,J＝1.7Hz,1H)(A),5.75(d,J＝1.7Hz,1H)(B),5.07(d,J＝9.4Hz,1H)(A),4.61-4.08(m,2H)(A/B),4.26–4.05(m,2H)(A/B),3.69–3.61(m,4H)(A/B),3.33–3.13(m,4H)(A/B),3.00–2.86(m,1H)(A),2.79(dt,J＝15.2,7.8Hz,5H)(A/B),1.81(q,J＝6.9Hz,3H)(A),1.12(d,J＝6.7Hz,3H)(A),1.09(d,J＝6.5Hz,2H)(B),1.05(s,18H)(A/B).
1.8 化合物8的制备
将原料7(10.4g)溶于THF和H 2O的混合溶剂(120ml/30ml)中，室温条件下加入一水合氢氧化锂(6.54g)，保持室温搅拌反应6-8h。反应完成后加水，分液，水相用正己烷提取，THF层减压浓缩后加正己烷溶解，有机相合并后用饱和磷酸二氢钠洗涤，饱和食盐水洗涤，加无水硫酸钠干燥，过滤，浓缩。柱层析纯化得到7.08g，收率87％。
1H NMR(400MHz,Chloroform-d)δ7.65(dd,J＝7.8,1.5Hz,5H),7.54–7.27(m,5H),6.16(dd,J＝1.5,0.8Hz,1H),5.70(d,J＝1.7Hz,1H),3.78–3.55(m,2H),2.63(dd,J＝16.4,6.5Hz,1H),2.52(td,J＝7.1,1.5Hz,3H),2.29(dd,J＝16.3,6.6Hz,1H),1.88–1.75(m,2H),1.05(s,9H),1.02(d,J＝6.5Hz,3H).

Claims (10)

  1. 式(8)化合物的制备方法，
    所述式(8)如下定义：
    Figure PCTCN2019116349-appb-100001
    其中，R 1选自羟基保护基；
    R 2、R 3相同或不同，彼此独立地选自H和OR a，R a独立的选自H、C 1-10烷基、R bSO 2，其中R b为C 1-10烷基；或者R 2和R 3均为OR a，且两个R a键链形成C 1-6亚烷基；或者R 2和R 3与其键链的碳一起形成羰基；
    X选自卤素、磺酰氧基；
    优选地，R 1选自甲硅烷类羟基保护基，例如TMS、TES、TBDMS、TBDPS、DIPS、DPS、TIPDS等。
    R 2、R 3中的一个选自H，另一个选自OR a，且R a为H或i-PrSO 2；或者R 2和R 3均为OR a，且两个R a键链形成亚正丙烷基；或者R 2和R 3与其键链的碳一起形成羰基；
    X选自氯、溴、碘等；
    所述方法包括如下步骤：
    Figure PCTCN2019116349-appb-100002
    其中，式(2)中的R 5选自甲硅烷基，例如TMS、TES、TBDMS、TBDPS、DIPS、DPS、TIPDS等；式(1)-(2)中的噁唑烷酮结构部分为噁唑烷酮类手性辅基，例如：R 4为C 1-10烷基，取代或未取代的苯基，或取代或未取代的苄基的2-氧代噁唑烷酮。优选地，所述R 4是异丙基，未取代或羟基、硝基、二甲氨基单取代或多取代的苯基或苄基；
    优选地，还包括将式(2)重结晶一次、二次或多次的步骤。
  2. 权利要求1的式(8)化合物的制备方法，进一步包括由式(2)至式(3)的如下步骤：
    Figure PCTCN2019116349-appb-100003
    优选地，进一步包括如下步骤：
    由噁唑烷酮类手性辅基与相应的酰基化合物制备式(1)化合物
    Figure PCTCN2019116349-appb-100004
    优选地，进一步包括如下步骤：由式(3)制备式(4)：
    Figure PCTCN2019116349-appb-100005
    优选地，进一步包括如下步骤由式(4)制备式(5)：
    Figure PCTCN2019116349-appb-100006
    优选地，进一步包括如下步骤：由式(5)和醛制备式(6)：
    Figure PCTCN2019116349-appb-100007
    优选地，进一步包括如下步骤：由式(6)制备式(7)：
    Figure PCTCN2019116349-appb-100008
    优选地，进一步包括如下步骤：由式(7)制备式(8)：
    Figure PCTCN2019116349-appb-100009
  3. 如权利要求1-2任一项所述的式(8)化合物的制备方法：
    所述式(2)由式(1)与格氏试剂R 6MgX或R 6Li反应得到，R 6为
    Figure PCTCN2019116349-appb-100010
    所述格氏试剂的制备方法包括以下步骤：
    乙烯基硅烷
    Figure PCTCN2019116349-appb-100011
    与卤代试剂在较低温度(例如-30～-10℃)下混合，室温下加入缚酸剂，回流反应得到卤代乙烯基硅烷。
    上述卤代乙烯基硅烷在非质子性溶剂中与金属镁或金属锂反应生成相应的格氏试剂或锂试剂。
    或者，上述卤代乙烯基硅烷也可在所述溶剂中与其他易得格氏试剂，如甲基，乙基，正丙基，异丙基格氏试剂等，或易得烷基锂试剂，如甲基，正丁基，仲丁基，叔丁基锂，进行金属-卤素交换反应，生成相应的格氏试剂或锂试剂。
  4. 如权利要求1-3任一项所述的制备方法，在由式(5)和醛制备式(6)的步骤中：
    Figure PCTCN2019116349-appb-100012
    所述醛的制备方法，包括如下步骤：
    (I)丁二醇与R nSiX 4-n在偶联剂的存在下反应得到单羟基保护的产物；
    其中X选自氯、溴、碘的卤素，R选自C 1-10烷基或氟代烷基，n为1～3的整数。所述卤代硅烷的实例可以是TMSCl，TMSI，TBDPSCl，TBDPSI等。
    (II)氧化步骤(I)的产物。
  5. 式(8)化合物的制备方法，所述方法包括如下步骤：
    Figure PCTCN2019116349-appb-100013
    根据本发明式(8)化合物的制备方法，
    优选地，还包括下式由R 2、R 3分别为H和OH的式(7)氧化反应得到R 2和R 3与其键链的碳一起形成羰基的式(7)的步骤：
    Figure PCTCN2019116349-appb-100014
    优选地，还包括下式的式(5)和式(6)制备R 2、R 3分别为H和OH的式(7)的步骤：
    Figure PCTCN2019116349-appb-100015
    优选地，还包括权利要求2所述的由式(4)到式(5)化合物的步骤；
    优选地，还包括权利要求2所述的由式(3)到式(4)化合物的步骤；
    优选地，还包括权利要求2所述的由式(2)到式(3)化合物的步骤；
    优选地，还包括权利要求2所述的由式(1)到式(2)化合物的步骤；
    优选地，还包括将式(2)重结晶一次、二次或多次的步骤；
    优选地，还包括权利要求2所述的噁唑烷酮类手性辅基到式(1)化合物的步骤。
  6. 下式(2)所示的化合物及其制备方法：
    Figure PCTCN2019116349-appb-100016
    其中R 4、R 5的定义如权利要求1-4中所述。
    式(2)化合物的制备方法，
    包括权利要求1的由式(1)制备式(2)的步骤；
    优选地，还进一步包括上述的重结晶一次、两次或多次的步骤。
    优选地，还进一步包括由噁唑烷酮类手性辅基与相应的酰基化合物制备式(1)的步骤。
  7. 下式(3)所示的化合物及其制备方法：
    Figure PCTCN2019116349-appb-100017
    其中，R 4、X的定义如权利要求1-4中所述。
    式(3)化合物的制备方法，包括：
    上述权利要求2所述的由式(2)制备式(3)的步骤。
    优选地，还进一步包括上述权利要求6所述的式(2)化合物的制备方法。
  8. 下式(7)所示的化合物及其制备方法：
    Figure PCTCN2019116349-appb-100018
    其中，R 1选自羟基保护基；
    R 2、R 3相同或不同，彼此独立地选自H和OR a，R a独立的选自H、C 1-10烷基、R bSO 2，其中R b为C 1-10烷基；或者R 2和R 3均为OR a，且两个R a键链形成C 1-6亚烷基；或者R 2和R 3与其键链的碳一起形成羰基；
    X选自、卤素、磺酰氧基。
    优选地，R 1选自甲硅烷类羟基保护基，例如TMS、TES、TBDMS、TBDPS、DIPS、DPS、TIPDS等。
    R 2、R 3中的一个选自H，另一个选自OR a，且R a为H或i-PrSO 2；或者R 2和R 3均为OR a，且两个R a键链形成亚正丙烷基；或者R 2和R 3与其键链的碳一起形成羰基；
    X选自氯、溴、碘等；
    所述式(7)化合物的制备方法，包括如下步骤：
    Figure PCTCN2019116349-appb-100019
    示例性的，所述反应在四氯化钛(TiCl 4)和三乙胺(TEA)的存在下，以惰性气氛保护，在较低温度-10～10℃，优选0℃，进行反应，所述反应溶剂可以是二氯甲烷(DCM)等。
  9. 一种制备软海绵素、艾日布林、其可药用盐、其类似物或它们的C20-C26部分的方法，包括使用权利要求1-8中所述的噁唑烷酮类手性辅基、式(1)至式(7)中的任一化合物，和/或使用权利要求1--8中任一项所述的制备方法中的一步或者多步反应。
  10. 权利要求1-8中所述的噁唑烷酮类手性辅基、式(1)至式(7)中的任一化合物在制备软海绵素、艾日布林、其可药用盐、其类似物或它们的C20-C26部分中的用途。
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